Innovation and Perspectives in

OLID PHASESYNTHESIS& COMBINATORIAL LIBRARIES

Peptides, Proteins and Nucleic AcidsSmall Molecule Organic Chemical Diversicy

1998Editor: Roger Epton

Collected PapersFifth International SymposiumLondon, England, UK

Mayflower Scientific Limited, Birmingham, 1999

TABLE OF CONTENTS

Foreword v

Acknowledgements vi

Abbreviations xix

Lecture Presentations

1. From Small to Large Molecules: Versatility of OrthogonalLigation Chemistry 1J.P. Tarn and L. Zhang

2. Solid Phase Synthesis of "Head-to-Tail" Cyclic andC-Terminal Modified Peptides 7F. Albericio, A. Frieden, M. del Fresno, M. Royo,J. Alsina, K.J. Jensen, S.A. Kates and G. Barany

3. Solid Phase Synthesis of Heterocyclic Positional ScanningCombinatorial Libraries 11R.A. Houghten, C.T. Dooley, M.A. Giulianotti, V.T. Hamashin,C.C. Schoner, J.M. Ostresh and A. Nefzi

4. Solid Phase Synthesis of Peptide Aldehydes 15M. Paris, C. Pothion, A. Heitz, L. Rocheblave, F. Rouch,J-A. Fehrentz and J. Martinez

5.. Azido AcidsTn a Novel Method of Solid Phase Synthesis 19M. Meldal, C. Tornoe, U. Tedebark, A.M. Jannson,M.A. Juliano, L. Panza and L. Lay

6. Improved Supports and Methods for Solid PhaseMediated Transformations 23J.H. Adams, R.M. Cook, D. Hudson, V. Jammalamadaka,M.H. Lyttle and M.F. Songster

7. Handles for Solid Phase Chemistry: Progress from Peptideto Small Molecule Synthesis ^ 31C. Blackburn, G, Barany, F. Albericio and S.A. Kates

8. Solid Phase Synthesis of Oligosaccharides via GlycalDerived Thioethyl Glycosyl Donors 39P.H. Seeberger, C. Zheng andS.J. Danishefsky

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9. Techniques for Massively Parallel Synthesis of SmallOrganic Molecules 43M. Lebl and V. Krchnak

10. A Novel Modular Synthesis Strategy for AutomatedSynthesis of Small Organic Molecules 47W. Rapp and W. Karn brock

11. Automated Liquid-Phase Biopolymer Synthesis 51A. Bagno, S. Bicciato, C. Di Bello and G.M. Bonora

12. Solid Phase Synthesis of New Galanins and Galanin Segments:Structure-Activity Relationships 55L. Baldspiri, T. Jandky, Z. Tegyei, F. Krajcsovits, G. BlazsoT. Takdcs and P Kdsa

13. Solid Phase Synthesis of Peptide Nucleic Analogue (PNA)Sequences Taken to New Lengths 59Y.M. Angel, K.J. Jensen, CM. Gross and G. Barany

14. ' Scaling-up Procedure for Continuous Flow SPPS 63V. Caciagli, F. Cardinali, A. Sisto and P. Lombardi

15. High-Throughput Synthesis of FunctionalisedOligonucleotides 67A. Andrus, S.Cox, S. Beavers, A. Parker, J. Anuskiewiczand B. Mullah

16. Chemical Synthesis of Branched Oligodeoxyribonucleotides(bDNA) for Use in Nucleic Acid Quantification Assays 71T. Horn, C-A Chang and M.S. Urdea

17. Organic Synthetic Methodology Extensions Forgottenin Peptide Synthesis 75Ch. Birr

18. Current Strategies for Disulfide Bridge Formation inSynthetic Peptides and Proteins 85G. Barany, Y.M. Angel, 1. Annis, L. Chen,CM. Gross and B. Hargittai

19. Synthesis and Folding Properties of Selenocystine-Containing Peptides 89S. Pegoraro, D. Besse, S. Fiori, S. Rudolph-Bohner,T.X. Watanabe, T. Kimura and L. Moroder

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20. New Developments in Hybridisation-based DNAScreening on Oligomer Arrays 93J. Weiler, S. Matysiak, H. Gausepohl andJ.D. Hoheisel

21. Light-directed Synthesis of High-density OligonucleotideProbe Arrays for Nucleic Acid Sequence Analysis 97G.H. McGall, A.D. Barone, J.E. Beecher, M. Diggelman,S.P.A. Fodor, M.J. Goldberg, N. Ngo andR.P. Rava

