January 30 – February 2 2012 European Institute of ... 30 – February 2 2012 European Institute of Chemistry and Biology Bordeaux-Pessac, FRANCE BOOK OF ABSTRACTS Plenary lectures

BORDEAUX 2012 SYMPOSIUM ON FOLDAMERS

a COST Action CM0803 – Marie Curie IAPP FOLDAPPI joint event

January 30 – February 2 2012

European Institute of Chemistry and Biology Bordeaux-Pessac, FRANCE

BOOK OF ABSTRACTS

Plenary lectures 1–6

Keynote lectures 1–11

Oral Communications 1–14

Posters 1–33

Plenary Lecture 1

Bordeaux 2012 Symposium on Foldamers January 30 – February 2 2012

From peptides to proteins: Analysis of the hierarchic organization of proteins

and de novo design of protein-like architectures

William DeGrado, PhD

University of California San Francisco, Adjunct Professor, Department of

Pharmaceutical Chemistry, Investigator, Cardiovascular Research Institute

[email protected]

The folding of water-soluble and membrane proteins reflects the hierarchic assembly of peptide-like

segments into a structural and functional unit. This talk will focus on the principles governing this

assembly process, with particular reference to the analysis and design of: 1) natural and designed

membrane proteins including the M2 proton channel from influenza A virus [1-3] and artificial

channel peptides; 2) metalloproteins [4] ; 3) nanostructured materials [5].

References

[1] G. Grigoryan, D. T. Moore, W. F. DeGrado, Transmembrane Communication: General

Principles and Lessons from the Structure and Function of the M2 Proton Channel, K(+) Channels,

and Integrin Receptors. Annu Rev Biochem, (2011).

[2] J. Wang, J. X. Qiu, C. Soto, W. F. DeGrado, Structural and dynamic mechanisms for the

function and inhibition of the M2 proton channel from influenza A virus. Curr Opin Struct Biol 21,

68 (2011).

[3] G. Fiorin, V. Carnevale, W. F. DeGrado, The Flu's Proton Escort. Science 330, 456 (2010).

[4] M. Faiella et al., An artificial di-iron oxo-protein with phenol oxidase activity. Nat Chem

Biol 5, 882 (2009).

[5] G. Grigoryan et al., Computational design of virus-like protein assemblies on carbon

nanotube surfaces. Science 332, 1071 (2011)

Plenary Lecture 2


Synthesis and Functions of Synthetic Helical Oligomers and Polymers

Eiji Yashima

Department of Molecular Design and Engineering, Graduate School of Engineering,

Nagoya University, Chikusa-ku, Nagoya 464-8603, Japan

E-mail: [email protected]

Unique macromolecules and oligomers that fold into a preferred-handed single- and double-

stranded helical conformation induced by chiral substituents covalently bonded to the main-chains

or external chiral stimuli followed by memory of the helical chirality are presented. The direct

observations of helical structures of artificial helical polymers by atomic force microscopy (AFM)

will be also presented. A series of double helices composed of different components and sequences

that exhibit specific functions, such as chirality sensing, chiral recognition, enantioselective

asymmetric catalysis, anisotropic spring-like motion, and remote-stereocontrol are also

described.[1,2]

Figure 1. Structures of double- and triple-stranded helical oligomers and polymers References [1] E. Yashima, K. Maeda, Y. Furusho, Acc. Chem. Res. 2008, 41, 1166. [2] E. Yashima, K. Maeda, H. Iida, Y. Furusho, K. Nagai, Chem. Rev. 2009, 109, 6102.

Plenary Lecture 3


Folded Conformations of Peptides with Hybrid Backbones

P. Balaram

Molecular Biophysics Unit, Indian Institute of Science, Bangalore-12, India

[email protected]

The versatility of backbone homologated amino acid residues, specifically beta and gamma

residues, in the construction of peptide foldamers is demonstrated by the crystallographic

characterization of helices and hairpins with hybrid backbones[1]. The γ-valine residue has been

used in conjunction with the Aib residue to generate (αγ)n C12-helices of varying length, upto 16

residues. The conformational constraints imposed by dialkyl backbone substituents are illustrated

with several example of foldamers generated with the γ-amino acid residue gabapentin, (Gpn)[2],

and the two possible β-amino acid homologs of 1-aminocyclohexane-1-carboxylic acid (Ac6c). The

characterization of foldamers with mixed directionality of backbone hydrogen bonds[3] is illustrated

with structures of alpha-beta and alpha-gamma hybrid sequences.

Figure 1: 16 residue C12 helix in Figure 2: β hairpin conformation in

Boc-[Aib-γ(R)Val]8-OMe Boc-Leu-Phe-Val-Aib-Gpn-Leu-Phe-Val-OMe

References

[1] P.G. Vasudev, S. Chatterjee, N. Shamala and P. Balaram Chem. Rev., 2011, 111, 657. [2] P.G. Vasudev, S. Chatterjee, N. Shamala and P. Balaram Acc. Chem. Res., 2009, 42, 1628. [3] P.G. Vasudev, S. Chatterjee, K. Ananda, N. Shamala and P. Balaram Angew. Chem. Int. Ed. Engl., 2008, 47,

6430.

Plenary Lecture 4


Synthetic Supramolecular Systems (th)at Work

Stefan Matile

University of Geneva, Geneva, Switzerland, www.unige.ch/sciences/chiorg/matile/

[email protected] The objective of this lecture is to exemplify what interesting structures - such as foldamers - could be used for. The unifying theme will be transport, beginning with the smallest, that is transport of electrons and holes in artificial photosystems (Figure 1).[1] Examples on the transport of anions with anion-π interactions[2] and halogen bonds[3] will follow. Transport of larger molecules, finally, will be involved in new approaches to bio-,[4] aptamero-[5] and differential sensing[6] in lipid bilayers as well as cellular uptake.[7]

n1n2n3p1

p3p2

pn

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h+

h+

h+

h+

h+

pn

n2 p2

n3 p1

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OMARG SHJs

h+

e-

n1 p3

n1n2

pn

biological photosystem

h+

e-e-

e-

e-e-e-

h+ h+

n2n3

n4n5n6

p1p2

n1

n3

n4

n5 n6

e-

h+

PC 2

P C 1

-4

-2

02

-3-1 0 1

3

-1

0

1

2

P C 3

4

Jean Paul Gaultier

Issey Miyake

Davidoff

ChanelNo 5

Calvin KleinYves

Saint Laurent

+++

✖✖✖

✙✙✙

NH

HN

O

ONH

O

ONH

N

N

N

PO

ON

N

NH

H

H

H

H

XOO

OX

OO

Figure 1. Lessons from nature for organic photovoltaics: Molecular-level charge-transporting channels with antiparallel redox cascades (left). Perfume sensing in lipid bilayers with an artificial nose (right). References [1] a) N. Sakai, S. Matile, J. Am. Chem. Soc. 2011, 133, 18542-18545. b) M. Lista, J. Areephong, N. Sakai, S. Matile,

J. Am. Chem. Soc. 2011, 133, 15228-15231. c) N. Sakai, M. Lista, O. Kel, S. Sakurai, D. Emery, J. Mareda, E. Vauthey, S. Matile, J. Am. Chem. Soc. 2011, 133, 15224-15227.

[2] R. E. Dawson, A. Hennig, D. P. Weimann, D. Emery, V. Ravikumar, J. Montenegro, T. Takeuchi, S. Gabutti, M. Mayor, J. Mareda, C. A. Schalley, S. Matile, Nature Chem. 2010, 2, 533-538

[3] A. Vargas Jentzsch, D. Emery, J. Mareda, P. Metrangolo, G. Resnati, S. Matile, Angew. Chem. Int. Ed. 2011, 50, 11675-11678.

[4] S. M. Butterfield, T. Miyatake, S. Matile, Angew. Chem. Int. Ed. 2009, 48, 325-328. [5] T. Takeuchi, S. Matile, J. Am. Chem. Soc. 2009, 131, 18048-18049. [6] T. Takeuchi, J. Montenegro, A. Hennig, S. Matile, Chem. Sci. 2011, 2, 303-307. [7] Financial support from the University of Geneva, the NCCR Chemical Biology, the Swiss NSF and the ERC is

acknowledged with appreciation.

Plenary Lecture 5


Design and pharmaceutical applications of foldamers

that act on membranes and polysaccharides

William DeGrado, PhD

University of California San Francisco, Adjunct Professor, Department of

Pharmaceutical Chemistry, Investigator, Cardiovascular Research Institute

[email protected]

This talk will focus on the interplay of structural, biophysical and computational studies to

probe the mechanism of action of molecules that act on membranes and heparin. Furthermore, we

use de novo foldamer design to test this mechanistic understanding. Two examples will be

described in which these fundamental studies have led to compounds that are currently being

evaluated in human clinical trials to address drug-resistant bacterial infections and as heparin

reversal agents. Computational and synthetic coarse-graining has been used to probe the key

features required for the antibacterial activity of antimicrobial peptides. The mechanism of action

and bacterial response to these compounds will be described. A second topic will be the design of

foldamers that reverse the action of the antithrombotic, heparin. Currently, protamine is used as a

heparin reversal agent to prevent unwanted bleeding following heparinization during surgery.

However, protamine has multiple unwanted side effects associated with its antigenicity and highly

cationic nature. We therefore have designed cationic foldamers that self-associate weakly to create a

bioactive heparin-binding hexamer. In the presence of heparin, the equilibrium is shifted towards

this self-associated state and the heparin is effectively neutralized. Any excess foldamer remains

primarily in the monomeric state, which has been designed to be highly susceptible to proteolysis.

Thus, any unused foldamer is rapidly cleaved, minimizing unwanted side effects of highly cationic

oligomers. [1]

Reference

[1] G. N. Tew, R. W. Scott, M. L. Klein, W. F. DeGrado, De novo design of antimicrobial polymers,

foldamers, and small molecules: from discovery to practical applications. Acc Chem Res 43, 30

(2010).

Plenary Lecture 6


Designer enzymes

DONALD HILVERT

Laboratory of Organic Chemistry, ETH Zürich, Zurich, Switzerland

[email protected]

Although nature evolves its catalysts over millions of years, enzyme engineers try to do it a bit

faster. Enzyme active sites provide highly optimized microenvironments for the catalysis of

biologically useful chemical transformations. Consequently, changes at these centers can have large

effects on enzyme activity. The prediction and control of these effects provides a promising way to

access new functions. The development of methods and strategies to explore the untapped catalytic

potential of natural enzyme scaffolds has been pushed by the increasing demand for industrial

biocatalysts. In this lecture, recent progress toward creation of enzymes capable of catalyzing any

desired chemical reaction will be discussed.

Keynote Lecture 1


Delineating the Rules that Govern Helix Formation in Aliphatic Oligomers

Comprising Urea Linkages

Gilles Guichard

Université de Bordeaux-CNRS UMR5248, Institut Européen de Chimie et Biologie,33607 Pessac, France

[email protected] Aliphatic urea oligomers are a class of peptidomimetic foldamers that form a well defined and remarkably stable helical fold akin to the α-helix.[1] Delineating the rules that govern helix formation depending on the nature of constituent units is of practical utility if one aims to utilize the oligourea scaffold to place side chains in the 3D-space and elaborate functional helices. Herein, we have investigated to what extent the helix geometry is affected by alternative substitution patterns and by “minimal” backbone modifications. A single residue in the sequence was replaced by guest units bearing various side chain arrangements, different levels of preorganization (e.g. cyclic versus acyclic residues) and different stereochemistries. The extent of helix perturbation or stabilization was primarily monitored by spectroscopic methods and X-ray crystallography. This method based on single substitutions within a homooligomer of known structure was extended to various isosteric replacements. Although the helical urea backbone geometry was found to be sensitive to certain variations in residue substitution patterns (position and stereochemistry), it remains remarkably tolerant to changes, a small number of urea units being sufficient to counterbalance the low folding propensity of some non canonical and isosteric units.

Figure 1. Formulae of (a) canonical units with known 2.5-helix propensity; (b) units with alternative side chain arrangements (c) some isosteric units References [1] For a review : L. Fischer, G. Guichard, Org. Biomol. Chem. 2010, 8, 3101-3117.

Keynote Lecture 2


Biophysical Killing Mechanisms of Human Host Defense Peptides (HDPs)

and Their Self-Assembling Helical Peptoid Mimics

Annelise E. Barrona

aW.M. Keck Associate Professor, Stanford University, Department of Bioengineering, 318 Campus

Drive, W300B James H. Clark Center, Stanford, CA 94305-5444 [email protected]

For 12+ years we have developed and studied host defense peptide (HDP) mimics based on oligo-N-substituted glycines (peptoids). These non-natural oligomers are made on solid phase, similarly to peptides, and emulate key peptide foldamer attributes including precise molecular homogeneity in chain length and monomer sequence and a structurally programmed propensity to adopt certain secondary structures and in some cases, tertiary structures. Our work has focused on creating and studying a large family of cationic, helical peptoids (<15mers) that display low-µM, HDP-like activity against Gram-negative and Gram-positive pathogenic bacteria as well as infection-causing fungi (C. Albicans) and viruses (Hepatitis C). In properly fed humans who receive sufficient skin exposure to UVB radiation (this group constitutes less than 50% of the worldwide human population, for reasons that will be discussed), pathogens of these types are kept under control by HDPs quite efficiently. HDP mimics based on particular peptoid oligomers adopt stable polyproline type I-like helices which, despite their +5 net charge, can self-associate into “coiled coil”-like (or perhaps better, dsDNA-like) structures via aromatic stacking of chiral phenylalanine-like side chains, forming structures physically evocative of a DNA double-helix (note that as for DNA, self-association of peptoids does not occur in pure water, i.e., in the absence of salt, due to excessive electrostatic repulsion). Like peptoids, certain HDPs, when in coiled-coil states, are extremely if not totally resistant to proteolysis under typical physiological conditions. We describe and discuss the mechanisms of action a family of peptoids that was meant to mimic the cationic, helical HDPs magainin-2 from frogs. Serendipitously, we discovered that peptoids are good mimics of the key human HDP LL-37 to an even greater degree. With this is mind, we studied mechanisms of antibacterial activity and pathogen-over-host-cell selectivity (or the lack of it, as is also seen) in many distinct sequence variants. For the purposes of our study, we define selectivity as the ability to incapacitate pathogens at low-µM concentrations, while causing little (or at least reparable) damage to host (mammalian) cells. In peptoids as for HDPs, activity and selectivity are found to relate to the level of positive charge, hydrophobicity, amphipathicity, and interestingly, the ability to self-associate into meta-stable coiled coils that come apart on binding to electronegative cell membranes. I will report the results of a battery of detailed mechanistic studies with peptoid variants that show high, or low, antibacterial activity, and high, or low, selectivity for killing bacteria over host cells. We then make the comparison of these peptoid mimic variants to selective and non-selective HDPs. Vesicle leakage, membrane depolarization, and TEM have yielded powerful new insights into the several different HDP mimic (and HDP) mechanisms of cell killing, which will be described in this lecture in detail. Knowledge of certain newly grasped aspects of these mechanisms promises to lead to a major paradigm shift in how HDPs are viewed in context of human innate immunity and in the maintenance or loss of cellular and organismal health.

Keynote Lecture 3


βγ-Foldameric sequences: Promising design elements for α-helical coiled coil Mimicry

Raheleh Rezaei Araghi, Beate Koksch

Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustraße 3, 14195 Berlin,

Germany [email protected]

Helix-helix interactions regulating fundamental cell functions, at molecular level are mediated by a

combination of different α-amino acid residue contacts. This fact has raised the assumption that

unnatural residues with comparable contact elements may result in similar helical assemblies. The

application of non-proteinogenic building blocks for the construction of helix binders not only

overcome the intrinsic protease-susceptibility of natural peptides but would also broaden the

accessible functionalities. Peptides composed of homologous amino acids are at present among the

most widely studied bio-mimetic oligomers that adopt well-defined conformations.[1]

In particular, the alternating sequence of β- and γ-amino acids is an attractive pattern as ab initio

MO studies have predicted their suitability to mimicking α-helical conformations.[2] Based on these

calculations, we provided the first insight into design and structural characterization of synthetic α-

helical coiled coil-based peptides containing β- and γ-amino acids.[3] The substitution of an entire

α-heptad by a foldameric fragment consisting of β- and γ-amino acids was applied to both homo-

and hetero-oligomerizing coiled coil model peptides as well as to native-derived GCN4 sequences

resulting in αβγ-chimeric sequences of diverse kinds. Moreover, the ability of the βγ-foldameric

sequence to mimic the catalytic function of the native α-heptad repeats was further confirmed by a

ligase activity of such an αβγ-chimera.[4] The structural consequences of the α→βγ backbone

modification such as retention of the global conformation and the stability of the fold, is another

aspect investigated in this project.[5] Additionally, we use SPOT peptide array analysis to elucidate

native peptide sequences binding to the αβγ-chimeras with high affinity and structural stability.

Altogether, the observations are consistent with the theoretical studies and show that the stability of

αβγ-peptide helix bundles can be tuned by controlling the extent of the side chain interactions at the

interhelical recognition domains.

References [1] S.H. Gellman, Acc. Chem. Res., 1998, 3, 173. [2] C. Baldauf, R. Günther, H-J. Hofmann, J. Org. Chem., 2006, 71, 1200. [3] R. Rezaei Araghi, C. Jäckel, H. Cölfen, M. Salwiczek, A. Völkel, S.C. Wagner, S. Wieczorek, C. Baldauf, Koksch

B., ChemBioChem, 2010, 11, 335. [4] R. Rezaei Araghi, B. Koksch, Chem. Commun., 2011, 47, 3544. [5] R. Rezaei Araghi, C. Baldauf, U.I. Gerling, C.D. Cadicamo, B. Koksch, Amino Acids, 2011, 47, 3544.

Keynote Lecture 4


DNA as Scaffold for New Bio-Inpsired Catalytic Systems

Gerard Roelfesa

aStratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen,

The Netherlands [email protected]

The DNA molecule represents one of the most versatile molecular structures in nature. The ubiquitous right-handed double-helix has become one of the icons of modern science, but in principle any molecular architecture is feasible using the simple rules of Watson-Crick base pairing. In our research we exploit the unique properties of DNA for the development of new bio-inspired catalytic systems. In DNA-based asymmetric catalysis,[1] a transition metal catalyst is brought in close proximity of the DNA double helix, allowing for transfer of chirality to the catalyzed reaction. This concept has been applied succesfully in several of the archetypical C-C bond forming reactions: the Cu2+ catalyzed Diels-Alder, Michael addition and Friedel-Crafts alkylation reactions in water.[2] It was found that DNA is not only responsible for the high enantioselectivities, but also gives rise to large rate accelerations. Recently, we have discovered a unique reaction: the first catalytic enantioselective syn-hydration of enones.[3] This is a reaction for which there is no alternative using conventional homogeneous catalysis, thus clearly underlining the power of this concept.

