Margaréta VOJTIČKOVÁ under the direction of: Assoc. Prof. Andrej BOHÁČ Dr. Gilles HANQUET 27 th...
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- Slide 1
- Margarta VOJTIKOV under the direction of: Assoc. Prof. Andrej
BOH Dr. Gilles HANQUET 27 th September 2013, Strasbourg
- Slide 2
- Summary 1) Introduction 2) Angiogenesis 3) Aim of the project
4) Study towards target ynamides 5) Azides 6) Click Chemistry 7)
Biological assays 8) General conclusion 2 IntroductionAngiogenesis
Aim of the project YnamidesAzides Click Chemistry Biological assays
General conclusion
- Slide 3
- Introduction WHO: Cancer is uncontrolled growth and spread of
cells Cancer leading cause of mortality 7.6 million dead people in
2008 (13 % of all deaths) neccessity to develop new active
compounds for cancer treatment 3
- Slide 4
- Angiogenesis 4
- Slide 5
- Aim of the project PDB: 1Y6A tyrosine kinase complex prepared
in low ca 10 % yield over 5 steps sensitive N-aryloxazole-2-amine
group 5 Harris, P. A.; Cheung, M.; Hunter, R. N.; Brown, M. L.;
Veal, J. M.; Nolte, R. T.; Wang, L.; Liu, W.; Crosby, R. M.;
Johnson, J. H.; Epperly, A. H.; Kumar, R.; Luttrell, D. K.;
Stafford, J. A. J. Med. Chem. 2005, 48, 1610.
- Slide 6
- 1,3-oxazole / 1,2,3-triazole replacement (me-too or me-better)
exchange of heterocyclic core: activity and/or selectivity higher
stability synthetic feasibility better physical and chemical
properties for bioavailability lower toxicity inhibitor novelty
6
- Slide 7
- Predicted 1,2,3-triazoles interaction analysis, molecular
modelling, docking 7 triazolic analogues of PDB : 1Y6A Discovery
Studio Visualizer 3.5 software Drug like properties prediction
toolkit Molinspiration 7 http://www.rcsb.org/pdb/home/home.do
http://accelrys.com/products/discovery-studio/visualization-download.php
Molinspiration Property Calculation Service
http://www.molinspiration.com/cgi-bin/properties
1,4-regioisomers
- Slide 8
- docking scores and ligand possess in VEGFR2 are less
interesting significantly higher price of ruthenium catalyst 8
1,5-regioisomers
- Slide 9
- Retrosynthetic approach 9
- Slide 10
- Ynamides Literature background 10 chemistry of ynamides
exploded in last decade heteroatom-substituted alkynes ynamines
unstable, the firts report in 1892 ynamides right balance between
stability and reactivity Bode, J. Liebigs Ann. Chem. 1892, 267,
268. DeKorver, K. A.; Li, H. ; Lohse, A. G. ; Hayashi, R. ; Lu, Z.
; Zhang, Y. ; Hsung, R. P. Chem. Rev. 2010, 110, 5064. Evano, G. ;
Jouvin, K.; Coste, A. Synthesis 2013, 45, 17.
- Slide 11
- Ynamides Literature background - preparation first synthesis of
electron deficient ynamines Viehe, 1972 Zhdankin & Stang, 1994
synthesis of ynamines using alkynyl iodonium triflate / tosylate
salts 11 Janousek, Z. ; Collard, J. ; Viehe, H. G. Angew. Chem.
Int. Ed. 1972, 11, 917. Murch, P.; Williamson, B. L.; Stang, P. J.
Synthesis 1994,1255. Kitamura, T.; Tashi, N.; Tsuda, K.; Fujiwara,
Y. Tetrahedron Lett. 1998, 39, 3787.
- Slide 12
- expansion of chemistry of ynamides Witulski, Rainer 12
Witulski, B.; Stengel, T. Angew. Chem. Int. Ed. 1998, 37, 489.
Witulski, B.; Gmann, M. Synlett 2000, 1793. Witulski, B.; Stengel,
T. Angew. Chem. Int. Ed. 1998, 38, 2426. Witulski, B.; Stengel, T.;
Fernandez-Hernandez, J.M. Chem. Commun. 2000, 1965. Witulski, B.;
Alayrac, C. Angew. Chem. Int. Ed. 2002, 41, 3281. Rainier, J. D.;
Imbriglio, J. E. J. Org. Chem. 2000, 65, 7272. Rainier, J. D.;
Imbriglio, J. E. Org. Lett. 1999, 1, 2037.
- Slide 13
- Elimination protocols Zemlicka, 1994 preparation of ynamides
via lithium-halogen exchange Brckner, 2000 preparation of ynamides
from formamides via lithium- halogen exchange 13 Brckner, D.