22. Translation of an Electrochemically-addressed DNA-Chipinto an Immunosensor via Peptide- or Antibody-Oligonucleotide Conjugates 101H. Bazin and T. Livache

23. Highly Efficient Preparation of 7KDa Peptides by theAssembly of Single Coupling without CappingFollowed by a Single Step of Purificationby Reverse-phase HPLC 105K. Nokihara and T. Yasuhara

24. Purification of Synthetic Polypeptides by ImmobilizedMetal Affinity Chromatography and Methionine Chemistry 111M.A. Roggero, C. Servis and G. Corradin

25. Peptide-Peptide, Peptide-Metal, Peptide-Protein InteractionStudy in Solution by NILIA-CD Spectroscopy 115G. Siligardi and R. Hussain

26. Solid Phase Syntheses of 5-Aminopyrazoles 119S.P. Watson and R.D. Wilson

27. Strategies for Rapid Generation of Small MoleculeLibraries on Solid Support 123J. Perumattam, S. Chakravarty and G. McEnroe

28. PhSiH,/Palladium Catalyst/Carboxyactivated Aminoacids:A Ternary System for Tandem Deprotection Coupling ofNa-Allocaminoacids and Suppression ofDKP Formation in SPPS 127N. Thieriet, J. Alsina, M. Dessolin, M-G. Guillerez, E. Giralt,F. Albericio, A. Loffet and F. Guibe

29. Homodetic Cyclic Peptides via Solid Phase Synthesis 129C. Blackburn and S.A. Kates

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30. Solid Phase Synthesis of Cyclosporins Involving On-Resinand Solution Cyclizations 135Y.M. Angell, P. Raman, G.R. Flentke and D.H. Rich

31. A Comparison of Solid Supports for PNA Synthesis 139R.A. Casale, C.H. Paul, l.S. Jensen, M.L Moyer,S.A. Kates and M. Eg holm

32. A Stem Peptide Carrier for Immunogenic Presentationof Peptides 143P.M.H. Heegaard, Y.S. B0g, P.H. Jakobsen and A. Holm

33. An Antibody Mimic Engineered by Combining TwoIndependent Functions in a 37-A A Miniprotein 147C. Vita, E. Drakopoulou, J. Vizzavona, J. Neyton,E. Bianchi and A. Pessi

34. Solid Phase Synthesis of Lipoamino Acid- and Carbohydrate-Modified Peptide Entities 151B. Kellam, B. Drouillat, G. Dekany, N. Flinn,M.S. Starr and 1. Toth

35. Scaffolded Peptide Combinatorial Libraries 155J. Eichler and R.A. Houghten

36. Positional Scanning Combinatorial Libraries:How and Why Complex Mixtures Work 159C. Pinilla, J.R. Appel and R.A. Houghten

37. Design of Catalytic Mimics for the Decarboxylation ofOxaloacetate Using Synthetic Combinatorial Libraries 163S.E. Blondelle, E. Takahashi, B.L.Robles,R.A. Houghten and E. Perez-Payd

38. Selection of Human Elastase Inhibitors from a Conformationally-Constrained Combinatorial Peptide Library 167J.D. McBride, N. Freeman and R.J. Leatherbarrow

39. Multiphosphorylated Synthetic Peptides as Antigensand Immunogens in Alzheimer's DiseasePaired Helical Filaments 173L. Otvos, Jr., V.M-Y. Lee, S. Leight, P. Davies,I. Varga and R. Hoffmann

40. Characterization of fS-Secretase Using Antibodies Specificto the Released N-Terminus of P-Amyloid 177B.M. Austen, E.R. Frears and D.J. Stephens

41. Predicted Three Dimensional Structure for Fib,Fibrinogen Binding Protein of Staphylococcus aureus 181D. Wade, J-l. Flock, K. Berndt, S. Galaktionovand G. V. Nikiforovich

42. Protein-like Molecular Structure: Synthesis and Applicationfor Inducing Cellular Receptor Binding and SignalTransduction 185J.L. Lauer and G.B. Fields

43. A New Fluorophore for Peptide Labelling: Synthesis andAnalysis of its Interaction with Interleukin-6 Receptor 189Sz. Bosze, Gy. Koczdn, G. Csi'k, A. Falus and F. Hudecz

44. Synthesis and Receptor Binding Activity of Analogues andFragments of Human Melanin-concentratingHormone (MCH) 193E. Hintermann, R. Drodz, H. Tanner and A.N. Eberle