Figure 1. DNA-based catalytic enantioselective syn-hydration of enones. In addition to DNA’s chirality, the highly specific Watson-Crick basepairing interactions are used for the modular assembly of new catalytic systems. This approach has been applied successfully to the assembly of new catalysts,[4] bio-inpired light harvesting systems and to control the enzymatic activity of a split enzyme.[5]

References [1] G. Roelfes, B.L. Feringa, Angew. Chem. Int. Ed., 2005, 44, 3230. [2] J. Oelerich, G. Roelfes, "DNA-Based Metal Catalysis" In Progress in Inorganic Chemistry vol

57, K.D. Karlin (Ed.), John Wiley & Sons, Inc., Hoboken, NJ, 2012, pp 353-393. [3] A.J. Boersma, D. Coquière, D. Geerdink, F. Rosati, B.L. Feringa, G. Roelfes, Nature Chem.

2010, 2, 991. [4] N. Sancho Oltra, G. Roelfes, Chem. Commun. 2008, 6039. [5] N. Sancho Oltra, J. Bos, G. Roelfes, ChemBioChem 2010, 11, 2255.

Keynote Lecture 5


Hydrogen bonded aromatic foldamers for molecular recognition and supramolecular

materials design

Zhan-Ting Li

Department of Chemistry, Fudan University, Shanghai 200433, China [email protected]

N−H⋅⋅⋅X (X = O, N, F) hydrogen bonding-induced aromatic amide oligomers may adopt folded, zigzag or other extended conformations, depending on the positions of the amides and hydrogen bonding sites on the aromatic rings.[1] In recent years, we have developed several series of this family of preorganized frameworks as acyclic receptors for both neutral and ionic guests.[2-4] We also found that this kind of defined aromatic backbones can be readily modified and appended with discrete functional units at the two ends and on the side chains. Therefore, they have been utilized for designing new molecular tweezers,[5] self-assembling ordered supramolecular architectures (organogels and vesicles),[6,7] and for directing the formation of macrocyclic and capsule systems.[8,9] When folded segments are incorporated to polymer backbones as cross-links, the resulting copolymers display unique reversible mechanical properties due to the breaking and recovering of the intramolecular hydrogen bonds.[10] When they are introduced to the thread component, they are able to tune the shuttling behavior of the related [2]rotaxanes.[11] Very recently, we found that the C−H⋅⋅⋅O hydrogen bonding of the 1,4-diphenyl-1,2,3-triazole can also induce triazole oligomers to form folded conformations, which are good halogen bonding receptors for fluoroorganohalides.[12]

[2]rotaxanes: n = 0, 1

OOO

S

S

S

S

O

O ON

O

NO

ON

O

H

H

NH

Me

Me

Me

O O O SOOOS

H

n

N N

NN+

+

+

+

O

CBPQT4+·4PF6-

dendrimer

NNN

H

RONN N

H

OR

NN N

OR

H

OR

NNN

ORH

RO

NNN

RO

H

RO

N N

NRO H

RO

RO N NN

RO

ORNNN

ORHBn Bn

H

MeMe

Me

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O

OF2C

O

F2C O

CF2

O

I

II

R = i-Bu This work was financially supported by NSFC. References [1] S. Hecht, I. Huc, (eds) Foldamers: Structure, Properties and Applications Wiley-VCH, Weinheim, 2007. [2] Z.-T. Li, J.-L. Hou, C. Li, H.-P. Yi, Chem. Asian J. 2006, 1, 766. [3] Z.-T. Li, J.-L. Hou, C. Li, Acc. Chem. Res. 2008, 41, 1343. [4] X. Zhao, Z.-T. Li, Chem. Commun. 2010, 46, 1601. [5] J.-L. Hou, H.-P. Yi, X.-B. Shao, C. Li, Z.-Q. Wu, X.-K. Jiang, L.-Z. Wu, C.-H. Tung, Z.-T. Li, Angew. Chem. Int.

Ed. 2006, 45, 796. [6] W. Cai, G.-T. Wang, Y.-X. Xu, X.-K. Jiang, Z.-T. Li, J. Am. Chem. Soc. 2008, 130, 6936. [7] W. Cai, G.-T. Wang, P. Du, R.-X. Wang, X.-K. Jiang, Z.-T. Li, J. Am. Chem. Soc. 2008, 130, 13450. [8] X.-N. Xu, J.-B. Lin, G.-T. Wang, X.-K. Jiang, Z.-T. Li, Chem. Eur. J. 2009, 15, 5763. [9] L. Wang, G.-T. Wang, X. Zhao, X.-K. Jiang, Z.-T. Li, J. Org. Chem. 2011, 76, 3531. [10] Z,-M. Shi, J. Huang, Z. Ma, Z. Guan, Z.-T. Li, Macromolecules 2010, 43, 6185. [11] K.-D. Zhang, X. Zhao, G.-T. Wang, Y. Liu, Y. Zhang, H.-J. Lu, X.-K. Jiang, Z.-T. Li, Z.-T. Angew. Chem. Int. Ed.

2011, 50, 9866. [12] L.-Y. You, S.-G. Chen, X. Zhao, Y. Liu, Y. Zhang, H.-J. Lu, C.-Y. Cao, Z.-T. Li, Angew. Chem. Int. Ed. accepted.

Keynote Lecture 6


Synthetic Polymers with Controlled Primary Structures:

Design, (Folding?) and Function

Jean-François Lutza

Precision Macromolecular Chemistry Group, Institut Charles Sadron, UPR22-CNRS, 23 rue du Loess, 67034 Strasbourg, France

[email protected] Sequence-controlled polymerizations play a key role in nature. Although formed from a rather modest library of monomers, sequence-defined macromolecules such as proteins or nucleic acids are largely responsible for the complexity and diversity of the biological world. By analogy, one may predict that synthetic sequence-defined polymers could play an important role in modern applied materials science (Figure 1).[1-4] Paradoxically, very little effort has been spent within the last decades for developing sequence-specific polymerization methods.

B A A B A

Controlled primary structures

A B C D E

Restricted monomer library

Controlled secondary and tertiary structures

Random sequences

Amorphous random coils

Broad palette of functional monomers

Current limiting step

Biopolymers

Synthetic Polymers

Figure 1. Sequence-controlled macromolecules: a new level of complexity in synthetic polymer science.

Herein, new approaches for controlling polymer sequences will be discussed.[5-6] Moreover, the advantages of the formed sequence-controlled polymers will be highlighted. For instance, the preparation of complex macromolecular structures such as 1D macromolecular arrays or folded polymer origamis will be presented.[7] References [1] N. Giuseppone, J.-F. Lutz, Nature 2011, 473, 40-41. [2] J.-F. Lutz, Nature Chem. 2010, 2, 84-85. [3] N. Badi, J.-F. Lutz, Chem. Soc. Rev. 2009, 38, 3383-3390. [4] M. Ouchi, N. Badi, J.-F. Lutz, M. Sawamoto, Nature Chem. 2011, 3, 917-924. [5] S. Pfeifer, J.-F. Lutz, J. Am. Chem. Soc. 2007, 129, 9542-9543. [6] S. Pfeifer, Z. Zarafshani, N. Badi, J.-F. Lutz, J. Am. Chem. Soc. 2009, 131, 9195-9197. [7] B. V. K. J. Schmidt, N. Fechler, J. Falkenhagen, J.-F. Lutz, Nature Chem. 2011, 3, 236-240.

Keynote Lecture 7


Unprecedented 3D Molecular Architectures: Folding into Shape

Hee-Seung Lee

Molecular-Level Interface Research Center,

Department of Chemistry, KAIST, Daejeon 305-701, Korea

[email protected]

Molecular self-assembly is the spontaneous assembly of molecules into structured aggregates by which nature builds complex functional systems. While numerous examples have focused on 2D self-assembly to understand the underlying mechanism and mimic this process to create artificial nano- and microstructures,[1] a limited progress has been made toward 3D self-assembly on the molecular level. This lack of progress is partially due to the difficultly of designing and using nondirectional noncovalent interactions, such as van der Waals and hydrophobic interactions, in synthetic, nonbiological molecular systems. Thus, we sought to establish a set of self-assembling components that could be linked to observable 3D shapes by which the governing parameters of self-assembly could be disentangled and tractable.

Recently, we discovered for the first time that artificial protein fragments (helical β-peptide foldamers) with well-defined hydrophobic surfaces self-assembled to form unprecedented 3D molecular architectures (“foldectures”) in a controlled manner in aqueous solution.[2-4] We anticipate that our strategy can be a starting point for the rational design of 3D organic molecular architectures with various functions. Furthermore, the self-assembly behavior of artificial protein fragments will be relevant for the development of synthetic foldamer proteins.

Figure 1. SEM images of 3D molecular architectures (windmill, petal, square bar, and molar tooth

shapes, respectively) by the self-assembly of 12-helical β-peptide foldamers. References [1] Han, T. H.; Ok, T.; Kim, J.; Shin, D. O.; Ihee, H.; Lee, H.-S.*; Kim, S. O.* Small, 2010, 6, 945-951. [2] Kwon, S.; Jeon, A.; Yoo, S. H.; Chung, I. S.; Lee, H.-S.* Angew. Chem. Int. Ed. 2010, 49, 8232-8236. [3] Kwon, S.; Shin, H. S.; Gong, J.; Eom, J.; Jeon, A.; Chung, I. S.; Cho, S. J.*; Lee, H.-S.*, J. Am. Chem. Soc. 2011,

133, 17618-17621. [4] Kim, J.; Kwon, S.; Kim, S. H.; Cho, S. J.; Lee, H.-S.*, Ihee, H.*, 2011, submitted.

Keynote Lecture 8


Protein assembly and cellular targeting via self-assembling foldameric architectures

Luc Brunsveld

Laboratory of Chemical Biology, Department of Biomedical Engineering,

Eindhoven University of Technology, the Netherlands [email protected]

Supramolecular chemistry has primarily found its inspiration in biological molecules, such as proteins and lipids, and their interactions. Currently the supramolecular assembly of designed compounds can be controlled to great extent. This provides the opportunity to combine these synthetic supramolecular elements with biomolecules for the study of biological phenomena. Supramolecular elements can for example be ideal platforms for the recognition and modulation of proteins and cells. Foldameric structures based on a disc-shaped or rod-like design self-assemble into nanoparticles of different shapes and with different dynamical features in water. These self-assembling supramolecular architectures provide attractive scaffolds for the organized display of biological ligands. The straightforward supramolecular, non-covalent, synthesis of these multivalent structures allows for a rapid and versatile introduction of multiple different functionalities. The columnar and spherical supramolecular nanoparticles can for example be pre- or post-functionalized with biological ligands such as sugars and proteins. The periphery of the resulting supramolecular nanoparticles can be used for the assembly of proteins along the dynamic supramolecular framework. Covalent and non-covalent attachment of proteins to this scaffold shows that the foldameric assemblies can act as platforms for directed and dynamic protein assembly. Alternatively, the functionalization of the nanoparticles with specific targeting groups allows the nanoparticles to bind to cells, or to be selectively internalized. The self-assembled particles consist out of different functionalities in which one type of foldamer accounts for the cellular internatilization properties of the nanoparticles, whereas other types of foldameric building blocks bear functional ligands for imaging or targeting. These self-assembling foldameric systems now provide an entry to enable supramolecular chemistry in the cell.

Keynote Lecture 9


A Systematic Approach for Targeting Protein-Protein Interactions

Paramjit Arora

Department of Chemistry, New York University, New York, NY 10003, U. S. A.

[email protected]

Proteins often utilize small folded domains for recognition of other biomolecules. The basic hypothesis guiding our research is that by mimicking these domains we can modulate the function of a particular protein with metabolically stable synthetic molecules. This presentation will discuss a method to stabilize peptide α-helices, termed hydrogen bond surrogate helices. HBS helices feature a covalent bond in place of the canonical intramolecular hydrogen bond. The ability of HBS helices to target intracellular protein-protein interactions will be discussed. A computational approach to identify suitable protein complexes as targets for stabilized helices will also be described.

Keynote Lecture 10


Hierarchical Buildup of Helicene-Containing Chiral Foldamers

Masahiko Yamaguchi

Advanced Institute for Materials Research (WPI-AIMR)

Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences Tohoku University

[email protected]

A methodology to form fibers/gels and vesicles by molecular assembly of foldamers and to control their properties is shown. Examined were two-component systems of pseudoenantiomeric ethynylhelicene foldamers, pentamer (M)-5 and tetramer (P)-4 with decyloxycarbonyl (D) side chains and 4-methyl-2-(2-methylpropyl)-1-pentyloxy-carbonyl (bD) side chains.[1,2]

Distinct aggregates were formed by changing solvents in three combinations of (P)-bD-5/(M)-bD-4, (P)-D-5/(M)-bD-4, and (P)-D-5/(M)-D-4. They formed gels in toluene, and fibrous assemblies were observed by atomic force microscopy (AFM). The minimum gel-forming concentration (MGC) decreased in the order of (P)-bD-5/(M)-bD-4 > (P)-D-5/(M)-bD-4 > (P)-D-5/(M)-D-4. In diethyl ether, vesicular formation was observed by DLS, AFM, and TEM, and the sizes of the vesicles decreased in the order of (P)-bD-5/(M)-bD-4 > (P)-D-5/(M)-bD-4 > (P)-D-5/(M)-D-4. Both fiber/gel and vesicle formation were accompanied by enhanced CDs and red-shifted UV-Vis absorptions with color changes to deep yellow. These are novel two-component systems of foldamers to form assemblies of fibers/gels and vesicles controlled by solvents, and the structures and properties of the assemblies were fine-tuned by the combinations of oligomers.

In m-difluorobenzene, a homogeneous solution was obtained with (P)-D-5/(M)-bD-4, which again exhibited enhanced CDs and red-shifted UV-Vis absorptions. VPO analysis showed the formation of a bimolecular hetero aggregate. The study indicated that pseudoenantiomeric oligomers formed hetero double helices, which hierarchically assembled to form fibers/gels and vesicles.

Figure 1. Hierarchical build up of helicene-containing chiral foldamers References [1] R. Amemiya, M. Yamaguchi, Org. Biomol. Chem. 2008, 6, 26. [2] R. Amemiya, M. Yamaguchi, Chem. Rec. 2008, 8, 116.

Keynote Lecture 11


Constrained Nucleic Acids: design and properties

Escudier Jean-Marc,a Maturano Mariea, Payrastre Corinnea

aSynthèse et Physisco-Chimie de Molécules d'Intérêt Biologique, UMR CNRS 5068,

Université Paul Sabatier, 31062 Toulouse Cedex 9 [email protected]

All of the particular behaviours of nucleic acids are associated with various and very often transient structures of these polymers. While the backbone organization of double-stranded DNA and RNA is normally quite regular, there are many others secondary and tertiary structures that DNA and RNA molecules can adopt in vivo in which significant local conformational heterogeneity in the sugar—phosphate backbone, play a crucial role in biological processes where protein—nucleic acid interactions, RNA folding, or RNA catalytic activity are involved. Therefore nucleic acids adopt biologically important disparate structures such as bulges, hairpin loops, U-turns, adenosine platforms, quadruplex or branched junctions. These structural motifs are indeed characterized by a variety of backbone conformations which markedly differ from the regular conformational states of double-stranded molecules. Considering the importance of the relationship between the local conformation and functional properties of nucleic acids, conformationally restricted oligonucleotides with modifications in the phosphodiester backbone unit, in the sugar unit and, to a limited extent, in the base units have been designed with the background of antisense applications. Much less attention has been paid to the design of conformationally restricted nucleosides with the aim of mimicking nucleic acid secondary structures containing non-Watson–Crick pairs or unpaired nucleotides. Therefore it is still a real challenge to design new conformationally constrained nucleotide building units in which the backbone torsional angles α−ζ can have predefined values that are either significantly different or close to the canonical values observed in DNA and RNA duplexes. We have developed dimeric building units, referred to as D-CNA, in which two or three backbone

torsion angles α−ζ are part of a six-membered 1,3,2-dioxaphosphorinane ring structure at key position along the sugar-phosphate backbone. As a proof of concept we showed that when reducing the conformational states of DNA single strands to those that match the geometry of this strand in duplex form, by locking α and β torsional angles, duplex stabilities were increased by +5°C/mod and +3°C/mod towards DNA and RNA counterparts, respectively.[1] On an another hand, we have developed a series of dinucleotide analogues in which the backbone torsion angles are constrained to values which are atypical for duplexes and likely to promote helical distortion or to induce localized unpaired conformations

that closely resemble the conformations of loops and/or bulges. This aspect is exemplified in loop induced stabilization by the "non-canonical" dimeric unit α,β-D-CNA (α = gauche(+), β = trans) with ∆Tm = +1 to +5 °C/mod.[2] These results highlights the important role that can be played by conformationally constrained nucleotides in order to define local structure of the sugar/phosphate backbone of nucleic acids that can impact on their folding ability. References [1] Dupouy, C.; Iché-Tarrat, N.; Durrieu, M. P.; Vigroux, A.; Escudier, J.-M. Org. Biomol. Chem. 2008, 6, 2849. [2] Dupouy, C.; Boissonet, A.; Millard, P.; Escudier, J-M. Chem. Commun. 2010, 46, 5142. Boissonnet A.; Dupouy,

C.; Millard. P.; Durrieu, M. P.; Iché-Tarrat, N.; Escudier, J.-M. New J. Chem. 2011, 35, 1528.

TpT

TpT

α,βα,βα,βα,β-D-CNAcanonical

α,βα,βα,βα,β-D-CNAuncanonical

Figure 5: superimposition of D-CNA with unmodified

Figure 1. Superimposition of α,β-D-CNA featuring canonical (blue) or non canonical (red) alpha torsion angle with unmodified TT dinucleotide.

Oral Communication 1


Functionalized Collagen Model Peptides

Roman S. Erdmann,a,b Helma Wennemers a,b

a ETH Zürich, Laboratorium für Organishe Chemie, Wolfgang-Pauli-Str.10, 8093 Zürich, Switzerland.

b University of Basel, Department of Chemistry, St. Johanns-Ring 19, 4056 Basel, Switzerland.

[email protected]

The stability and many functions of collagen, which is the most abundant protein in mammals, depend to a large extent on functional groups attached to its backbone.[1] Aside from hydroxylations other modifications such as for example galactosylations are known to influence the stability of the collagen triple helix.[2] Derivatized collagens are also becoming increasingly attractive for the development of synthetic functional materials. Herein we introduce azidoproline (Azp)-containing collagen model peptides that can easily be functionalized with various groups using “click” chemistry (Figure 1).[3-6] In addition, we demonstrate that Azp residues have effects on the stability of collagen that are similar to those of hydroxyproline.[3,4,6]

Figure 1. Synthesis, functionalization and self assembly of Collagen Model Peptides. References [1] Shoulders, M. D.; Raines, R. T. Annu Rev Biochem 2009, 78, 929. [2] Bann, J. G.; Peyton, D. H.; Bachinger, H. P. Febs Lett 2000, 473, 23. [3] Erdmann, R. S.; Wennemers, H., Synthesis 2009, 143-147. [4] Erdmann, R. S.; Wennemers, H., J. Am. Chem. Soc. 2010, 132, 13957. [5] Erdmann, R. S.; Wennemers, H., Angew. Chem., Int Ed. 2011, 50, 6835. [6] Erdmann, R. S.; Wennemers, H., Org. Biomol. Chem 2012, accepted.



Gels and Lipid Layers From Oxazolidin-2-ones Based Foldamers

Claudia Tomasini,a Nicola Castellucci a

aDipartimento di Chimica “Ciamician”, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy

[email protected] The self-assembly of small foldamers represents a key structural motif for the development of new materials and nanoscaled objects. Various applications in all fields of chemistry and material science have already been demonstrated. We want to show here our recent results in the preparation of supramolecular materials that are derived from the foldamer Boc-L-Phe-D-Oxd-OBn [Boc = t-butyloxycarbonyl; L-Phe = L-phenylalanine; D-Oxd = (4R,5S)-4-carboxy-5-methyl oxazolidin-2-one; Bn = benzyl]. This compound showed a strong tendency to form a β-sheet structure, that is generally retained by its derivatives.[1] Thus we studied the formation of lipidated foldamers that have general formula R-L-Phe-D-Oxd-OR’, where R is an aliphatic chain and R’ may be a benzyl group or an hydrogen (Figure 1) and we could obtain the formation of gels and lipid layers.

Figure 1. Some examples of lipidated foldamers R-L-Phe-D-Oxd-OR’.

For example, a small library of LMWGs (low molecular weight gelators) has been synthesized by coupling the -L-Phe-D-Oxd- motif with azelaic acid, a long chain dicarboxylic acid.[2] The ability to form gels in the presence of several solvents and of five metal ions, differing for their coordination chemistry and charge density has been analyzed. Very good results have been obtained with Zn(II) and Cu(II) ions, that form gels in several conditions, while the formation of gels in the presence of Cu(I), Al(III) and Mg(II) affords less satisfactory results. Recently we developed similar compounds of pharmacological interest. Furthermore we found that β-sheet-like nanostructures are formed by the lapidated -L-Phe-D-Oxd- motif in the absence of membranes.[3] In the presence of lipid membranes, the nanofibered structure only partially prevails; the molecules can also disaggregate and be immersed in the lipid membrane as many lipidated proteins and peptides do. References [1] C. Tomasini, G. Angelici, N. Castellucci, Eur. J. Org. Chem., 2011, 3648-3669. [2] N. Castellucci, G. Falini, G. Angelici, C. Tomasini, Amino Acids, 2011, 41, 609-620. [3] H. A. Scheidt, A. Sickert, T. Meier, N. Castellucci, C. Tomasini, D. Huster, Org. & Biomol. Chem., 2011, 9, 6998-

7006.



Mechanism and maximization of screw-sense control in helical oligomers of Aib

Robert A. Brown, Matteo De Poli, Liam Byrne, Juan Aguilar, and Jonathan Clayden*

aUniversity of Manchester, Oxford Rd., Manchester M13 9PL

[email protected] Oligomers of the achiral amino acid Aib adopt 310 helical conformations which interconvert rapidly between the M and P helical forms.[1] A single chiral residue located at the terminus of the helix is sufficient to impose some degree of bias over the screw-sense preference which extends to at least 20 residues.[2] We have proposed, and demonstrated in a proof of principle study,[3] that switching screw sense by inversion of absolute configuration at this chiral controller can provide a mechanism for transmitting information through molecules reminiscent of the conformational communication mechanisms used by biomolecules such as G-protein coupled receptors.

3-phenyllactatehelicity controller

switchable helix ofn x Aib monomers

isotopically labelled Aibhelicity detector

read signal by 13C NMR

switchablecentre

NH

O

HN

O

NHNH

N

O

OH

N

O

O

HO

O

H

NH

O

O

OMe

H3C 13CH3

n–5

Figure 1. Conformation communication by helical switching.

The contribution will describe conformational studies of Aib oligomers capped by N-terminal chiral amino acid residues, whose conformational preferences have been characterized by dynamic NMR techniques.[4] Using combined NMR, CD, and time-dependent DFT studies, we show that simple tertiary L-amino acids unexpected induce left-handed helicity in the Aib chain, which quaternary L-amino acids induce right-handed helicity (Figure 2).[5] By using 2-D NMR techniques to assign 13C and 1H signals to individual methyl groups we show that the conformational preferences observed are due to the relative stabilities of Type II and Type III β turns at the N-terminus of the helix. Armed with this information, we have been able to maximize the degree of conformational influence exerted by the terminal controllers

Figure 2. Dependence of conformation on the N-terminal amino acid [1] R.–P. Hummel, C. Toniolo, G. Jung Angew. Chem. Int. Ed. 1987, 26, 1150–1152 [2] J. Clayden, A. Castellanos, J. Solà, G. A. Morris, Angew. Chem. Int. Ed. 2009, 48, 5962–5965 [3] J. Solà, S. P. Fletcher, A. Castellanos, J. Clayden, Angew. Chem. Int. Ed. 2010, 49, 6836–6829 [4] J. Solà, G. A. Morris, J. Clayden, J. Am. Chem. Soc. 2011, 133, 3712–3715 [5] R. A. Brown, T. Marcelli, M. De Poli, J. Solà, J. Clayden, Angew. Chem. Int. Ed. 2012 in press.



Conformational and metal binding studies of α,β-peptoids

Emiliana De Santis,a Thomas Hjelmgaard,b Sophie Faure,b Bruce D. Alexander,c

Claude Taillefumierb and Alison A. Edwardsa a Medway School of Pharmacy, Universities of Kent and Greenwich, Chatham, Kent, UK, ME4 4TB

bUniversité Blaise Pascal, Laboratoire SEESIB, Clermont Ferrand, France cSchool of Science, University of Greenwich at Medway, Chatham, Kent, UK, ME4 4TB

[email protected]

Peptoids are synthetic polyamides structurally related to natural α-peptides where the side chain is moved from the α-carbon to the adjacent amide nitrogen. Further modifications can involve the backbone and/or the side chains. This versatility means that peptoids have significant potential for application as peptidomimetics. Novel alternating α,β-peptoids have been prepared and investigated for secondary structural preference[1] and their metal-binding ability. The presence of tertiary amides in the peptoid backbone decreases the energy barrier for cis/trans isomerisation, thus both conformers can be populated. This complicates interpretation of NMR spectra and, as a result, chiroptical techniques such as circular dichroism (CD) become essential tools for conformational investigation.

Figure 1. Titration of Mg2+ into a cyclic α,β-peptoid hexamer

(from 1:0 to 1:18 peptoid:Mg2+ molar ratio). Electronic and synchrotron radiation CD showed that, despite the decreased hydrogen bonding potential of the peptoid backbone, linear and cyclic α,β-peptoids can adopt more than one ordered conformation[1] which can be perturbed by different solvent environments and temperature. The structural features responsible for conformational stabilization of cyclic species have also been determined[2] and the effect of terminal protecting groups on linear α,β−peptoids investigated.[3] Ongoing studies have also demonstrated that cyclic α,β-peptoids can form metal complexes with biologically important cations (Figure 1).

[1] T. Hjelmgaard, S. Faure, C. Caumes, E. De Santis, A. A. Edwards, C. Taillefumier, Org. Letters 2009, 11, 4100-

4103. [2] E. De Santis, T. Hjelmgaard, S. Faure, O. Roy, C. Didierjean, B. D. Alexander, G. Siligardi, R. Hussain, T. Javorfi,

A. A. Edwards, C. Taillefumier Amino Acids 2011 41, 663-672. [3] E. De Santis, T. Hjelmgaard, C. Caumes, S. Faure, B. D. Alexander, S. J. Holder, G. Siligardi, C. Taillefumier, A. A. Edwards, Organic and Biomolecular Chemistry, DOI:10.1039/C1OB06386C.



New cyclobutane based scaffolds for functional and self-assembling molecules

Alessandro Sorrenti, Marta Sans, Mireia Bouzas, Ona Illa, Rosa M. Ortuño

Departament de Quimica, Universitat Autonoma de Barcelona, 08193, Bellaterra, Spain. [email protected]

Alicyclic homo and hetero 1,2- disubstituted compounds are extremely versatile building blocks in organic chemistry, used as scaffolds for the preparation of different kinds of derivatives ranging from peptidomimetic foldamers[1] to low molecular weight gelators[2] (LMWGs) and self-assembling amphiphilic molecules,[3,4] thanks to the possibility to control, exploit and modulate their stereochemistry, steric demand and rigidity. For example cyclic β-aminoacids have been widely used for the synthesis of β-peptides and β-oligomers capable to fold in a rich variety of well defined secondary structures (various helices, strands and turns) and to self-assemble to form nano-sized fibers and gels, depending on their chirality and conformational constraints.[1] These foldamers are important not only for their promising biological activity, but also as models to investigate the mechanisms by which the molecular and chiral information embedded in the monomers is translated to their hierarchical organization. On the other hand, trans-1,2-diaminocyclohexane has been largely exploited as a versatile scaffold for the preparation of bisamide and bisurea derivatives with strong gelating ability[2] and of chiral cationic bola surfactants whose self-assemblies have been used as organic templates (structure-directing agents) for the production of inorganic metal-oxide and silica nanostructure, by sol-gel polymerization protocols.[4] Interestingly, derivatives of the cis isomer hardly form any gels.

Herein we report, for the first time, on the stereoselective synthesis of the four stereoisomers of orthogonally protected 1,2-diaminocyclobutane (Scheme 1) and on their potential application as chiral scaffolds for the preparation of various derivatives such as organocatalysts, surfactants and hydrogelators with the aim to investigate how the conformational constraints imposed by the rigid four-membered ring will affect their properties, aggregation behavior and the hierarchical transfer of chirality. References [1] R. P. Cheng, S. H. Gellman, W. F. DeGrado, Chem Rev 2001, 101, 3219-3232; F. Fulop, T. A. Martinek, G. K.

Toth, Chem Soc Rev 2006, 35, 323-334; E. Torres, et al., Org Biomol Chem 2010, 8, 564-575; E. Gorrea, et al., Chemistry 2011, 17, 4588-4597.

[2] M. de Loos, et al., J. Am. Chem. Soc. 1997, 119, 12675-12676; M. de Loos, et al., Angew Chem Int Ed Engl 2001, 40, 613-616; M. de Loos, et al., Org Biomol Chem 2005, 3, 1631-1639; N. Zweep, et al., Langmuir 2009, 25, 8802-8809.

[3] A. Pal, P. Besenius, R. P. Sijbesma, J. Am. Chem. Soc. 2011, 133, 12987-12989. [4] J. H. Jung, et al., J. Am. Chem. Soc. 2000, 122, 5008-5009; S. Kobayashi, et al., Chem. Mater. 2000, 12, 1523-

1525; S. Kobayashi, et al., J. Am. Chem. Soc. 2002, 124, 6550-6551.

NHR1

NHR2 COOMe

COOHNHR1

NHR2

NHR1

NHR2

NHR2

NHR1

Scheme 1



Crystallographic Characterization of Secondary Structures in Unnatural Peptides

Soo Hyuk Choi,⊥ Ilia A. Guzei, Lara C. Spencer, Monika Ivancic and Samuel H.

Gellman*Department of Chemistry, University of Wisconsin, Madison, Wisconsin, USA

[email protected] ⊥ Current address: Department of Chemistry, Yonsei University, Seoul, Republic of Korea

Oligomers that contain unnatural β-amino acids, α/β-peptides and β-peptides, could adopt

secondary structures analogous to those for α-peptides. The four new types of helical secondary

structures were characterized crystallographically for α/β-peptides with three types of α:β-residue

repeat patterns (1:1, 2:1 and 1:2). For 1:1 α/β-peptides, 14 crystal structures displayed two types of

distinct helical conformations: the 11-helix and 14/15-helix arising from (i, i+3) and (i, i+4)

hydrogen bonds, respectively.[1] The crystallographic data are consistent with the proposed length-

dependence of helix preference among 1:1 α/β-peptides by NMR analysis previously;[2] the 14/15-

helix is favored relative to the 11-helix as the 1:1 α/β-peptide backbone grows longer. Various

statistical analyses suggest that the relationship between the two 1:1 α/β-peptide helices is

analogous to the relationship between the 310-helix and the α-helix in α-peptides. For 2:1 and 1:2

α/β-peptides, the two i,i+3 C=O⋅⋅⋅H-N hydrogen-bonded helical conformations were discovered

from 13 crystal structures.[3] Additionally, the five crystal structures were obtained for β-peptides

containing side chain groups.[4] These structures displayed fully-folded 12-helical conformations,

suggesting ways to introduce functional side chains into the 12-helical β-peptide scaffold. The other

secondary structures, such as turns and extended conformations were characterized as well. All of

these atomic resolution structural data sets would be valuable contribution to function-based

foldamer design.

Figure 1. 1:1 α/β-peptide helices. References [1] Choi, S. H.; Guzei, I. A.; Spencer, L. C.; Gellman, S. H. J. Am. Chem. Soc. 2008, 130, 6544. [2] Schmitt, M. A.; Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc. 2004, 126, 6848. [3] Choi, S. H.; Guzei, I. A.; Spencer, L. C.; Gellman, S. H. J. Am. Chem. Soc. 2009, 131, 2917. [4] Choi, S. H.; Guzei, I. A.; Spencer, L. C.; Gellman, S. H. J. Am. Chem. Soc. 2010, 132, 13879.



Molecular Apple Peels

Yann Ferrand,a Ivan Huca

a Université de Bordeaux - CNRS UMR5248, Institut Européen de Chimie et Biologie

2 rue Robert Escarpit, 33607 Pessac (France) [email protected]

A major line of research in our group focuses on the study of various aspects of one function –

namely molecular endo-recognition – in foldamer-based molecular containers[1] possessing

structures remote from those of biopolymers. The unique design on which our receptors rest

consists in a helically folded structure whose diameter is narrow at the ends and wide in the center,

which results in a hollow space with specific recognition properties (Figure 1). Each aromatic

amino-acid monomer of the sequence brings its own features to the final folded helical capsule:

cavity size, helix stability, recognition properties.

Figure 1. Capture and release of a guest molecule by a helical capsule in which the diameter is

wider in the center than at the ends. Guest release is slowed down because it requires a partial helix

unfolding.

This presentation will give you an overview of how we brought and evolved these designs to full

scale receptors capable of encapsulating large and complex chiral organic guests in various

solvents. Molecular recognition will be considered in terms of affinity, selectivity, predictability

and kinetic control.

References [1] a) J. Garric, J.-M. Léger, I. Huc Angew. Chem. Int. Ed. 2005, 44, 1954; b) C. Bao, B. Kauffmann, Q. Gan, K.

Srinivas, H. Jiang, I. Huc Angew. Chem. Int. Ed. 2008, 47, 4153; c) Y. Ferrand, A. M. Kendhale, B. Kauffmann, A. Grélard, C. Marie, V. Blot, M. Pipelier, D. Dubreuil, I. Huc J. Am. Chem. Soc. 2010, 132, 7858.



Development of strong peptoid cis-amide side chains inducers

Cécile Caumes,a,b Sophie Faurea,b, Olivier Roya,b, Claude Taillefumiera,b

aCNRS, UMR6504, Laboratoire SEESIB, 63177 Aubière cedex bClermont Université, Université

Blaise Pascal, BP 10448, 63000 Clermont-Ferrand, France [email protected]

Peptoids are a class of peptidomimetics that were developed in the early 1990s to answer the demand of large set of compounds for high throughput screening.[1] Structurally, peptoids can be regarded as peptide regioisomers where the side chains are located on the amide nitrogens rather than on the α-carbons. The peptoid concept has been further expanded to β-peptides, given rise to the β-peptoid family[2] and the combination of α- and β-peptoid monomers in alternation has engendered the α,β-peptoid family. [3] Peptoids are characterized by a greater flexibility compared to peptides. This can be explained by their decrease ability to form intrachain H-bonding but the primary cause is the presence of tertiary amides in the backbone which can populate both cis and trans conformations. Despite great efforts to restrict the conformational freedom of peptoids, generating homogeneous peptoids in solution is still challenging, particularly peptoid oligomers where all the amides are cis, which are meant to adopt the PPI-like conformation. The control of the amide geometry stands on the design of side chains able to form local non-covalent interactions with the backbone, including reinstallation of H-bonding, electronic and steric contributions. [4] In this communication, recent results on the design of side chains that force peptoids amides to adopt the cis conformation while maintaining chemical diversity will be presented. This work opens the door to the engineering of decorated peptoid helices. References [1] R. J. Simon, R. S. Kania, R. N. Zuckermann, V. D. Huebner, D. A. Jewell, S. Banville, S. Ng, L. Wang, S.

Rosenberg, D. C. Spellmeyer, R. Tan, A. D. Frankel, D. V. Santi, F. E. Cohen, and P. A. Bartlett, Proc. Natl. Acad. Sci. USA, 1992, 89, 9367-9371.

[2] B. C. Hamper, S. A. Kolodziej, A. M. Scates, R. G. Smith, and E. Cortez, J. Org. Chem, 1998, 63, 708-718. [3] (a) T. Hjelmgaard, S. Faure, C. Caumes, E. De Santis, A. A. Edwards, C. Taillefumier, Organic Letters 2009, 11,

4100-4103. (b) E. De Santis, T. Hjelmgaard, S. Faure, O. Roy, C. Didierjean, B. D. Alexander, G. Siligardi, R. Hussain, T. Javorfi, A. A. Edwards, C. Taillefumier Amino Acids 2011 41, 663-672. (c) E. De Santis, T.

Hjelmgaard, C. Caumes, S. Faure, B. D. Alexander, S. J. Holder, G. Siligardi, C. Taillefumier, A. A. Edwards, Organic and Biomolecular Chemistry, DOI:10.1039/C1OB06386C. [4] B. C. Gorske, J. R. Stringer, B. L. Bastian, S. A. Fowler, and H. E. Blackwell, J. Am. Chem. Soc., 2009, 131,

16555-16567.