45. Using the Copper-catalyzed Benzidine Blue Reaction for theDetection of Binding of Hexahistidine-tagged Proteins andPeptides to Combinatorial Library Beads 197R. Liu, R. Sherlock and H.P. Nestler

46. From Liquid Phase Multicomponent Reactions toSolid Phase Libraries 201/. Ugi, A. Dbmling, B. Gruber, S. Heckand M.Heilingbrunner

47. New Methods for Encoding Combinatorial Libraries 205T.J. Sowin, J.E. Hochlowski and A-L. Grillot

48. Solution Synthesis of Heterocyclic Libraries: NucleophilicAromatic Substitution and Automated Solid SupportedLiquid-Liquid Extraction 209C.R. Johnson, B. Zhang, P. Fantauzzi, M. Hocker and K. Yager

49. Design and Synthesis of Novel Src Homology-2 DomainInhibitors 211R.J. Broadbridge, R.P. Sharma and M. Akhtar

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50. Pentafluorophenyluronium Reagents and Allylic AnchoringGroups in Solid-Phase Glycopeptide Synthesis 217J. Habermann and H. Kunz

51. Coupling of Highly Hindered Systems Using ProtectedAmino Acid Chlorides 221P. Henklein, D. lonescu, A. El-Faham, H. Wenschuh,M. Bienert, LA. Carpino and M. Beyermann

52. Solid Phase Synthesis of O-Boranophosphopeptidesand O-Dithiophosphopeptides 225K.E. Jenkins, A.P. Higson, P.H. Seeberger and M.H. Caruthers

53. Solid Phase Synthesis of KDEL Peptides Labelled withFluorophore and/or Bifunctional Chelating Agentfor Receptor Localisation 229l.B. Nagy, M. Mdk, 1. Varga, J. Kovdcs, E. Fellingerand F. Hudecz

54. A Novel Purification Protocol for Soluble CombinatorialPeptide Libraries 231H.R. Swenson, K. Shaw and R. Ramage

55. Use of Tetrabenzo[a,c,g,i] fluorene as an Anchor GroupTowards the Synthesis of Ciprofloxacin' 235A.M. Hay, S. Hobbs-Dewitt, D. Leonard, A.A. MacDonaldand R. Ramage

56. A Novel Chemically Robust Amine Releasing Linker 239C. Kay, P.J. Murray, L. Sandow and A.B. Holmes

57. Parallel Solution Phase Synthesis of a Small ChemicalLibrary Based on a Carbohydrate Analogueas a Chiral Scaffold 243C. Rosenbohm and J. Wengel

Poster Presentations

58. Minimization of Cysteine Racemization During StepwiseSolid Phase Peptide Synthesis 247Y.M. Angel, Y. Han, F. Albericio and G. Barany

59. Mild Solid Phase Reagents for Facile Formation ofIntramolecular Disulfide Bonds in Peptides and Proteins 249/. Annis, L. Chen and G. Barany

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60. The ATP Binding Site of DNA Topoisomerases II - Designof New Inhibitors 253L. Assairi

61. Flexible Approaches for High Speed Synthesis:A Multiple Platform Strategy 257B. Bankaitis-Davis, G. Beaton, K. Bjergarde, W. Callaway,A. Cook, M. Curtis, C. Herrera, L. Huang, J. Josey,M. Munson and C. Tarlton

62. PNA on Particles for DNA Capture 259F. Beck, K. Adelhorst, K.H. Petersen, L. Winterand J. Farmer

63. PEG Polymer Supported Liquid Phase Parallel Synthesisof Suzuki and Heck Products 263C.G. Blettner, T. Schotten, W. Stenzel and W.A. Kbnig

64. Synthesis and Characterization of Very Short Peptide-Oligonucleotide Conjugates Used for the Transportof Antisense Oligonucleotides 267P. Bondardt, M. Gerster and E. Bayer

65. Mapping of Conformational B Cell Epitopes withina- Helical Coiled-Coil Proteins 271J.A. Cooper, H. Kagawa and A. Saul

66. Applications of CLEAR Resin for Solid Phase OrganicSynthesis: Comparison with Polystyrene Based Resin 275K. Darlak, C. Narayana and A. Spatola

67. Inhibitory Specificity Spectrum of Peptide oc-AmylaseInhibitors Designed by Limited Combinatorial Libraries 277L Dole&ovd, M. Pavlik, M. Mares and I. Kluh

68. The 5-Phenyl-5H-dibenzo[a,d]cyclohepten-5-yl (Pdbs) andthe 5-Anisyl-5H-dibenzo[a,d]cyclohepten-5-yl (Adbs) Residues:Two New Protecting Groups for the Nim-Function of Histidine 279H. Echner and W. Voelter