Asymmetric synthesis and selective deprotection of

γ-chloro-α,β-diamino acid derivatives

Gert Callebaut,a Sven Mangelinckx,a Loránd Kiss,b Reijo Sillanpää,c Ferenc Fülöp,b and Norbert De Kimpea

aDepartment of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering,

Ghent University, Coupure Links 653, B-9000 Ghent, Belgium; bInstitute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, P.O. Box 427, Hungary; and cDepartment of

Chemistry, University of Jyväskylä, Fin-40351, Jyväskylä, Finland [email protected]

Nature uses α-amino acid derivatives with a leaving group at the γ-position as versatile building blocks in the biosynthesis of a broad range of biologically important natural products. Moreover, the γ-chloro-α-amino acid moiety is present in a wide range of natural products. Some of these γ-chloro-α-amino acids are also biologically active as a free amino acid. Next to γ-chloro-α-amino acid derivatives, β-amino acids and α,β-diamino acid derivatives have also gained a lot of attention as non-proteinogenic amino acids serving as building blocks for the synthesis of new heterocyclic compounds and peptides. In this presentation, results on the efficient asymmetric synthesis of new chiral γ-chloro-α,β-diamino acid derivatives 3 via highly diastereoselective Mannich-type reactions of N-(diphenylmethylene) glycine esters and amides 1 across a chiral α-chloro-N-p-toluenesulfinylimine 2 are discussed. The γ-chloro-α,β-diamino acid derivatives 3 proved to be excellent building blocks for ring closure towards optically pure anti- and syn-β,γ-aziridino-α-amino esters 4, and subsequent ring transformation into trans-3-aminoazetidine-2-carboxylic acid derivatives 5 and α,β-diamino-γ-butyrolactones 6. Synthetic efforts to prepare the deprotected γ-chloro-α,β-diamino acid derivatives 7 and 8, as well as the deprotected 2-aziridinyl acetate 9 are also disclosed.

(R)(S)

NH2

HN

R

O

(R)

Cl

(R)O

R

NH

N Ph

Ph

S(S)O

N

Ph

Ph

(R)

Cl

(S)O

R

NH

N Ph

S(S)

O

2)

H

NS

(S)

Cl

1) LDA or LiHMDS

p-Tol

H

OEt

O

O

p-Tol

p-Tol

HN (S)(R)

COOH

NHTos

.HCl(R)(R)

O O

H2N NH2HCl.

(R)(S)

NS

(S) Op-Tol

NO

R

Ph

Ph

H

(R)

Cl

(S)NH

S(S)O

p-Tol

NH2

O

N n

8 (n = 1,2)

TFA

TFA

(R)

Cl

(R)O

OEt

NH

NH2

S(S)O

p-Tol

R = Ot-Bu, OEt, OMe, N(CH2)4, N(CH2)5

Ph

K2CO3TFA

1

2

syn-3

anti-3

4

5

6

7

9



Structural and Biological studies of O-alkylated oligomers as α-helix mimetics

Panchami Prabhakaran,a,b Natasha Murphy a,b Thomas A. Edwards,a,b Andrew J. Wilson* a,b

aSchool of Chemistry, and bAstbury Centre for Structural Molecular Biology, University of Leeds,

Woodhouse Lane, Leeds LS29JT, United Kingdom. [email protected]

Synthetic molecules that mimic the secondary elements of proteins - structurally and/or

functionally - have received significant attention in recent years.[1] These de novo designed molecules with diverse backbones find applications in molecular recognition, drug design and material sciences.[2] Through proper design, these conformational mimetics can act as inhibitors of therapeutically relevant protein-protein interactions (PPIs),[3] for instance, a class of aromatic oligoamides with different side chains reported from our group, act as potent inhibitors of the p53-hDM2 PPI (Fig. 1c).[4]

This presentation describes the structural and conformational studies of oligomers, optimization of oligomers for in-vivo and in-vitro studies, and the biological screening of molecules against different PPIs. Conformational analyses of these oligomers using X-ray and 2D NMR provide key insight for future inhibitor design (Fig.1a,b). In order to optimize this generic aromatic oligoamide template for in-vivo and in-vitro studies by improving the solubility profile and to permit appendage of useful functionality that will permit their use as chemical probes, different strategies to incorporate hydrophilic groups on the backbone of these oligomers will be described (Fig. 1d-f). These results will be considered in our ongoing efforts to develop α-helix mimetics tailored to a range of biological targets.

a) b) c) d) e) f)

Figure 1. (a) and (b) Single crystal X-ray analyses of oligoamides having different side chain functionalities. (c) Structure of helix mimetic scaffold; (d) and (e) modification of the scaffold with hydrophilic functionality and (e) with amino acids (AA). References [1] (a) C. M. Goodman, S. Choi, S. Shandler and W. F. DeGrado Nat Chem Biol., 2007, 3, 252.; (b) I. Saraogi and A. D. Hamilton, Biochem. Soc. Trans., 2008, 36, 1414. [2] W. S. Horne, M. D. Boersma, M. A. Windsor, and S. H. Gellman Angew. Chem. Int. Ed. 2008, 47, 2853-2856 [3] A. J. Wilson, Chem. Soc. Rev., 2009, 38, 3289. [4] J. P. Plante, T. Burnley, B. Malkova, M. E. Webb, S. L. Warriner, T. A. Edwards, and A. J. Wilson, Chem. Commun. 2009, 5091.



From the posttranslational modifications to the synthetic foldamers

Gábor K. Tótha

aDepartment of Medical Chemistry, University of Szeged, H-6720 Szeged, Dóm tér 8. HUNGARY [email protected]

About 5% of the genome of eukaryotes is devoted to enzymes that carry out post-translational modifications. Post-translational modifications may increase the number of unique proteins in an organism by more than an order of magnitude. Post-translational modifications induce conformational changes in proteins, and affect oligomerization and ligand binding. Practically the modified amino acid residues (e.g. glycosylated, phosphorylated, methylated etc.) can be considered as “natural foldamers”, building blocks having more restricted dihedral angles. The combination of the non-natural amino acids as foldamers with the proteinogenic ones and posttranslational modifications could increase the available tools for the design of artificial molecules aiming application in chemistry, biology, medicine or nanoscience. While the synthesis of the medium-sized oligopeptides could be considered as a more or less routine work, the application of several conformationally constrained building block (including synthetic foldamers or post-translationally modified amino acid residues) is sometimes not trouble free. Not only the completion of the coupling step, but the analytical control and the integrity of the glyco- or phospho- moiety should be solved. An additional problem is the hydropholicity: most of the synthetic foldamers suffered from the low water solubility.

Figure 1. NMR structure of a chimeric β-amino acid-aza-amino acid peptide References [1] A. Hetényi, G. K. Tóth, C. Somlai, E. Vass, T. A. Martinek, F. Fülöp, Chem. Eur. J. 2009, 15, 10736-10741. [2] G. K.Tóth, Z. Kele, Gy.Váradi, Curr. Org. Chem. 2007, 11, 409-426.



BoronoNucleic Acids Foldamers

Michael Smietana, Anthony R. Martin, Jean-Jacques Vasseur

Institut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS-Université Montpellier 1 et Université Montpellier 2, Place Eugène Bataillon, 34095 Montpellier

[email protected] A common characteristic of all living organisms is the dependence upon self-assembly of molecular units to be morphed into well-defined architectures. The functional integrity of these biopolymers is achieved by means of a variety of selective and corrective dynamic processes. Thus, the development of synthetic systems displaying spontaneous recognition, folding and stimuli-responsive properties is an emerging field with wide applications from biotechnology to medicine. In this context, natural or artificial nucleic acid foldamers are high-ranking biopolymers allowing unprecedented control over new functional biomaterials.[1] Recently, we developed a stimuli-responsive nucleic acid-based system relying on the reversible formation of cyclic boronate internucleosidic linkages. The dynamic assembly of this new borono-based helix has been accomplished through a DNA- or a RNA-templated autoligation process featuring a 5’-ended boronic acid oligonucleotide connecting to a 3’-ended ribonucleosidic oligonucleotide partner (Figure 1). The autoligation process was found to be reversibly controlled by various external stimuli such as variations of pH, temperature or by the presence of anions.[2-4] The modular characteristics of these new architectures will be exposed.

N

NH2

O

N

OHO

O

NH

O

O

N

OO

B

TTTTTT

CCGTCG

HO

HO

OH

N

NH2

O

N

O

O

NH

O

O

N

OO

O

TTTTTT

CCGTCG

B O

Recognition Ligation

Figure 1. Dynamic borono-based autoligation process References [1] A. Chworos, L. Jaeger, in Foldamers, Wiley-VCH, S. Hecht and I. Huc Eds, 2007, 291. [2] D. Luvino, C. Baraguey, M. Smietana, J.-J. Vasseur Chem. Commun. 2008, 2352. [3] A.R. Martin, K. Mohanan, D. Luvino, N. Floquet, C. Baraguey, M. Smietana, J.-J. Vasseur Org. Biomol. Chem.

2009, 7, 4369. [4] A.R. Martin, I. Barvik, D. Luvino, M. Smietana, J.-J. Vasseur, Angewandte Chemie Int. Ed. 2011, 50, 4193.



Synthesis and Biological Activity of a Library of functional "Glyco" Foldamers

Tushar K. Chakraborty,1 Kiran Kumar,1 Saumya Roy,2 Omprakash Bande,2 Subhash Ghosh,5 José

M. García Fernández,3 Johannes W. Vad Pedersen,4 Henrik Clausen,4 Ravi S. Ampapathi,1 Aloysius

Siriwardena.2 1Central Drug Research Institute (CSIR), Chattar Manzil Palace, Lucknow - 226 001, UP, India, 2Laboratoire des Glucides, UMR 6912-CNRS, 33 Rue St Leu, 80039, Amiens, France, 3Instituto de Investigaciones Químicas, CSIC, Américo Vespucio 49, Isla de la Cartuja, E-41092 Sevilla, Spain, 4Københavns Universitet, Det Sundhedsvidenskabelige Fakultet, Institut for Cellulær og Molekylær Medicin Blegdamsvej 3B, 2200 København, Denmark, 5Indian Institute of Chemical Technology, Hyderabad – 500 007, India

[email protected]

Research into foldamers - synthetic oligomers akin to natural polymers such as peptides, proteins

and oligonucleotides - has given valuable insights into how non-covalent interactions can regulate

the folding, assembly and catalysis of their natural counterparts. A limited number of “designer”

foldamers have also been demonstrated to be functional.1

We describe here the study of a family of foldamers comprising pseudopeptide backbones derived

from sugar amino acids (SAAs) onto which glycans are grafted. These can be thought of as

glycopeptide mimics or “glyco”-foldamers and are relevant in that the majority of proteins are

glycosylated. Consequently, there is much interest in designing mimetics that are functional as they

could provide an understanding of how glycopeptides themselves might exert their biological

activity.2 We demonstrate that various members of this new family of mimetics do adopt well-

defined secondary structures that depend both on the nature of the SAA backbone and the structure

of grafted glycan. In several cases the secondary structures of the glyco-foldamers are maintained in

aqueous solution. The unique structural and physical features of our glyco-foldamer family has

given us a rare opportunity to investigate their activity against a variety of biological targets which

has revealed certain of them indeed to be functional.

Data on the synthesis, conformational preferences and biological activity of examples of these

novel glyco-foldamers will be presented.

References 1. Goodman, C. A.; Choi, S.; Shandler, S.; DeGrado, W. F., Nature Chemical Biology 2007, 3, 252 and references

cited therein.

2. Wennemers, H.; Erdman, R. S., J. Am. Chem. Soc, 2010, 132, 13957



Soft materials from foldamers: structure and function

Debasish Haldar*, Sibaprasad Maity, Poulami Jana, Suman K Maity, Santu Bera

Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata,

Mohanpur, West Bengal – 741252, India.

[email protected]

Developing biomimetic materials, such as the folded structures of biopolymers, by the self-

assembly of foldamers are highly interesting.[1] The interest stems from their structural versatility,

biocompatibility, robustness and a relative experimental simplicity. Self-assembled materials

having unique bulk, surface and structural properties are highly interesting due to their potential

importance in various fields like catalysis, sensor, ion exchange, separation, purifications and bio-

molecular isolation.[2] Different kinds of stimuli like pH change, solvent polarity, light, ultrasound,

ions, enzymes, and so forth are usually used to tune the behavior of the molecular self-assembly for

functional soft materials. In this context, we have designed and synthesized several foldamers

containing rigid aromatic backbone and coded and noncoded amino acids.[3] The urea capped

foldamers can form a duplex through intermolecular hydrogen bonding interaction. Moreover, the

foldamers may response to ultrasonic stimuli to form fibril and organogel in a wide range of

solvents. Sonication is providing the energy to cleave self-locked intramolecular hydrogen bonds or

π stacking to form interlocked structures through intermolecular interactions.[4] The foldamer based

gel may use to immobilized UCNP nanocrystals and as delivery vehicles. The presentation will be

focused on the structure and function of self-assembled foldamers based soft materials.

Figure 1. Structure and function of foldamers based soft materials. References [1] D. Haldar, C. Schmuck, Chem. Soc. Rev. 2009, 2, 363. [2] (a) P. Jana, S. Maity, D. Haldar, CrystEngComm 2011, 13, 973; (b) S. Maity, P. Jana, S. K. Maity, D. Haldar, Langmuir 2011, 27, 3835; (c) S. Maity, P. Jana, D. Haldar, CrystEngComm 2011, 13, 3064; (d) P. Jana, S. Maity, S. K. Maity, D. Haldar, Chem. Commun. 2011, 47, 2092. [3] (a) P. Jana, S. Maity, D. Haldar, Curr. Org. Synth. 2010, 7, 224; (b) D. Haldar, Curr. Org. Synth. 2008, 5, 61. [4] S. Maity, P. Kumar, D. Haldar, Soft Matter 2011, 7, 5239.

Poster 1


Cyclobutane ββββ-amino acid–proline PNA: a ring size effect?

David J. Aitken,a Árpád Balás,a Woraluk Mansawat,b Chotima Vilaivan,b Tirayut Vilaivanb

aLaboratoire de Synthèse Organique & Méthodologie, ICMMO, Université Paris-Sud, 91400 Orsay, France. bOrganic Synthesis Research Unit, Department of Chemistry, Chulalongkorn University,

Bangkok 10330, Thailand [email protected], [email protected]

Peptide nucleic acid (PNA) is a class of bio-inspired synthetic material which displays a

sequence of nucleic bases on a peptide backbone, this latter feature replacing the deoxyribose-phosphate backbone of DNA. In previous work, the Thai group has examined a new type of PNA: mixed α/β peptides comprised of alternating nucleobase-substituted-D-proline and a five-membered cyclic β-amino acid, trans-(1S,2S)-2-amino-1-cyclopentanecarboxylic acid (Figure 1, left). These PNA materials bound selectively to complementary DNA, according to the Watson-Crick base pairing rules.[1,2]

In the present work, the Orsay group has profited from their recently established practical access to enantiomerically pure trans-(1S,2S)-2-amino-1-cyclobutanecarboxylic acid (ACBC),[3,4] to facilitate the preparation of analogous PNA materials featuring a four-membered cyclic β-amino acid (Figure 1, right). This communication will present the syntheses of these new materials, and their hybridization properties. In particular, the consequences of the ring-size modification on binding stability will be considered.

n

N

O

HNO

B

n

N

O

HNO

B

Figure 1. Mixed α/β PNA containing cyclic β-amino acids: previously studied (left), and new materials discussed in this communication (right).

References [1] T. Vilaivan, C. Srisuwannaket, Org. Lett. 2006, 9, 1897. [2] C. Suparpprom, C. Srisuwannaket, P. Sangvanich, T. Vilaivan, Tetrahedron Lett. 2005, 46, 2833. [3] C. Fernandes, E. Pereira, S. Faure, D. J. Aitken, J. Org. Chem. 2009, 74, 3217. [4] V. Declerck, D. J. Aitken, Amino Acids 2011, 41, 587.

Poster 2


A large-diameter β-peptidic H18/20 mixed helix

Anasztázia Hetényi,a Éva Szolnoki,

b Ferenc Fülöp,

b Tamás A. Martinek,

b

aDepartment of Medical Chemistry, Szeged, H-6720, Dóm tér 8, Hungary

bInstitute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary

[email protected]

The β-peptidic H10/12 helix is an important representative of the mixed helix type among

foldamers.[1] It can be stabilized by using the alternating sequences of β2-β

3 or (1S,2R)-ACPC-

(1R,2S)-ACPC (aminocyclopentane carboxylic acid) motifs.[2]

It is the only known mixed helix

geometry found among β-peptidic foldamers. Our goal was to study the effects of the chain

elongation on the geometry of the alternating heterochiral ACPC sequences. We were interested in

which terminus is responsible for the stereochemical induction of the helix handedness, and in any

potential change of the helix diameter.

In this study, we show that the stereochemical configuration of the N-terminal plays crucial role in

the induction of the helicity of the (H-[(1S,2R)-ACPC-(1R,2S)-ACPC]n-NH2 oligomers. Moreover,

heptameric chains exhibited a dramatic change in the helix diameter, and the NMR structure

refinement revealed a H18/20 helix stabilized by i – i+4 and i – i-5 H-bonding contacts. The new

structure was characterized by NMR, CD and molecular modeling.

Figure 1. Side and top views of the H18/20 mixed helix.

References [1] D. Seebach, S. Abele, K. Gademann, G. Guichard, T. Hintermann, B. Jaun, J. L. Matthews, J. V. Schreiber,

Helv Chim Acta 1998, 81, 932-982.

[2] T. A. Martinek, I. M. Mandity, L. Fulop, G. K. Toth, E. Vass, M. Hollosi, E. Forro, F. Fulop, J Am Chem Soc

2006, 128, 13539-13544.

Poster 3


Influence of (N-pyrrolidine-2ylmethyl)ureido units on Oligourea Helices

J. Fremauxa, L. Fischera, B. Kauffmanna, G. Guicharda

a Institut Européen de Chimie et Biologie, CBMN, Université de Bordeaux-CNRS UMR 5248, 2 rue Robert Escarpit, 33607 Pessac

[email protected] Abstract

N,N’-Disubstituted oligourea foldamers (1) that were developed in our laboratory are aza analogues of gamma peptides that adopt well-defined helical secondary structures [1, 2].

NN'

H

Ri H

O n

αβ

1

O N

ONH

ON

O

O

O

O NH

HN

HN

NH

O

O

NH

OHN N

ONH

NH

OHN

HN

NH

O

NH

OHN

HN

On

2

A

Recently, while developing a fragment condensation approach to synthesize aliphatic oligourea foldamers, we found that the non canonical unit A resembling proline can be introduced at discrete positions in oligoureas (e.g. 2; n = 1) without impairing their 2.5-helical folding [3]. Although the incorporation of noncontiguous pyrrolidine units at various ratios is compatible with the canonical 2.5-helix geometry, it is nevertheless destabilizing as revealed by electronic circular dichroism (ECD) and NMR studies. Destabilization is likely to arise from the loss of one hydrogen bond and from local backbone distortions imposed by the pyrrolidine ring.

We have now investigated the effect of incorporating multiple adjacent pyrrolidine units on 2.5-

helical folding. We have prepared a series of oligoureas containing central oligopyrrolidine segments ranging from 2 to 7 units and evaluated their folding propensity in solution and in the crystal state. We found that segments up to five pyrrolidine units are well tolerated when inserted in-between short canonical sequences with strong helix propensity. The corresponding oligoureas (2, n = 2 to 5) display the hallmarks of 2.5-helical structures. ECD signatures may however suggest a different folding behaviour for oligomers with more than 5 consecutives pyrrolidine residues (e.g. 2, n = 7). It is noteworthy that oligomers consisting exclusively of pyrrolidine units (polyproline type) did not show any evidence of a secondary structure. Overall this study reveals that (i) short oligopyrrolidine segments have low helix-forming propensity and that (ii ) short N,N’-disubstituted oligourea sequences display a pronounced helix nucleation effect on segments with no intrinsic folding propensity. References [1] L. Fischer, G. Guichard, Org. Biomol. Chem., 2010, 8, 3101-3117 [2] L. Fischer, P. Claudon, N. Pendem, E. Miclet, C. Didierjean, E. Ennifar, G. Guichard, Angew. Chem. Int. Ed.,

2010, 49, 1067-1070 [3] J. Fremaux, L. Fischer, T. Arbogast, B. Kauffmann, G. Guichard, Angew. Chem. Int. Ed., 2011, 50, 11382-11385

Poster 4


Chiral cyclobutane platforms:applications to new MRI

contrast agents development

Raquel Gutiérrez-Abad,a Sílvia Lope,b Ona Illaa and Rosa M. Ortuñoa

aDepartament de Química, Universitat Autònoma de Barcelona, 08193-Bellaterra, Spain; bServei de Ressonància Magnètica Nuclear, Universitat Autònoma de Barcelona,08193-Bellaterra, Spain

[email protected] Magnetic Resonance Imaging (MRI) contrast agents are important tools in biomedicine and diagnosis. The search for new Gd complexation agents is of huge importance.[1] In the context of a research program based on chiral cyclobutane platforms,[2] we have synthesized two cyclobutane substituted triamines, 1 and 2. These molecules have been coupled to DOTA in order to increase the performance of DOTA itself by introducing rigidity to the system. Complexation of Gd3+ has been carried out and MRI assays have been conducted in vitro. Results show that the two new contrast agents 3 and 4 (Figure 1) give better results than DOTAREM in relaxativity experiments (Figure 2).

Figure 1. Structures of DOTA, chiral cyclobutane platforms 1 and 2, DOTAREM and complexes 3 and 4.

Figure 2. T1W image of commercial DOTAREM , 3 and 4. Some tests in vivo have been conducted and preliminary results are very promising. References [1] See for example: (a) D. Delli Castelli, E. Gianolio, S. Aime, Bioinorganic Medicinal Chemistry 2011, 223. (b) E.

J. Werner, A. Datta, C. J. Jocher, K. N. Raymond, Angew. Chem. Int. Ed. 2008, 47, 8568. (c) K. W.-Y. Chan, W.-T. Wong, Coordination Chemistry Reviews 2007, 251, 2428.

[2] R. Gutiérrez-Abad, O. Illa, R. M. Ortuño, Org. Lett. 2010, 12, 3148.

Poster 5


Figure 2. Crystal structures of cyclic triamides. a) Hydrogen bond network of 2, b) dimer formation of 2, and c) chiral dimer formation of 3.

Molecular Chirality and Capsule-type Dimer Formation of Cyclic Triamides

with Hydrogen Bonding Interactions

Mio Matsumura,a Noriko Fujimoto,

a Hyuma Masu,

b Shizuka Nishiyama,

a Kosuke Katagiri,

c

Isao Azumaya,c Hiroyuki Kagechika

d and Aya Tanatani

a

aOchanomizu University,

bChiba University,

cTokushima Bunri University,

dTokyo Medical and Dental University

[email protected]

Aromatic secondary amides such as benzanilide exist in trans-amide form, whereas N-

methylated benzanilides exist in cis form. The cis conformational preference is general as observed

in various N-methylated amides/amidines and

N,N’-dimethylated ureas/guanidines, and can

be applied to construct the aromatic foldamers

with unique conformational properties, such as

helical amide polymers and aromatic

multilayered ureas.[1],[2]

Based on the folded N-

methylbenzamide structure, the cyclic

oligoamides could be synthesized by the

condensation of m-(N-methylamino)benzoic

acid, including triamide 1 (Fig. 1a) as the

major product.[3]

The crystal structure of cyclic triamide 1 is syn structure that has a small cavity and molecular

chirality based on the direction of the amide bonds. The crystal contained both enantiomers with 1:1

ratio. In solution, 1 existed in the equilibrium between syn (major) and anti conformers (Fig. 1b).

In this study, several cyclic triamide derivatives bearing carboxyl (2) or carboxamide (3)

groups on the aromatic rings are synthesized with the aim to form unique three-dimensional

structures by hydrogen bond networks.

All crystals of the examined cyclic triamides had syn conformation, and some compounds

afforded pseudopolymorphs. For example, compound 2 afforded the crystals with intermolecular

hydrogen bond network structure (Fig. 2a), while the others had the capsule-type dimeric structure

of syn conformer by triple hydrogen bonds between the carboxyl groups (Fig. 2b). Interestingly, the

compound 3 afforded the chiral crystals with chiral capsule-type dimeric structure (Fig. 2c). The

enantiomeric chiral crystal was

distinguished by CD spectra of the

crystal of 3 in KBr. Further, the

chiral induction of 2 was observed

by the addition of chiral amine in

the solution of 2. The properties of

chirality and capsule formation of

cyclic triamides could be applied for

development of novel functional

macrocycles.

References [1] A. Tanatani, A.Yokozawa, I. Azumaya, et al., J. Am. Chem. Soc., 2005, 127, 8553-8561

[2] A. Tanatani, K. Yamaguchi, I. Azumaya, et al., J. Am. Chem. Soc., 1998, 120, 6433-6442.

[3] I. Azumaya, H. Kagechika, K. Yamaguchi, et al., Tetrahedron Lett., 1996, 37, 5003-5006.

Figure 1. a) Structures of cyclic triamides 1 – 3. b) Equilibrium of cyclic triamide 1 in solution.

mailto:[email protected]

Poster 6


Foldaxanes: Helically Folded Oligomers

around Dumbbell Molecules

Quan Gan,a Yann Ferrand,a Brice Kauffmann,a Axelle Grélard,a Hua Jiang,b Ivan Huc,a

aIECB UMR 5248 - Université de Bordeaux - 2, Rue Robert Escarpit, 33607, Pessac, France

bInstitute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China [email protected]

Synthetic molecular machines are often designed to mimic the functions of their natural

counterparts. Interlocked molecules are appealing systems for the construction of molecular machines, in which molecular components can process relative motions without dissociating due to irreversible intermolecular mechanical linkages that prevent disassembly.[1-3] An important improvement to these designs would use reversible assembly to avoid the difficulty of mechanically interlocking molecular components. Meanwhile the machines would be effective only if assembly and disassembly remain slow compared their work regime, just as biological molecular machines

Herein we show that helical molecular tapes can slowly wind around rod-like guests and form stable complexes called foldaxanes, without requiring an irreversible attachment. The winding process requires helix unfolding and refolding, as well as a strict match between helix length and anchor points on the rods. Because the time scales of helical unwinding are relatively slow, the helices can undergo some motion, such as shuttling[4] and screwing,[5] along the guests without dissociating. This modular design and dynamic assembly open up promising capabilities in molecular machinery.

Figure 1. Schematic representation of the formation of foldaxane: helix winds around rod like guest via unfolding and refolding mechanism References [1] S. P. Fletcher, F. Dumur, M. M. Pollard, B. L. Feringa, Science 2005, 310, 80-82. [2] T. Muraoka, K. Kinbara, T. Aida, Nature 2006, 440, 512-515. [3] V. Serreli, C.-F. Lee, E. R. Kay, D. A. Leigh, Nature 2007, 445, 523-527. [4] Q. Gan, Y. Ferrand, C. Bao, B. Kauffmann, A. Grélard, H. Jiang, I. Huc, Science 2011, 331, 1172-1175. [5] Y. Ferrand, Q. Gan, B. Kauffmann, H. Jiang, I. Huc, Angew. Chem. Int. Ed. 2011, 50, 7572

Poster 7


Solution- and solid-phase submonomer synthesis of

o-, m- and p-arylopeptoids [oligomeric N-substituted aminomethyl benzamides]

Thomas Hjelmgaard,a Sophie Faure,b,c Dan Staerk,a Claude Taillefumier,b,c John Nielsena

a Department of Basic Sciences and Environment, University of Copenhagen, Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark, b CNRS, UMR6504, Laboratoire SEESIB, 63177 Aubière cedex c

Clermont Université, Université Blaise Pascal, BP 10448, 63000 Clermont-Ferrand, France [email protected]

During the last decade, aryl-based foldamers have proven to be well suited for structural and functional mimicry of biopolymers. Arylopeptoids i.e. N-substituted aminomethyl benzamides, represent a new group of oligomers with potential folding propensities as a result of their relatively rigid aromatic amide core structure even though their backbones are deprived of free amide protons. Importantly, its original structure allows this artificial polyamide to retain the favorable characteristics of peptoids (oligomeric N-substituted glycines or β-alanines) such as large potential for diversity and straightforward synthesis using submonomer methods. The access to arylopeptoids of the para- and meta-series was reported by Lokey in 2007[1] but no conformational study was done. We have recently developed versatile methods both in solution and on solid support that have enabled the efficient access to homo- and hetero-oligomers of up to 12 mer length.[2] Moreover, we have been able to adapt our methodologies to the preparation of the first ortho-arylopeptoids whose conformational preferences are under investigation.

O

Cl

ClNH2

R

XH

O

NR

Bz

O

Br

Br

XH

O

NR

BzXH

ONR

Bz

ortho-arylopeptoids

submonomermethod

Solution-phase Solid-phase

n

meta-arylopeptoids

n

para-arylopeptoids

n

X = NH, On = 1 to 12

The development of an improved methodology for iterative solid- and solution-phase synthesis of para-, meta- and ortho-arylopeptoids using benzoyl chloride or bromide and primary amine building blocks will be described. Preliminary NMR conformational studies of these arylopeptoids bearing side chains which allow for complete control over the amide conformation will be presented. References [1] D. J. Combs, R. S. Lokey, Tetrahedron Lett. 2007, 48, 2679-2682. [2] (a) T. Hjelmgaard, S. Faure, D. Staerk, C. Taillefumier, J. Nielsen Eur. J. Org. Chem. 2011, 17, 4131-4132; (b) T.

Hjelmgaard, S. Faure, D. Staerk, C. Taillefumier, J. Nielsen Org. Biomol. Chem. 2011, 9, 6832-6843; (c) T. Hjelmgaard, S. Faure, E. De Santis, D. Staerk, B. D. Alexander, A. A. Edwards, C. Taillefumier, J. Nielsen Tetrahedron, submitted.

Poster 8


Functionalizable Collagen Model Peptides

Roman Erdmann, Christiane Siebler, Helma Wennemers

ETH Zürich, Lab. für Organische Chemie, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland

[email protected]

Collagen is the most abundant protein in mammals. Understanding the tripelhelical collagen structure and factors that have an influence on this structure is important. The collagen triple helix consists of X-Y-Gly reapeating units, with Pro-(4R)Hyp-Gly as the most stable one in nature. Raines et al. showed by replacing (4R)Hyp with (4R)Fluoroproline that stereoelectronic effects contribute to the stability of the collagen helix.[1] The Wennemers group showed that the azido group exerts a similarly strong stereoelectronic effect[2], e.g. (4R)Azidoproline (Azp) can be used to stabilize the PPII conformation within polyprolines.[3] In this work we incorporated Azp into the collagen triple helix and demonstrate that the triple helix derived from H-(Pro-(4R)Azp-Gly)7-OH has a comparable stability as that of H-(Pro-(4R)Hyp-Gly)7-OH.[4] The advantage of the azidoproline containing peptide is its functionalizability by 1,3-dipolar cycloadditions.

N

O

N

O

HN

O

NH2

N3

Ac

7 Figure 1: Triplehelical collagen structure (left) and model peptide (right).

References [1] S. K. Holmgren, K. M. Taylor, L. E. Bretscher, R. T. Raines, Nature 1998, 392, 666- 667. [2] L.-S. Sonntag, S. Schweizer, C. Ochsenfeld, H. Wennemers, J. Am. Chem. Soc. 2006, 128, 14697-14703. [3] M. Kümin, L.-S. Sonntag, H. Wennemers, J. Am. Chem. Soc. 2007, 129, 466-467. [4] Erdmann, R. S.; Wennemers, H., J. Am. Chem. Soc. 2010, 132, 13957.

.

Poster 9


Aromatic garlands as new foldamers to mimic protein secondary structure

Anne Sophie Voisin-Chiret,a Serge Perato,a Marcella De Giorgi,a,b Jana Sopková-de Oliveira

Santos,a Sylvain Rault.a

a Université de Caen Basse-Normandie, Centre d’Etudes et de Recherche sur le Médicament de Normandie (UPRES EA 4258-FR CNRS 3038 INC3M), UFR des Sciences Pharmaceutiques, F-

14032 Caen Cedex, France b Université de Bari, Département de Chimie médicinale, I-70125 Bari, Italie.

[email protected] Proteins modulate the majority of all biological functions and are composed of highly organized secondary structural elements such as helices, turns and sheets. Many of these functions are affected by a small number of key structural element protein-protein interactions. Their mimicry by peptide and non-peptide scaffolds has become a major focus of contemporary research.. Among all of non-peptide oligomeric system, we are especially interested in Jacoby and Hamilton oligophenyl foldamers. At the same time, Che and Hamilton studied terpyridyl scaffolds and predicted a better percentage of helicity for terpyridyl than for terphenyl compounds (Figure 1).[1] Our proposed synthesis of the oligomeric pyridyl system as peptidomimetics involves three approaches of Jacoby, Hamilton and Che and uses the Garlanding concept[2] which allows building a linear chain from one ring by the implementation of cross-coupling reactions between boronic species and dihalogenated compounds. This is a regioselective, flexible and highly reproducible approach to introduce various (het)aromatic rings especially since our laboratory is specialized in the preparation of boronic species and in the study of their ability to be good coupling partners. We will highlight the subtle role that the conformation of oligo(het)arylpyridines can play in adopting helical or elongated conformations. Here, we describe the synthesis of oligopyridyl-,[3] oligophenylpyridyl-[4] and oligothienylpyridyl-garlands[5] and present preliminary results showing that these compounds act alpha-helix mimetics.[6]

R'

R''

R

R2

R1

R3

Y=C, N, S n=1,2R1, R2, R3=H, CH3

i

i+3i+4

i+7

N

Y

Y( )n

( )n

Figure 1. Oligopyridyl-, oligophenylpyridyl- and oligothienylpyridyl-garlands. References [1] a) Bourne, G.T.; Kuster, D.J.; Marshal, G.R. Chem. Eur J. 2010, 16, 8439-8445; b) Jacoby, E. Bioorg. Med. Chem.

Lett. 2002, 12, 891-893; c) Ernst, J.T.; Becerril, J.; Park, H.S.; Yin, H.; Hamilton, A.D. Angew. Chem. Int. Ed. 2003, 42, 535-539; d) Che, Y.; Marshall, G.R. Expert Opin. Ther. Targets 2008, 12, 1-14.

[2] a) Bouillon, A.; Voisin, A.S.; Robic, A.; Lancelot, J.C.; Collot, V.; Rault, S. J. Org. Chem. 2003, 68, 10178-10180; b) Voisin-Chiret, A.S.; Bouillon, A.; Burzicki, G.; Célant, M.; Legay, R.; El-Kashef, H.; Rault, S. Tetrahedron 2009, 65, 607-612.

[3] a) Burzicki, G.; Voisin-Chiret, A.S.; Sopkovà-de Oliveira Santos, J.; Rault, S. Tetrahedron 2009, 65, 5413-5417; b) Burzicki, G.; Voisin-Chiret, A.S.; Sopkovà de Oliveira Santos, J.; Rault, S. Synthesis 2010, 16, 2804-2810.

[4] Perato, S.; Voisin-Chiret, A.S.; Sopkovà-de Oliveira Santos, J.; Sebban, M.; Legay, R.; Oulyadi, H.; Rault, S. Tetrahedron 2011, accepted.

[5] De Giorgi, M.; Voisin-Chiret, A.S.; Sopková-de Oliveira Santos, J.; Corbo, F.; Franchini, C.; Rault, S. Tetrahedron 2011, 67, 6145-6154.

[6] Sopkovà-de Oliveira Santos, J.; Voisin-Chiret, A.S.; Burzicki, G.; Sebaoun, L.; Sebban, M.; Lohier, J.F.; Legay, R.; Oulyadi, H.; Bureau, R.; Rault, S. J. Chem. Inf. Model. 2011, accepted.

Poster 10


Synthetic Antifreeze Glycopeptide Analogs

Tanja Fröhr1, Lilly Nagel1, Carsten Budke2, Zsuzsa Majer3, Thomas Koop2, Norbert Sewald1

1Organic and Bioorganic Chemistry, Bielefeld University, Bielefeld, Germany. 2Physical Chemistry, Bielefeld University, Bielefeld, Germany.

3Organic Chemistry, Eötvös Loránd University, Budapest, Hungary.

Efficient biological antifreeze agents are crucial for survival in arctic and antarctic waters, where the temperature declines below the colligative freezing point of physiological fluids. One of these agents are classified as antifreeze glycoproteins (AFGP), which have been barely investigated due to problematic purification from natural sources and challenging synthesis of heavily glycosylated peptides.