69. a-Hydroxymethacrylic Acid in Solid Phase Synthesis: AnExtremely Nucleophile Sensitive Linker 283H-M. Eggenweiler, N. Clausen and E. Bayer

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70. Practical Synthesis and Application of a B-Turn Mimeticfor SPPS 287I.M. Eggleston, C. Peggion, J.S. Svendsen and M. Mutter

11. Assembly of Two Cysteine-containing Peptides that Mimicthe Primary Structure of the Channel-like Domains ofRabbit Uteroglobin Induces Spontaneous SelectiveHeterodimerization 291T. Ferrer, E. Nicholas and E. Giralt

72. The Synthesis, Melting Studies and Primer Extension Assayof PNA/DNA Chimeric Oligomers 293P.J. Finn, C.L. Smith, R.A. Fallon, A.L. Hamilton and T. Brown

73. Motif-Scanning: A Combinatorial Randomization Approachfor the Elucidation of Key Residues in Linear Epitopes 295R. Frank

74. Influence of Palmitoylation and Conjugation to BranchedPolypeptide Carriers on the Interaction of HAV-VP3(101-121)Synthetic Peptide with Phospholipid Bilayers 297M. Garcia, F. Hudecz, F. Reig, G. Mezo, M.A. Alsina and I. Haro

75. A Novel Solid Phase Extraction System for OligonudeotidesUsing Cationic Nanoparticles 301M. Gerster, M. Maier, J. Schewitz, H. Fritz and E. Bayer

76. Suspension 3IP-NMR as a New Method to CharacterizeAntisense Oligonudeotides 305U. Gb'tz, M. Raitza, K. Albert and E. Bayer

11. Solution Structure of Uronium and Phosphonium Salts 309P. Henklein, C. Miigge, B. Costicella, V. Wray, T. Domke,A. El-Faham, Y. Lee, S.A. Kates and L.A. Carpino

78. Optimization of Synthesis and DNA Hybridisation ofPeptide Nucleic Acids 311R. Hoffmann, H.C.J. Ertl, A.M. Pease, G. Rovera and L. Otvos, Jr

79. Solid Phase Peptide Synthesis Using 2-(4-Nitrophenyl)sulphonyl-ethoxycarbonyl(NSC) Amino Acids for Salmon Calcitonin 315Y-D. Kim, B-K. Cho, J-l. Park, S-H. Lee and H-J. Kim

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80. Introduction of Different Methoxy-substituted 9-Phenyl-9-fluorenylamine Linkers: Mildly Cleavable AnchoringGroups for the Synthesis of Peptide Amides 319H-J. Kohlbau, M. Meisenbach, H. Echner and W. Voelter

81. Influence of Hydrophilic Amino Acids on the Ion ChannelActivity of Alamethicin 323C. Kaduk, M. Dathe and M. Bienert

82. Synthesis and Structure of a-Helical Model Of Aib-Peptides 325H. Kodama, Y. Higashimoto, T. Hara, H. Yamaguchi,M. Jelok-Niaraki and M. Kondo

83. PNA: Synthesis and Use for Nucleic Acid Purification 329T. Koefoed, M. Borre, M. Naesby, H. 0rum and T. Koch

84. The Synthesis of Surface Grafted Polystyrene Resins withPolyethylene Glycols Using Ozone Oxidation andTheir Application in Enzyme Immobilization 333Y-S. Lee, Y. Wang and J-W. Byun

85. Design, Synthesis and Characterization of a Beta-turnMimic Library 335R.W.A. Luke and P.G.T. Boyce

86. Fmoc-Lys(Mmt)-OH: A Convenient Building Block forthe Preparation of Branched and Cyclic Peptides 339S. Matysiak, T. Boldicke, W. Tegge and R. Frank

87. Functional Requirement for Threonine in the P2 Positionof a Cyclic Peptide Mimetic of a Bowman-BirkProteinase Inhibitor 341J.D. McBride, A.B.E. Brauer, M. Nievo and R.J. Leatherbarrow

88. Methoxy Substituted 9-Phenylxanthenylamine Linkers:Useful Tools for the Solid Phase Synthesis ofProtected Peptide Amides 345M. Meisenbach, H. Echner, H-J. Kohlbau and W. Voelter

89. A General Method for N to C Terminal Solid Phase SynthesisApplied to Bioactive Peptidic Boronates 349S.A.M. Merette, D. Green, G. Patel, M.F. Scully,V.V. Kakkar and J J. Deadman