AFGPs usually consist of a varying number of [AAT]n-repeating units (n=4-50), where every threonine side chain is glycosidically linked to β-D-galactosyl-(1-3)-α-N-acetyl-D-galactosamine. Although this pattern is highly conserved among different species, minor sequence mutations were found, e. g. substitution of alanine by proline. The antifreeze activity is usually proven by suppression of the recrystallisation and ice nucleation, thermal hysteresis and change of the crystal habitus. This antifreeze activity is influenced by certain properties, e. g. the N-acetyl group at the C2 position of the galactosamine, the α-configured glycosidic bond between the carbohydrate and the threonine residue as well as the γ-methyl group of threonine, what should be considered in synthesis.1 Furthermore it has been postulated that AFGPs adopt a threefold left-handed helix similar to a polyproline type II helix. The structure seems to be highly flexible and may changes significantly upon contact to the ice surface.

Such glycosylated peptides with varying sequences and lengths can be successfully obtained by solid phase peptide synthesis. The difficult synthesis of peptides, because of the heavy glycosylation, is efficiently performed upon HATU activation and microwave-assistance during the cycles.2,3

Synthetic AFGP analogs were examined by CD and NMR studies in water and DMSO at different temperatures. Furthermore the peptides were analysed microphysically according to their effect on ice recrystallisation, inhibitory activity and influence on the crystal habitus.4

References 1. Y. Tachibana, G. L. Fletcher, N. Fujitani, S. Tsuda, K. Monde, S. Nishimura, Angew. Chem. 2004, 116,

874-880. 2. C. Heggemann, C. Budke, B. Schomburg, Z. Majer, M. Wißbrock, T. Koop, N. Sewald, Amino Acids

2009, 38(1), 213-22. 3. L. Nagel, C. Plattner, C. Budke, Z. Majer, A. L. DeVries, T. Berkemeier, T. Koop, N. Sewald, Amino

Acids 2011, 41(3), 719-732. 4. C. Budke, C. Heggemann, M. Koch, N. Sewald, T. Koop, J. Phys. Chem. B 2009, 113, 2865-2873.

Poster 11


Helically Folded Capsules Based On Aromatic Oligoamide Foldamers For The

Recognition of Chiral Carboxylic Acids

G. Lautrette, Y. Ferrand and I. Huc*

Institut Européen de Chimie et Biologie 2, Rue Robert Escarpit - 33607 PESSAC - France

[email protected] A major trend both in chemistry and modern biology is the development of technologies that

widen the structural and functional diversity of folded biopolymers beyond naturally occurring patterns. Over the last ten years, foldamers – synthetic oligomers or polymers possessing well-defined, bio-inspired, folded conformations in solution – have fundamentally shifted our knowledge of biopolymer folding in showing that molecular backbones chemically remote from those that nature uses are also able to adopt folded secondary motifs such as helices, turns and linear strands.[1] More recently artificial tertiary and quaternary foldamer motifs have also been produced. Interest in foldamer research stems from the fact that, if protein and other biopolymer structures may be mimicked, their functions may be mimicked as well and even further expanded, paving the way to countless applications.

NN

O

H

δ-

δ-δ-

N

We have recently proposed a unique design of helically folded capsules based on sequences of aromatic amino-acids which code for a large helix hollow in the center and a narrow helix diameter at the end of the sequence (Figure above, right). Preliminary proof of concept has been made for polar and chiral guests.[2]

In this poster, we present a new generation of aromatic oligoamide foldamers that can encapsulate

and release sizeable chiral polar organic acid (eg. tartaric acid and malic acid), in a controlled fashion, using the helical design shown above. References [1] Hecht, S. M.; Huc, I. Foldamers : Structure, Properties and Applications; Wiley-VCH: Weinheim, Germany, 2007. [2] Y. Ferrand, A. M. Kendhale, B. Kauffmann, A. Grélard, C. Marie, V. Blot, M. Pipelier, D. Dubreuil, I. Huc, J. Am. Chem. Soc., 2010, 132, 7858–7859.

Poster 12


A Photoswitchable Foldamer for Anion Recognition

Lin Xue, Ying Wang and Hua Jiang*

Beijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Photochemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China

[email protected]

Artificial oligomers with well-defined conformation termed as foldamers represent a new

family of self-assemble supramolecular architectures in the past decade.[1] Considerable

advancement has been achieved not only on secondary structures, but on functions such as

recognition, chiral amplification, catalysis and molecular machines triggered by acid/base, light and

environment.[2] Recently, 1,2,3- triazole has been received much attention in many fields. One of

most appealing features of triazole is the large dipole moment in the ring (5D) that could be

engineered into foldamers. [3] Here, we present our recent discoveries on oligotriazole foldamers

driven by anions, particularly, foldamers acting as a photoswitch.[4]

References

[1] (a) Hecht, S; Huc, I. Foldamers: Structure, Properties, and Applications, Wiley-VCH Verlag GmbH, 2007. (b)

Huc, I; Jiang, H. Organic Foldamers and Helices, chapter in Supramolecular Chemistry: From Molecules to

Nanomaterials, Edited by Philip A. Gale and Jonathan W. Steed, Wiley, 2012.

[2] (a) Dolain, C., Maurizot, V., Huc, I. Angew. Chem. Int. Ed. 2003, 42, 2737. (b) Khan, A.; Kaiser, C.; Hecht, S.

Angew. Chem. Int. Ed. 2006, 45, 1878. (c) Ikeda, M.; Hasegawa, T., Numata, M., Sugikawa, K.; Sakurai, K.,

Fujiki, M.; Shinkai, S. J. Am. Chem. Soc. 2007, 129, 3739. (d) Goto, H.; Furusho, Y.; Yashima, E. J. Am. Chem.

Soc. 2007, 129, 109. (e) Q. Gan, Y. Ferrand, C. Bao, B. Kauffmann, A. Grélard, H. Jiang and I. Huc, Science,

2011, 331, 1172-1175.

[3] (a) Angelo, N. G.; Arora, P. S. J. Am. Chem. Soc. 2005, 127, 17134. (b) Juwarker, H.; Lenhardt, J. M.; Pham, D.

M.; Craig, S. L. Angew. Chem. Int. Ed. 2008, 47, 3740. (c) Meudtner, R. M.; Hecht, S. Angew. Chem. Int. Ed.

2008, 47, 4926. (d) Li, Y.; Pink, M.; Karty, J. A.; Flood, A. H. J. Am. Chem. Soc. 2008, 130, 17293. (e) Li, Y.;

Flood, A. H. J. Am. Chem. Soc. 2008, 130, 12111.

[4] (a) Wang, Y., Li, F., Han, M., Wang, F. Jiang, H. Chem.-A Eur. J. 2009, 15 (37), 9424. (b) Wang, Y; Bie, F; Jiang,

H. Org. Lett. 2010, 12(16), 3630. (c) Wang, Y., Xiang, J., Jiang, H., Chem.-A Eur. J. 2011, 17(2), 613-619.

Poster 13


Synthesis of pyrrole strands by electrochemical ring contraction of pyridazine precursors and applications

Christophe Aubé,a Virginie Blot,a Christine Thobie-Gautier,a Karène Urgin,b Sylvie Condon,b Eric

Léonel,b Yann Ferrand,c Ivan Huc,c Jacques Lebreton,a Muriel Pipeliera and Didier Dubreuila

a CEISAM, UMR 6230 - 2 rue de la Houssinière BP 92208 - 44322 NANTES - FRANCE

b ICMPE, UMR 7182 – 2 rue Henri Dunant – 94320 THIAIS - FRANCE c IECB, UMR 5248 – 2 rue Robert Escarpit – 33607 PESSAC – France

[email protected]

Aromatic nitrogen sequences containing pyridazine and pyrrole heterocycles are ubiquitous in a wide range of natural products and pharmaceutically relevant molecules. They also attract widespread interest because of potential applications in catalysis, molecular recognition and are belling in supramolecular chemistry. The introduction of these heterocyclic subunits is confronted, in both pyridazine and pyrrole series, to difficult chemical access due to multiple and versatile side reactions. Consequently, ring contraction of heterocycle precursors remains one of the most potent procedure to accede to pyrrole derivatives.[1] We thus have investigated an original soft alternative to produce a variety of pyrrolic sequences by electrochemical ring contraction of corresponding pyridazinic precursors.[2] Extension of the strategy consist in providing an efficient access to a variety of pyridyl-pyridazinic precursors, A and C, presenting α,α-linked or alternated sequences, prior to attempt electrochemical nitrogen extrusion leading to original pyridyl-pyrroles, B and D (Figure 1).[3,4]

N

N

N

N

N

N

spacer

R R

n

n

NH

N

HN

N

R R

electrochemical

reduction

n

n

N N N N

R RR N

HNH R

n

-poly-pyrroles

electrochemical

reduction

n

-poly-pyridazines bridged poly-pyridazines bridged poly-pyrroles

1 - Synthesis of oligopyridazine precursors

2 - Ring contaction to oligopyrroles by electroreduction

A CB D

spacer

Figure 1: Targets molecules and electrochemical process.

Pyridazine and pyrrole containing oligomers possess hydrogen bond donor and acceptors that make them good partners for self-organisation of foldamers presenting all important features to act as receptor mimics.[5] References: [1] H. Joshi, M. Pipelier, S. Naud, D. Dubreuil, Current Org. Chem. 2005, 9, 261.

[2] G.T. Manh, R. Hazard, A. Tallec, J.-P. Pradere, D. Dubreuil, M. Thiam, L. Toupet, Electrochemica Acta, 2002, 47, 2833.

[3] S. Sengmany, F. Polissaint, E. Léonel, J.-Y. Nédélec, M. Pipelier, C. Thobie, D. Dubreuil, J. Org. Chem. 2007, 72, 5631.

[4] A. Tabatchnik, C. Aubé, H. Bakkali, T. Delaunay, G. Thia Manh, V. Blot, C. Thobie-Gautier, Y. Ferrand, I. Huc, J. Lebreton, D. Jacquemin, M. Pipelier, D. Dubreuil, Chem. Eur. J. 2010, 16, 11876.

[5] Y. Ferrand, A. M. Kendhale, B. Kauffmann, A. Grélard, C. Marie, V. Blot, D. Dubreuil, I. Huc, J. Am. Chem. Soc. 2010, 132, 7858.

Poster 14


γγγγ-peptides indole substituted as a new type of antimalarials

Alba López-Ibáñez,a Daniel Carbajo, a Reto Brun, b Patricia Marin, c José M. Bautista, c Fernando Albericio, d and Miriam Royo a

aCombinatorial Chemistry Unit, Barcelona Science Park and CIBER-BBN, Networking Centre on

Bioengineering, Biomaterials, and Nanomedicine, Barcelona Science Park, b Swiss Tropical Health Institute, c Department of Biochemistry and Molecular Biology IV and Instituto de

Investigación Hospital 12 de Octubre, Universidad Complutense de Madrid,

d Institute for Research in Biomedicine, Barcelona Science Park, Department of Organic Chemistry University of Barcelona and CIBER-BBN, Networking Centre on Bioengineering, Biomaterials, and

Nanomedicine, Barcelona Science Park.

[email protected]

Recently, our group has described a new cell-penetrating-peptide family based on cis-γ-Amino-L-Proline moiety.[1][2] The peptides presented low cytotoxicity, high stability against proteases and medium efficiency to penetrate cell membranes. The library has been tested in vitro against different parasites, in the screening platform of the Swiss Tropical Health Institute. Two of these peptides gave possitive results against Plasmodium Falciparum in K1 strain and were re-evaluated in front 3D7A stain with an IC50 similar to chloroquine. Interestingly both of them have a very characteristic and similar structure based on the indole moiety. The therapeutic effect of one of these peptides is currently assayed in vivo by José M. Bautista laboratory. In the present work, we show the synthesis of a new family of 12 γ-peptides with the aim to explore diverse structural parameters hoping to find compounds with higher activity against P.Falciparum. The mechanism of action of those peptides that give activity will also be studied. These new peptides have been synthesised following the strategy previously described[1] that was modified when we needed. The mimetic side chains were introduced by reductive amination or amide coupling reactions into the α-amino groups giving the corresponding alkylated or amidated derivatives. Currently these new peptides are under biological evaluation.

Figure 1. Skeleton of γ-peptides indole substituted family. References [1] J. Farrera-Sinfreu, E. Giralt, S. Castel, F. Albericio, M. Royo, J.Am. Chem. Soc.; 2005; 127(26); 9459-9468. [2] J. Farrera-Sinfreu, L. Zaccaro, D. Vidal, X.Salvatella, E. Giralt, M. Pons, F. Albericio, M. Royo J. Am. Chem. Soc.; 2004; 126(19); 6048-6057

Poster 15


An activated building block for the introduction of the histidine side-chain in

aliphatic oligourea foldamers

Céline Douat-Casassus a, Yella-Reddy Nelli a, Paul Claudon a,b, Brice Kauffmannc, Claude Didierjean d and Gilles Guichard a

a Université de Bordeaux‒CNRS UMR5248, Institut Européen de Chimie et Biologie, CBMN, 2 rue Robert Escarpit, Pessac 33607, France

b CNRS, Institut de Biologie Moléculaire et Cellulaire, Laboratoire d’Immunologie et Chimie Thérapeutiques, Strasbourg 67000, France

c Université de Bordeaux‒CNRS UMS3033, Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, Pessac 33607, France

d CRM2, UMR-CNRS 7036, Groupe Biocristallographie, Université Henri Poincaré, BP 239, Vandoeuvre 54506, France

[email protected]

Histidine, with its (1H-imidazolyl-4yl)methyl side-chain is a remarkable amino acid in many

ways. Besides its intrinsic basicity, crucial to the catalytic properties of many enzymes, the ability of the imidazole ring to bind and coordinate metal ions is widely used to stabilize tertiary folds and helical structures.1 However, examples of peptidomimetic foldamers with His-type side chains at their surface are scarce.2 This can be ascribed in part to synthetic difficulties created by the basic and nucleophilic 1H-imidazole ring. With the aim to expand our arsenal of proteinogenic building blocks and to append His-type side chains at the surface of oligourea helices,3 we report the synthesis of a new N-Boc-protected monomer (1) which has been prepared in 7 steps from Trt-His(τ-Trt)-OMe.4 This protecting group combination on histidine was found to be critical to ensure efficient access to the requisite activated building block. The utility of this new monomer for the solid phase synthesis of several imidazole-containing oligourea foldamers has been demonstrated. Access to new oligourea sequences with His-type blocks at selected positions is likely to be useful for the design of more sophisticated foldamer architectures and will certainly contribute to expand the scope of their possible applications (e.g. metal ion recognition and/or catalysis).

References [1] Y. Lu, N. Yeung, N. Sieracki, N. M. Marshall, Nature 2009, 460, 855. [2] (a) F.Rossi, G. Lelais, D. Seebach, Helv. Chim. Acta 2003, 86, 2653; (b) G. Lelais, D. Seebach, B. Jaun, R. I.

Mathad, O. Flögel, F. Rossi, M. Campo, A. Wortmann, Helv. Chim. Acta 2006, 89, 361; (c) B.-C. Lee, T. K. Chu, K. A. Dill, R. N. Zuckermann, J. Am. Chem. Soc. 2008, 130, 8847.

[3] (a) J. Fremaux, L. Fischer, T. Arbogast, B. Kauffmann, G. Guichard, Angew. Chem. Int. Ed. 2011, 50, 11382; (b) L. Fischer, P. Claudon, N. Pendem, E. Miclet, C. Didierjean, E.Ennifar, G. Guichard, Angew. Chem. Int. Ed. 2010, 49, 1067.

[4] Y-R. Nelli, C. Douat-Casassus, P. Claudon, B. Kauffmann, C. Didierjean, G. Guichard, Tetrahedron, 2011, in press, dx.doi.org/10.1016/j.tet.2011.11.066.

Poster 16


Thermodynamic and Kinetic Stabilities of Complementary Double Helices Utilizing

Amidinium-Carboxylate Salt Bridges

Hidekazu Yamada,a Zong-Quan Wu,

a Takeshi Maeda,

b Kazuhiro Miwa,

a Yoshio Furusho,

a,b

Eiji Yashima a,b

aDepartment of Molecular Design and Engineering, Graduate School of Engineering,

Nagoya University, Chikusa-ku, Nagoya 464-8603, Japan bYashima Super-structured Helix Project, Exploratory Research for Advanced Technology

(ERATO), Japan Science and Technology Agency (JST), Japan

[email protected]

Naturally occurring biomacromolecules, such as proteins and DNA, fold into a unique and

characteristic helical structure, such as a single α-helix and a right-handed double helix,

respectively, which is of key importance, directing their sophisticated functions in living systems.

Inspired by their fascinating structures and highly exquisite functions, there has been significant

interest in the development of artificial helices. A modular strategy that we have recently developed

is a powerful tool for constructing complementary artificial double-stranded helices with a

controlled helicity, utilizing amidinium-carboxylate salt-bridge formations.[1]

This modular strategy

made it possible to prepare a series of novel complementary duplexes bearing a various kind of

linkages.

In this study, we prepared a series of amidine dimers ((R)-1–(R)-4) and their complementary

carboxylic acid dimers (5–8) with a various type of linkages, such as diacetylene, Pt(II)-acetylide,

and p-diethynylbenzene linkages by modular strategy, and their chiroptical properties on the double

helix formation ((R)-1·5, (R)-2·6, (R)-3·7, and (R)-4·8) and their thermodynamic and kinetic

stabilities were investigated.

Reference [1] Y. Tanaka, H. Katagiri, Y. Furusho, E. Yashima, Angew. Chem., Int. Ed. 2005, 44, 3867.


Poster 17


Double Helix Formation of m-Terphenyl-based Conjugated Polymer Bearing

Carboxylic Acid Groups and One-handed Helix Induction with Chiral Amines

Wataru Makiguchi, Shinzo Kobayashi, Yoshio Furusho, Eiji Yashima

Department of Molecular Design and Engineering, Graduate School of Engineering,

Nagoya University, Chikusa-ku, Nagoya 464-8603, Japan

[email protected]

We have recently reported that the m-terphenyl-based conjugated polymers bearing optically active

amidine groups and achiral carboxyl groups (poly-(R)-A and poly-C) assemble into a

predominantly one-handed double helix through amidinium–carboxylate salt bridges. [1, 2]

Here we report on the double helix formation of poly-C and the chirality induction on poly-C with

optically active amines. Poly-C self-associated to form a racemic homo-duplex through the

interstrand hydrogen bonding interaction of the carboxyl groups in the solid state, and the double-

helical structure was directly observed by high-resolution atomic force microscopy (AFM)

measurements of the two-dimentional crystals of the self-associated poly-C on a substrate.

Poly-C exhibited a characteristic induced circular dichroism (ICD) in the absorption region of the

p-diethynylbenzene linkage chromophores in the presence of chiral amines, indicating that poly-C

formed a chiral main-chain structure assisted by noncovalent interactions with the chiral auxiliaries.

Moreover, poly-C showed a positive non-linear effect between the Cotton effect intensities and the

enantiomeric excess of the chiral amine.

References [1] Y. Tanaka, H. Katagiri, Y. Furusho, E. Yashima, Angew. Chem., Int. Ed. 2005, 44, 3867.

[2] E. Yashima, K. Maeda, Y. Furusho, Acc. Chem. Res. 2008, 41, 1166.


Poster 18


Oligo(p-phenylenevinylene)-Peptide Conjugates in Water. Synthesis and Self-Assembly Properties

Alessandro Moretto,a Miriam Mba,a Lidia Armelao,b Marco Crisma,c Michele Maggini,a

Claudio Toniolo a

a Department of Chemistry, University of Padova, 35131 Padova, Italy¸ b ISTM-CNR, INSTM, Department of Chemistry, University of Padova, 35131 Padova, Italy; c ICB, Padova Unit, CNR,

Department of Chemistry, University of Padova, 35131 Padova, Italy. [email protected]

Molecular self-organization is a useful approach to prepare soft and flexible, functional micro- and nano-architectures. A practical principle to self-assemble structures is based on simple π-π tacking of π-conjugated oligomers. Self-assembly (SA) of functionalized oligo(p-phenylenevinylene)s (OPV), for instance, gives organogels with interesting photophysical properties and potential applications in light-emitting diodes and lightharvesting systems. However, organized, robust molecular structures are difficult to obtain by π-π stacking alone. Therefore, a variety of promoters able to establish additional noncovalent interactions, such as directional hydrogen bonds, have recently received increasing attention. Among them, peptide amphiphiles, made of a π-conjugated unit and hydrophilic peptide sequences, have been considered in view of their strong tendency to form well-defined secondary structures and to self-assemble in water.

In this work, we describe SPPS aspects and SA characteristics of two OPV-peptide conjugates (OPV-1 and OPV-2) in which a new OPV-based ω-amino acid has been incorporated in two different β-sheet forming sequences. In these systems, a reversible SA to a stable, fluorescent hydrogel was triggered by changing pH (Figure1).

Figure 1. Left: synthesis of peptides OPV-1 and OPV-2. Reagents and conditions: (i) NaH, THF, 25 ºC, 6h, 78%; (ii) Pd(OAc)2, triethylamine, tri(o-tolyl)phosphine, DMF, 90 ºC, microwave, 15 min, 63%; (iii) trifluoroacetic acid, CH2Cl2, 25 ºC, 2 h, then trimethylsilyl chloride, diisopropylethyl amine, 9-fluorenylmethylchloroformate, 24 h, 87%. Right: TEM images of self-assembled OPV-1 (A) and OPV-2 (B). In particular, the Orn-rich OPV-1 selfassembles at basic pH, whereas for OPV-2, which contains Glu residues, SA occurs at acidic pH. A detailed (TEM and AFM) analysis of SAs revealed the formation of complex networks in which helical fibers are present. [1] References [1] M. Mba, A. Moretto, L. Armelao, M. Crisma, C.Toniolo, M. Maggini, Chem. Eur. J. 2011, 17, 2044-2047.

Poster 19


Protein assembly and cellular targeting

via self-assembling columnar multivalent architectures

Katja Petkau-Milroy, Dana Uhlenheuer, Michael Sonntag, Thuur van Onzen, Luc Brunsveld*

Laboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of

Technology, Den Dolech 2, 5612 AZ Eindhoven, the Netherlands

[email protected]

Supramolecular chemistry has primarily found its inspiration in biological molecules, such as

proteins and lipids, and their interactions. Currently the supramolecular assembly of designed

compounds can be controlled to great extent. This provides the opportunity to combine these

synthetic supramolecular elements with biomolecules for the study of biological phenomena.[1]

Supramolecular elements can for example be ideal platforms for the assembly of proteins or for

targeting cells as on their self-assembled dynamic backbone multiple ligands can be displayed. A

multivalent system that can adapt its structure and the position of functional groups upon the

environment will enable an optimal binding to a cell surface.

In this work we show that supramolecular discotics can successfully self-assemble to a dynamic

multivalent architecture in water, displaying ligands at will at the periphery. The intrinsic

fluorescence of the discotics enables investigation with optical techniques such as fluorescence

microscopy or FRET. The functionalization of these molecules with bioactive ligands leads for

example to a strong binding to E. coli bacteria in a specific, selective and multivalent manner.[2]

Covalent and non-covalent attachment of proteins to this scaffold shows that these columnar

assemblies can act as platforms for directed and dynamic protein assembly.[3]

Additionally,

internalization of specifically functionalized discotics into the cell provides an entry to utilizing

these systems for supramolecular chemistry in the cell

440 460 480 500 520 540 560 580 600 620 640

0

100

200

300

400

500

600

Inte

nsity (

a.u

.)

Wavelenght (nm)

SS

S

SS

S

MIX

SS

S

S-

S-

I

II

Figure 1. I) Chemical structure of the 9NH2 Disc and its cellular uptake by HeLa cells. II) Discotics

functionalized with a benzylguanine moiety can be functionalized with fluorescent proteins and via

FRET the dynamic intermixing of the differently functionalized discs can be shown.

References [1] Uhlenheuer, D.; Petkau, K.; Brunsveld, L. Chem. Soc. Rev. 2010, 39, 2817.

[2] Müller, M.; Brunsveld, L. Angew. Chem. Int. Ed. 2009, 48, 2921.

[3] Müller, M.; Petkau, K.; Brunsveld, L. Chem. Commun., 2011, 47, 310.

Poster 20


A peptidic turn for metal ions coordination

S. Pires,a O. Iranzo,a

aInstituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. República, Estação Agronómica Nacional, 2780-157 Oeiras, Portugal

[email protected] One of the most important environmental issues nowadays is water contamination and among the rich diversity of pollutants, which affect water resources, heavy metals are one of the most common contaminants. These metals are extremely dangerous substances considering their strong toxicity at very low concentration for living organisms.[1] Over the years, it has been observed an increase of environmental contamination by these agents due to human activity. Therefore, different strategies have been developed to remediate heavy metals contamination from aqueous environments and are still being developed, since more effective and economical strategies are required.[2] Our aim is to design new chelating ligands for the removal of these metal ions from water. In this work, we will present the general design strategy of the ligand and the studies of its metal ion coordination properties using different spectroscopic techniques (UV-Vis, Raman, Perturbed Angular Correlation (PAC) and CD) and ESI-mass spectrometry. References [1] EPA, Drinking Water Contaminants - National Primary Drinking Water, Regulations

Available at: http://water.epa.gov/drink/contaminants/index.cfm# (Accessed 2011-12-15) [2] O.B. Akpor, M. Muchie, Int. J. Phys. Sci. 2010, 5, 1807.

Poster 21


Alkylidene malonamides and acetacetamides as intermediates for the preparation of

constrained dipeptide mimetics.

Alessandra Tolomelli, Luca Gentilucci, Angelo Viola

aDepartment of Chemistry “G.Ciamician”, University of Bologna, Via Selmi 2, 40126 Bologna, Italy

[email protected] On the basis of our previous experience in the synthesis of alkylidene malonates and acetoacetates,[1] we turned our attention to the microwave assisted Knövenagel reaction leading to alkylidene malonamides and acetoacetamides. In particular we prepared derivatives of α-aminoester, that may be envisaged as useful intermediates in the synthesis of constrained dipeptide mimetics. The presence of a reactive double bond offers indeed the opportunity to perform conjugate additions of nitrogen nucleophiles[2] or allylic substitutions on the corresponding reduced derivatives.[3] Through these protocols, novel structures containing an α-amino ester linked to a β-amino acid derivative have been obtained. These building blocks may be properly functionalized to mimick ligands of biologically relevant receptors or coupled to form oligomers, with the aim to verify their possible application as secondary structures inducers.

Figure 1. Selected examples constrained dipeptide mimetics prepared starting from alkylidene malonamides and acetacetamides. References [1] G. Cardillo, S. Fabbroni, L. Gentilucci, M. Gianotti, A. Tolomelli , Synt. Comm. 2003, 33, 1587-1594. [2] F. Benfatti, G. Cardillo, S. Contaldi, L. Gentilucci, E. Mosconi, A. Tolomelli, E. Juaristi, G. Reyes-Rangel

Tetrahedron, 2009, 65, 2478-2483. [3] G. Cardillo, A. Gennari, L. Gentilucci, E. Mosconi, A. Tolomelli, S. Troisi Eur. J. Org. Chem. 2009, 34, 5991-

5997.

Poster 22


Interaction of foldamers with the tumornursing protein galectin-1

Zsófia Hegedüs,a Edit Wéber,a Éva Monostori,b Tamás A. Martineka

aInstitute of Pharmaceutical Chemistry, University of Szeged, Hungary,bLymphocyte Signal Transduction Laboratory, Institue of Genetics Biological Research Center of the Hungarian

Academy of Sciences, Hungary

[email protected]

Galectin-1 (gal-1) is a β-galactoside binding protein, which recognizes glycoproteins through its carbohydrate binding site. Immunosuppressive and promotes tumor angiogenesis and metastasis, therefore inhibition of gal-1 would be a major therapeutic benefit.[1,2] Our goal was to design inhibitor candidate foldamers targeting gal-1, by their propensity to fold predictable, stable secondary structures.

β-peptide ligands were designed by molecular modeling, by using the X-ray and NMR solution structures of gal-1, and the assumed binding properties of a previously described angiogenesis inhibitor anginex. A β-peptide 14-helix was chosen as a template, with natural amino acid homologue monomers to ensure the specific binding to the target.

Ligands were synthesized via Fmoc solid phase peptide synthesis. To determine the binding location of the ligands NMR measurements were carried out. To calculate Kd values isothermal titration calorimetry (ITC) and ELISA measurements were performed. The 15N HSQC NMR titration data indicates, that one of the designed ligands interacts with the defined binding site of gal-1. ITC and ELISA methods shows that one of the foldamers exhibit Kd in the submicromolar range.

Figure 1. Model structures of foldamer-gal-1 complex References [1] Salatino, M.; Croci, D. O.; Bianco, G. A.; Ilarregui, J. M.; Toscano, M. A.; Rabinovich, G. A. Expert. Opin. Biol.

Ther. 2008, 8, 47-57. [2] Camby, I.; Le Mercier, M.; Lefranc, F.; Kiss, R. Glycobiology 2006, 16, 137R-157R

Poster 23


Targeting a TNF Receptor through Screening of On-Bead Foldamer Libraries

Neil W. Owens,a,b Karine Gionnet,a,b Katell Bathany,a,c Jean-Marie Schmitter,a,c Hinrich Gronemeyer,d Olivier Micheau,e,f Miriam Royo,g Fernando Albericio,g and Gilles Guicharda,b

aChimie et Biologie des Membranes et des Nanoobjets CNRS UMR 5248, Pessac, France, bInstitut Européen de Chimie et Biologie, Université de Bordeaux I, Pessac, France, cCentre de Génomique Fonctionnelle, Bordeaux, France, dInstitut Génétique de Biologie Moléculaire et Cellulaire, Illkirch, France, eInstitut National de la Santé et de la Recherche Médicale U866, Dijon, France, fUniversité

de Bourgogne, Dijon, France, gParc Cientific Barcelona, Barcelona, Spain

[email protected] The Tumor Necrosis Factor (TNF)-related apoptosis inducing ligand (TRAIL) has recently gained attention as a promising lead for the treatment of cancer because of its ability to selectively activate the apoptosis pathway in tumors in vivo without causing toxicity to healthy cells.[1] Recently the Guichard group has evaluated a smaller peptide analogue (TRAIL-M1c) that can, once dimerized, effectively, and potently replicate the apoptotic function of TRAIL in vitro through binding to one of its cognate receptors: DR5.[2] We have endeavored to expand on this work by identifying helical foldamers which can replicate TRAIL activity. After having optimized several parameters for the screening of on-bead ligands, including the resin and spacer type, the incubation parameters, and the fluorescent probe, several one-bead one-foldamer (OBOF) libraries were synthesized and screened against the DR5 receptor. The removal of false positives and isolation of beads that appear to bind to DR5 was accomplished using a fluorescence-activated flow cytometry sorter: the Complex Object Parametric Analyzer and Sorter (COPASTM) instrument. The identification of lead sequences is now underway through analysis of selected beads using tandem mass spectrometry (MS/MS). References [1] R. W. Johnstone et al. Nature Rev. 2008, 8, 782-798. [2] V. Pavet et al. Cancer Res. 2010, 70, 1101-1110.

Poster 24


Synthesis of 2:1[αααα/aza] pseudopeptidic macrocycles towards the design of nanotube

Zhou Zhou,a Jacques Bodiguel a, Régis Vanderesse, a Brigitte Jamart-Grégoire a

aLaboratoire de Chimie Physique Macromoléculaire, UMR 7568 CNRS-INPL, ENSIC, 1 rue Grandville 54001 Nancy cedex, France

[email protected]

During the past 10 years studies aiming at the design and synthesis of molecules able to self-assemble into supramolecular structures have received increased attention.1 A particular attractive system is the cyclic peptides which can lead to extended hollow tubular structures, so-called peptide nanotubes, by forming hydrogen bonds between amino acid residues of adjacent rings. Some of these nanotubes have been used in the transport of glucose2 or in transmembrane ion channels3 or even as potential antibiotics against drug-resistant bacteria.4

More recently, it has been found that cyclic pseudopeptides as, for example, cyclic oligoureas or mixed urea / amide5 can also form nanotubular structures. Some years ago, we described the synthesis of a new kind of linear 2:1-[α/aza]-oligomers.6 We report, here, structural investigations performed on the linear peptide Boc-(Phe-azaPhe-Ala)2-OMe and the corresponding cyclic hexapseudopeptide (Figure 1). Interestingly, the X-ray diffraction analysis of one of the 2:1[α/aza] pseudopeptidic macrocycle confirms its capacity to self-assemble into a nanotubular structure.

BocHN

O

Ph

NN

H

N

O

OMe

H OPh

HN

O

Ph

NN

H

N

O

H OPh2 2

Figure1. Mixed 2:1 [a/aza] Boc-(Phe-azaPhe-Ala)2-OMe linear and cyclic oligomer synthesis

Figure2. X-ray analysis of a self-assembling of cyclo[-Phe-azaPhe-Ala-]2 References (1) Desiraju, D. R. Nature 2001, 412, 397-400 (2) Granja, J. R.; Ghadiri, M. R. J. Am. Chem. Soc. 1994, 116, 10785-10786. (3) Clark, T. D.; Buehler, L. K.; Ghadiri, M. R. J. Am. Chem. Soc.1998, 120, 651-656. (b) Sanchez-Ouesada, J.; Isler, M. P.; Ghadiri, M. R. J. Am. Chem. Soc. 2002, 124, 10004-10005. (4) Fernandez-Lopez, S.; Kim, H.-S.; Choi, E. C.; Delgado, M.; Granja, J. R.; Khasanov, A.; Kraehenbuehl, K.; Long, G.; Weinberger, D. A.; Wilcoxen, K. M.; Ghadiri, M. R. Nature 2001, 412, 452-455. (5) Semetey, V., Didierjean, C., Briand, J. P., Aubry, A., Guichard, G. Angew. Chem. Int. Ed. 2002, 41, 1895-1898; Fischer, L., Decossas, M., Briand, J. P., Didierjean, C., Guichard, G. Angew. Chem. Int. Ed. 2009, 48, 1625-1628. (6) C. Abbas, G. Pickaert, C. Didierjean, B. Jamart-Grégoire, R. Vanderesse Original and efficient synthesis of 2 :1-[α/aza]-oligomer precursors Tetrahedron lett. 2009, 50, 4158-4160

Poster 25


Synthesis of pseudopeptidic macrocycles [αααα/αααα-Nαααα-hydrazino] towards the design of transmembrane channels

Ralph-Olivier Moussodia,a Samir Acherar a, Régis Vanderesse a, Brigitte Jamart-Grégoire a

aLaboratoire de Chimie Physique Macromoléculaire, UMR 7568 CNRS-INPL, ENSIC, 1 rue Grandville

54001 Nancy cedex, France

[email protected]

During an initial project developed within an ANR (Synthefoldame), we have identified a new family of foldamers, of which the backbone is enriched in nitrogen atoms, that are locally structured by short-distance hydrogen bonds. These compounds have conformational properties that enable efficient cyclisation. As short-distance intramolecular contacts within the cyclic molecules may be kept cyclofoldamers can be designed, i.e. macrocycles of perfectly defined conformation thanks to secondary structuration by hydrogen bonding. We expected that under favourable conditions, these components could give rise to nanotube formation, of chosen pore diameter, due to piling up (stacking) of cycles through π-π-stacking type interactions and/or intramolecular H-bonding. Studies were already performed in the lab in order to cyclise oligomers from a specific series NHN-R1 (with R1 = H). However, these have proved to be insoluble beyond the linear tetramer, thus avoiding a further cyclisation.

We showed that oligomer’s solubility in organic solvents can be considerably increased by introducing a benzyl group on the nitrogen (R1 = Bn). These compounds can lead to the corresponding cyclo-oligomers which were studied in order to analyse their conformation. X ray analysis allows us to confirm their nanotubular organization.

NH

NOMe

O

R2Boc

NO

R

H R1

NH

NO

R2

NO

R

H R1

**n

**n

Figure 1. Mixed 1:1 [a/a-Na-hydrazino] linear and cyclic oligomer synthesis

Figure 2. X ray analysis of self-assembling from the 1:1 [a/a-Na-hydrazino] cyclic tetramer References [1] Hoffmann, R.; Kim, H.O. Tetrahedron Lett. 1990, 31, 2953-2956. [2] Acherar, S.; Jamart-Grégoire, B. Tetrahedron Lett. 2009, 46, 6277-6279. [3] Moussodia, R.-O.; Acherar, S.; Bordessa, A.; Vanderesse, R.; Jamart-Grégoire, B. Tetrahedron 2011 (submitted).

Poster 26


Aza-ββββ3-peptidic macrocyclic foldamers: where is the limit of conformational homogeneity?

Philippe Le Grel, † Arnaud Salaün, †† Barbara Le Grel,†

†ICMV and CSM, UMR CNRS 6226, Université de Rennes I, 263 avenue du Général Leclerc 35042 Rennes Cedex, France. †† IECB, 2 rue Robert Escarpit 33607 Pessac, France.