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90. Polymeric Diphenyldiazomethane: A Useful Resin for SPPSand Solid Phase Organic Chemistry 351M. Mergler and R. Nyfeler

91. Application of Cyclohexyloxycarbonyl Protecting Group in BocChemistry for the Synthesis of Protected Peptide Fragment 355G. Mezo, N. Mihala, G. Koczdn and F. Hudecz

92. A New Generation of Reversible Backbone Amide Protection 357J. Offer, M. Quibell and T. Johnson

93. Synthesis of Phosphorothioated Oligonudeotides Using3-Ethoxy-l,2,4-dithiazolin-5-one (EDITH) 361C. Paul, H. Rastogi, B. Dooley, A. Wolter, S. Purkayastha,Q. Xu, L. Chen, K. Musier-Forsyth, R.P. Hammerand G. Barany

94. Asparagine as Racemization Sensitive Site in Analogs ofNeurohypophyseal Hormones 365

Z Pdnek, M. Pavlik and M. Flegel

95. Using 2-Chlorotrityl Resin Tactics for the Preparation ofDABCYL-EDANS Derivatized Peptides: Application toa Fluorogenic Substrate for an Aspartyl Proteinasefrom Human Malaria Parasite 367M.W. Pennington, P. Baur, J. Westling and B.M. Dunn

96. Angiotensin and Thrombin: Is there a Bioregulatory Similarity? 371L Polevaya, J. Matsoukas, D. Vlahakos, I. Mutule,R. Vitolina and V. Klusa

97. New Methods for the Rapid Derivatization and Cleavage ofSolid Phase Supports for Oligonucleotide Synthesis 373R.T. PonandS. Yu

98. Discovery of a Novel Gyrase Inhibitor by Combinatorial SolidPhase Synthesis of 1,2,3,4-Tetrahydro-B-carbolines 377T. Redemann, M.E. Brooks and G. Jung

99. Formation of Ally lie Alcohols via Baylis-Hillman Reactionfor the Synthesis of Isoxazolines 381H. Richter, A. Hb'tzel and G. Jung

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100. Sanger's reagent: An Excellent End-Capping and/orLabeling Agent for SPPS 385M. Rinnovd, M. Soucek, Z. Voburka, M. Lebl and M. Fusek

101. Development of an Automated System for the MultipleParallel Production of Synthetic Oligonudeotides 387O. Schreuer, S. Matysaik, G. Panke, R. Frank, S. Taudien,A. Rosenthal and H. Gausepohl

102. Convergent Solid Phase Synthesis of Immunoglobulin-likeDomains of Macrophage Specific Fc Receptor (FcyRI) 391J.M. Sheridan, G. Hayes and B.M. Austen

103. A Synthetic Approach for a SAR Study of the Pro- andArg-rich Bactenecin Bac 7 395B. Skerlavaj, M. Scocchi, A. Tossi, D. Romeo and R. Gennaro

104. Contribution of Solid Phase in Antibody Binding Activityof Synthetic Peptides 399J.W. Slootstra, W.M.M. Schaaper, W.C. Puijk, G.J. Ligtvoet,D. Kuperus and R.H. Meloen

105. Covalent Coupling of HAV-VP3(110-121) Peptide Sequenceto Liposomes: Effect on CD Peptide Spectra 401A. Vea, M.J. Gomara, F. Reig and I. Haw

106. Synthetic Glycopeptide Dendrimers with Tn AntigenicStructure: Immunobiological Study - II 405J. Velek, J, Jeiek, P. Veprek, V. Velkovd, T. Trnka,J. Pecka and M. Pisaca

107. High-affinity Non-inhibitory Ligands for Alkaline PhosphataseRevealed from a Restricted Heptapeptide Library 407S. Vetter

108. Antibiotic Activity of a Synthetic Cecropin-Melittin Hybrid' Peptide on Anaerobic Bacteria . 411

D. Wade, C. Edlund, A. Engstrom, M. Hedberg and J-I. Flock

109. Fibrinogen Binding Sites of the Staphylococcus aureusFib Protein 413D. Wade, M. Sdllberg, J. Silberring and J-I. Flock

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110. Transfer Active Ester Condensation: A Novel TechniqueUsed for PeptideSegment Coupling 415P. Wang, M. Langdon, R. Layfield, R.J. Mayer and R. Ramage

111. Preliminary Studies Towards the Solid Phase Synthesis ofCyclic Natural Product Analogues 417C.J. Welch and J. Fick

Author Index 421

Subject Index 427

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