[email protected] Aza-β3-peptides are pseudopeptidic foldamers. Their backbone organization relies on cooperative C8 pseudocycles where the nitrogen chiral atoms participate to H-bonding (figure 1). [1]

Yet, they are unusual, or borderline, foldamers because nitrogen pyramidal inversion (NPI) contributes to modulate permanently the shape of the folded oligomers (chiral sequence scanning). This H-bonding is maintained in aza-β3-macrocyclic structures. It follows that aza-β3-cyclotetrapeptides and aza-β3-cyclohexapeptides are confined into syndiotactic chiral sequences, the only compatible with such an uninterrupted H-bond network at these ring-size scales (figure 2). Furthermore, the conformational constraint slows down the NPI to unexpected levels. [2] The corresponding 16 and 24 membered rings are dynamic racemates which undergo a full reversal of chiral elements in a correlated manner, with rate constants depending on the bulkiness of the side chains (figure 3). Interestingly, full inhibition of the NPI can be obtained by introducing a single optically pure center inside the macrocycle.[3] The synthesis and conformational analysis of new compounds has been planed to determine if advantage can be taken from these conformational constraints in order to control the shape of larger aza-β3-peptidic macrocycles (from 32 to 48 membered rings) (figure 4).

O

NN

N

ONi+1

HN

O

H

N

Hi+2

N

OR R RN

H

OR

N-terminus C-terminus

Aza-β3-peptide

i

O

N N

O

HN

O

Hi HN

Oi+2

H

OR R R R

N-terminus C-terminus

L-β3-peptide

Figure 1 Figure 2

Figure 3 Figure 4

References [1] (a) Salaün, A.; Favre, A.; Le Grel, B.; Potel, M.; Le Grel, P. J. Org. Chem.; 2006; 71, 150. (b) C. Simo, A. Salaün,

C. Arnarez , L. Delemotte, A. Haegy, A. Kachmar, A.D. Lauren, J. Thomas, B. Jamart-Grégoire, P. Le Grel, A. Hocquet. J. Mol. Structure: THEOCHEM 869, 2008, 41.

[2] Le Grel, P. ; Salaün, A.; Potel, M.; Le Grel, B.; Lassagne, F.; J. Org. Chem.; 2006, 71, 5638. [3] Mocquet, C.; Salaun, A.; Le Grel, B.; Potel, M.; Guichard, G.; Jamart, B.; Le Grel, P. J .Am. Chem. Soc. 2009, 131,

14521.

Poster 27


Dihydropyridones as derivatives of unsaturated cyclic β-amino acids

Gunars Duburs, Rufus Smits, Zenta Kalme, Brigita Vigante Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia

[email protected]

NH

O

R1

R

O

OX

CH3 NH

CH3 CH3

OX

O

R

O

OX'

Figure 1.

3,4-Dihydro-2(1H)-pyridones are close relatives of 1,4-dihydropyridines which are 3,4-dihydropyridine vinylogs. 3,4-Dihydropyridones are cyclic acylated β-amino vinylcarbonyl compounds. Due to the partially hydrogenated azine character of the above mentioned compounds they can be oxidized to pyridones. The 2-pyridones possess interesting and useful pharmacological properties such as cardiotonic (e.g., amrinone, milrinone), reverse transcriptase inhibition of human immuno deficiency virus-HIV. 3,4-Dihydro-2(H)-pyridones have antioxidant activity.

The 3,4-dihydro-2(1H)-pyridone moiety can be used as a spacer to connect hydrophilic organic cations (pyridinium or triphenylphosphonium) with aliphatic chains (including highly fluorinated ones). Cationic amphiphiles possess self-assembly properties to form nanoaggregates. Their sizes have been characterized by atomic force microscopy and dynamic light scattering [1].

OO

CH3 CH3

O O

+OO

CH3 O(CF2)7CF3

+ PhCHO + NH4OAc

NH

O CH3

Ph

O

O

(CF2)7CF3

NH

O

Ph

O

O

(CF2)7CF3

Cat+

Figure 2.

Acknowledgement This study was supported by The Latvian National Research Programme 2010–2013 „Development of new prevention, treatment, diagnostics means and practices and biomedicine technologies for improvement of public health”.

References [1] R. Smits, Y. Goncharenko, I. Vesere, B. Skrivele, O. Petrichenko, B. Vigante, M. Petrova, A. Plotniece, G. Duburs, J.Fluorine Chem. 2011, vol. 132 , 414–419.

Poster 28


Exploring Foldamers Consisting of Quinoline and Natural Amino Acid

Mayumi Kudo,a, b Victor Maurizot,a Aya Tanatani,b Ivan Huc,a

aEuropean Institute of Chemistry and Biology, University of Bordeaux 1, Pessac Cedex 3360,

France, bOchanomizu University, Tokyo 112-8610, Japan [email protected]

The Helix is a key structural motif in natural biopolymers, such as proteins and DNA. By

analogy, a wide variety of synthetic oligomers folding into helical structures have been developed. In our group, we developed unique helical aromatic oligoamides in which hydrogen bonds between amide protons and the endocyclic nitrogens of adjacent aromatic rings determined stable conformations. For instance, oligoamides of 8-amino-4-isobutoxy-2-quinolinecarboxylic acid were synthesized and characterized to form helices that were wider, with a smaller helical pitch, and much more stable than those of peptides.[1] These helical oligomers currently attract much attention, since they feature advantageous properties such as high tunability and predictability.

We set to synthesize a new type of quinoline-derived oligoamides that consists of quinoline rings and of chiral aliphatic amino acids and to clarify the structures and properties of these quinoline-derived oligoamides in the crystal, and in various solvents.

At first, two types of sequences, (AQ)n (n = 1, 2, 4, 8) and (AQQ)n (n = 1, 2, 4) (Figure 1a), were synthesized by condensation reactions between aliphatic amino acid “A”, leucine in this case, and quinoline derivative “Q”, and the development of their efficient synthetic methods was achieved. Then, the structures of these compounds in solution were analyzed by using 1H NMR, UV and CD spectroscopy. For (AQ)n oligomers, the signals of amide protons shifted a little to lower magnetic field in CDCl3 upon increasing the length of AQ sequences, but oligomers (AQ)4 and (AQ)8 showed very weak CD signals in chloroform in 240-330 nm, which suggested that the conformations of (AQ)n oligomers were not helical. On the other hand, (AQQ)n oligomers showed interesting properties. 1H NMR spectra of (AQQ)2 and (AQQ)4 showed broadening peaks at room temperature, and the peaks separated to two kinds of signals by decreasing temperature, which indicated that there were two different conformations in solution. Furthermore, CD spectra showed strong cotton effects in chloroform, acetone, and acetonitrile (Figure 1b). Therefore, it can be said that (AQQ)n oligomers formed helical structures and the handedness were controlled by the configuration of the asymmetric carbon atoms. The detailed analysis of the helical structures of these oligomers will be discussed. a) b) Figure 1. a) Structures of (AQ)n and (AQQ)n oligomers. b) CD spectra of (AQQ)2 in acetonitrile (concentration; 6.06×10-5 M). References [1] E. R. Gillies, F. Deiss, C. Staedel, J. M. Schmitter, I. Huc, et al. Angew. Chem. Int. Ed. 2007, 46, 4081-4084.

Poster 29


DEVELOPING A NOVEL CLASS OF FOLDAMERS :

TOWARDS β-SHEET-LIKE STRUCTURES

L. Sebaoun, V. Maurizot, I. Huc

Institut Européen de Chimie et Biologie, Université de Bordeaux–CNRS UMR 5248, 2 rue Robert Escarpit, F-33607 Pessac, France.

[email protected] In recent years, many abiotic foldamers have been synthesized and characterized. These molecules can adopt folded architectures stabilised by non-covalent interactions and mimicking natural protein secondary structures. Although natural proteins are a wide source of inspiration for designing new architectures, the collection of described abiotic foldamers is less diverse than expected. Most of these foldamers display helical conformations whereas foldamers with β-sheet-like structures are still rare. In this context, we endeavored to expand foldamer diversity by developing a novel class of β-sheet-like architectures. The concept is to mimic the stabilization of β-strands, which occurs through a regular hydrogen bond network, by using inter-strand π-π aromatic stacking from aromatic oligoamide and oligoamine sequences. These sequences are connected by a U-shaped moiety that will create a turn and initiate the strand formation. These molecules are designed to adopt compact folded structures that can be studied in solution and in the solid state. Herein, we report our preliminary results in the design, synthesis and structural elucidation by X-ray crystallography of new aromatic oligomers. Optimization of U-shape moities and improvement of π-π aromatic stacking will be discussed by analysing experimental data.

Figure 1 : β-sheet-like Structures,

From Concept to Structural Elucidation by X-ray cristallography. References [1] S. Hecht and I. Huc, Foldamers : Structure, Properties and Applications, Wiley-VCH, Weinheim, 2007. [2] G. Guichard, I. Huc, Chem. Comm. 2011, 47, 5933. [3] V. Maurizot, S. Massip, J-M. Léger, G. Déléris, Chem. Comm. 2009, 38, 5698.

Poster 30


Subcelular localization studies of γγγγ-cell penetrating peptides based on (2S, 4S)-4-amino-L-proline

Daniel Carbajoa, Ximena Pulidoa, Elena Rebollob, Fernando Albericioc and Miriam Royoa

aCombinatorial Chemistry Unit, Barcelona Science Park, Universitiy of Barcelona, Josep Samitier 1-5, 08028- Barcelona, Spain, bAdvanced Fluorescence Microscopy Unit, Barcelona Science Park, Baldiri Reixac 15-21, 08028-Barcelona, Spain, cInstitute for Research in Biomedicine, Barcelona

Science Park, Baldiri Reixac 10-12, 08028-Barcelona, Spain, and Department of Organic Chemistry, Martí i Franqués 1, University of Barcelona, 08028-Barcelona, Spain

[email protected]

Recently, our group has described a family of cell-penetrating peptides based on (2S, 4S)-4-amino-L-proline [1] [2]. Based on this results, a second library of γ-cell-penetrating peptides was synthesized with the intention to improve the medium internalizing efficiency that the first family demonstrated. The cell-uptake properties of the newly synthesized peptides have been studied on HeLa cells by flow cytometry and some peptides showed internalization properties similar and even better than TAT peptide, considered a gold standard in the field. Additionally, the peptides showed low cytotoxicity and resistance to proteases. In the present work, we show the results of the confocal microscopy studies of the best three peptides selected from the second library, with the intention to confirm that the cell-penetrating peptides are located inside the cells -and not attached to the cell membrane- and to study their subcellular localization. The experiments were performed at different peptide incubation conditions with a variety of fluorescent labels that tagged cytoplasm, mitochondrias and lysosomes. The characteristics of the fluorescent objects detected were studied (e. g. size, number or sphericity). The results demonstrated that the peptides were clearly located inside the cells. No peptide fluorescence could be detected inside the nucleus or attached to the plasma membrane. Colocalization studies demonstrated that the peptides did not colocalize with mitochondria, but confocal microscopy images showed that the γ-peptides had colocalization with lysosomes.

Figure 1. Example of confocal image illustrating the internalization of the γ-peptide inside HeLa cells. Peptides are in green. Cytoplasm is marked in red. References [1] J. Farrera-Sinfreu, E. Giralt, S. Castel, F. Albericio, M. Royo, J.Am. Chem. Soc.; 2005; 127(26); 9459-9468 [2] J. Farrera-Sinfreu, L. Zaccaro, D. Vidal, X.Salvatella, E. Giralt, M. Pons, F. Albericio, M. Royo J. Am. Chem. Soc.; 2004; 126(19); 6048-6057.

Poster 31


Aromatic foldamers : a new Family of G-quadruplex ligands

T. Deschrijvera, Z. Donga, L. Delaurièrea, F. Goddea, J.-J. Toulméa, I. Huca

a Institut Européen de Chimie et Biologie, Université de Bordeaux – CNRS UMR 5248 et UMS3033,

2 Rue Roberts Escarpit, 33607 Pessac, France

[email protected] Guanine rich DNA sequences are known to fold into compact, four stranded structures, called G-

quadruplexes, in the presence of monovalent cations. They are found in the chromosomes termini

(telomeres) and in protooncogenic DNA (cancer related genes). The stabilization and binding of

these noncanonical DNA structures may inhibit cell growth of cancer cells. Therefore, any molecule

capable of stabilizing these sequences would be an anti-cancer drug candidate.

We herein present aromatic oligamide foldamers as a new family of G-quadruplex ligands.[1] They

have shown good affinity for human telomeric DNA and protooncogenes such as K-ras. The latter

is involved in pancreatic cancer, a “silent killer” for which few treatments are known. Even more,

side-chain selective, end-group selective, diastereoselective, and RNA- vs. DNA-selective

interactions have been revealed between these multiturn helical aromatic amide foldamers having

cationic side chains and G-quadruplex aptamers. [2] Their helical shape suggests a new, unique and

special interaction mechanism with G quadruplexes, making them even more interesting for anti-

cancer therapy development.

References [1] P. S., Shirude, E. R. Gillies, S. Ladame, F. Godde, K. Shin-ya, I. Huc, S. Balasubramanian, J. Am. Chem. Soc. 2007, 129, 11890. P. V. Jena, P. S. Shirude, B. Okumus, K. Laxmi-Reddy, F. Godde, I. Huc, S. Balasubramanian, T. Ha, J. Am. Chem. Soc. 2009, 131, 12522. [2] L. Delaurière, Z. Dong, K. Laxmi-Reddy, F. Godde, J.-J. Toulmé, I. Huc, Angew. Chem. Int. Ed. 2012, 51, in press.

Poster 32


Oligobenzamide α-helix mimetic scaffolds with controllable side chain spacing

Valeria Azzarito, a, b Stuart L. Warriner, a, b Andrew J. Wilson* a, b

a School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK

b Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK

[email protected], [email protected]

While it is generally known that many cellular processes depend on enzymatic reactions, in recent years there has been a growing interest in the role that protein-protein interactions (PPIs) play in the development of a large number of diseases. [1],[2],[3] The main goal in the design of proteomimetic inhibitors of PPIs is to use simple synthetic molecules which incorporate binding functionalities that mimic the exact spatial orientation of the desired secondary structure. In this context it has been shown that solvent exposed α-helices play a fundamental role in mediating many PPIs involved in cancer development. The binding with the protein partner involves key residues which are generally located on one side of the helix at the i, i + 4, i + 7 (8) positions. Because of the key role played in oncogenesis, considerable attention has been devoted to p53/hDM2 and Bcl-xL/BAK PPIs, which represent potential therapeutic targets. Our group is interested in using synthetic oligoamides[4] (foldamers)[5] as α-helix mimetics. The present poster will outline the design and synthesis of a new oligobenzamide scaffold possessing a 6-membered intramolecular hydrogen-bond and comparing its behaviour with our previously reported mimetic possessing a 5-membered intramolecular hydrogen-bond.[6] Preliminary screening against the p53-hDM2 PPI will also be disclosed.

Figure 1. Oligobenzamide proteomimetics: α-Helix and reproduction of the spatial positioning of helix side chains in the i, i +4 and i + 7 positions (middle); 3-O-alkylated aromatic oligoamide helix mimetic with 5-membered intramolecular hydrogen bond (left); new 2-O-alkylated aromatic oligoamide helix mimetic with 6-membered intramolecular hydrogen bond (right).

References [1] S. K. Sia, et al., "Short constrained peptides that inhibit HIV-1 entry," Proceedings of the National Academy of

Sciences of the United States of America, vol. 99, pp. 14664-14669, Nov 2002. [2] M. Sattler, et al., "Structure of Bcl-xL-Bak Peptide Complex: Recognition Between Regulators of Apoptosis,"

Science, vol. 275, pp. 983-986, February 14, 1997 1997. [3] P. H. Kussie, et al., "Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation

domain," Science, vol. 274, pp. 948-953, Nov 1996. [4] J. P. Plante, et al., "Oligobenzamide proteomimetic inhibitors of the p53–hDM2 protein–protein interaction,"

Chemical Communications, p. 5091, 2009. [5] I. Huc, "Aromatic Oligoamide Foldamers," European Journal of Organic Chemistry, vol. 2004, pp. 17-29,

2004. [6] J. Plante, et al., "Synthesis of functionalised aromatic oligamide rods," Organic & Biomolecular Chemistry,

vol. 6, p. 138, 2008.

Poster 33


Study of amino-acid-based Low-molecular-weight organogels and corresponding aerogels

F. Allix,a P. Curcio,a V. Felix,b D. Barth,c A. Degiovanni,b B. Jamart-Gregoirea

aLaboratoire de Chimie Physique Macromoléculaire, UMR 7568 CNRS-INPL, ENSIC, 1 rue Grandville

54001 Nancy cedex, France bLEMTA, Nancy-Université, CNRS, 2 avenue de la forêt de Haye, 54504, Vandoeuvre-lès-Nancy, France

cLRGP, Nancy-Université, CNRS, 1 rue Grandville, 54001, Nancy, France.

[email protected] A family of amino acid-type organogelators obtained via an easy and inexpensive way has been studied. We described first the solvent parameters study which let us to define a favourable narrow δh Hansen parameter domain for gelation including aromatic and chlorinated solvents. A comparative IR and NMR study of two LMWG based on aminoacid derivatives allowed to point out the hierarchy of the gelation assembly process. This type of organogels can be easily transformed into the corresponding aerogel by a supercritical CO2 drying process. Aerogels display noteworthy properties among them an extremely low thermal conductivity under vacuum. Finally, we finalize a three layers device method which allowed to measure the thermal conductivity as well as to estimate the different pore sizes of the aerogels.

References F. Allix, P. Curcio, P. Quoc Nghi; G. Pickaert, B. Jamart-Grégoire Evidence of Intercolumnar π−π Stacking

Interactions in Aminoacid-Based Low Molecular Weight Organogels. Langmuir (2010), 26(22), 16818-16827 P. Curcio, F. Allix, G. Pickaert, B. Jamart-Grégoire, Favourable Narrow δh Hansen Parameter Domain for Gelation of

Low-Molecular-Weight Amino Acid Derivatives Chemistry : A European Journal, 2011, Chem.201101423 Jamart-Grégoire Brigitte, Brosse Nicolas, Quoc Nghi Pham, Danielle Barth, Alexandre Scondo, Degiovanni Alain.

Utilisation d’aérogels pour la préparation de matériau pour isolation thermique INPL, Br. Fr. n°09/53363 du 20 mai 2009

Jamart-Grégoire Brigitte, Brosse Nicolas, Quoc Nghi Pham, Danielle Barth, Alexandre Scondo, Degiovanni Alain. Utilisation d’aérogels pour la préparation de matériau pour isolation thermique. PCT Int. Appl. (2010), WO 2010133798 A2 20101125.

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Documents

January 30 – February 2 2012 European Institute of ... 30 – February 2 2012 European Institute of Chemistry and Biology Bordeaux-Pessac, FRANCE BOOK OF ABSTRACTS Plenary lectures