Synlett 2000, 1402. Brckner,D. Tetrahedron 2006, 62, 3809. Yang, B.
H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125.
- Slide 14
- Direct N-alkynylation using bromoalkynes Buchwald copper
catalyzed (CuSO 4. 5H 2 O, CuI, Cu 2 O, Cu(OAc) 2 N-arylations of
amides Tam, 1996 improvement of the methodology using KHMDS
Skrydstrup, 2008 second generation of Hsungs protocol mild base - K
3 PO 4 or K 2 CO 3 higher yields 52 91 % 14 J. Am. Chem. Soc. 2002,
124, 7421. Tetrahedron 2006, 62, 3823 J. Org. Chem. 2008, 73,
9447
- Slide 15
- Ynamides Literature background - utilization 2013 Evano modular
indole synthesis 2006 Cintrant - -addition of ynamides
hydrostannylation 2006 Hsung et al. Lindlar type hydrogenation of
ynamides 15 Org. Lett. 2013, 15, 3122. Tetrahedron Lett. 2006, 47,
3139 J. Org. Chem. 2006, 71, 4170.
- Slide 16
- Tam 2006 ruthenium catalyzed [2+2]-cycloaddition of alkenes
(bi- and tricyclic) with ynamides Saito 2012 total synthesis of
(-)-Herbindoles A-C - [2+2+2]-cycloaddition Click chemistry K. B.
Sharpless 2001 16 Riddell, N.; Villeneuve, K.; Tam, W. Tetrahedron
2005, 7, 3681. Villeneuve, K.; Riddell, N.; Tam, W. Tetrahedron
2006, 62, 3823. Saito, N.; Ichimaru, T.; Sato, Y. Org. Lett. 2012,
14, 1914.
- Slide 17
- Ynamides - Proposed synthesis 17
- Slide 18
- Preparation of model ynamide A) Corey-Fuchs approach published
by Brckner crucial step - selection of EWG (Boc, Piv, Ts) B)
Bestmann-Ohira reaction one step synthesis, all the attempts failed
18 Brckner, D. Synlett 2000, 1402. Brckner,D. Tetrahedron 2006, 62,
3809.
- Slide 19
- Preparation of target ynamide Pathway A: via Corey-Fuchs
approach problematic preparation of Corey-Fuchs precursor 19
- Slide 20
- Pathway A: formylation in good yield tosylation - p-TsCl,
without or with (Et 3 N, pyridine, NaH, n-BuLi) base Pathway B:
tosylation in good yield formylation HCOOH + DCC, CDI; BtCHO;
HCOOEt + base; Vilsmeier-Haack formylation; Eschenmoser salt;
acetic-formic anhydride + base 20
- Slide 21
- 21 Application of Corey-Fuchs approach on tosylated
N-formamide.
- Slide 22
- Pathway C: Transformation of trichloroacetamides to ynamides
Speziale, Smith - 1962; Himbert, Regitz 1972 key step conversion of
trichloroenamine to lithiated ynamine 22 Speziale, A. J.; Smith, L.
R. J. Am. Chem. Soc. 1962, 84, 1868. Himbert, G.; Regitz, M.
Chemische Berichte 1972, 105, 2963.
- Slide 23
- Pathway D: Direct N-alkynylation of arylamines using iodonium
triflate salts Preparation of triflate salt 23 Tanaka, K.;
Takeishi, K. Synthesis 2007, 18, 2920. Kerwin, S.; Nadipuram, A.
Synlett 2004, 1404. potentialy explosive
- Slide 24
- using bromoalkynes 2 possible reagents: Tams protocol -COOMe
EWG small yield of alkynylation step 28 %; overall yield 26 % (3
steps) 24 Pathway D: Direct N-alkynylation of arylamines low
boiling point
- Slide 25
- Skrydstrup protocol 2 key ynamides prepared using COOMe -
Overall yield 88 % over 3 steps alkynylation step 97 % using Boc-
EWG overall yield 52 % over 3 steps 25 Skrydstrup., T. ;
Dooleweerdt, K. ; Birkedal, H. ; Ruhland, T. J. Org. Chem. 2008,
73, 9447.
- Slide 26
- Azides synthesis of several aromatic azides as partners for
Click Chemistry discovered 140 years ago by Grie polar mesomeric
structures Preparation: from diazonium salts 26 Grie, P. Philos.
Trans. R. Soc. London 1864, 13, 377. Grie, P. Justus Liebigs Ann.
Chem. 1865, 135, 131. Capitosti, S. M.; Hansen, T. P.; Brown, M. L.
Org. Lett. 2003, 5, 2865.
- Slide 27
- SN aromatic SN aromatic from non-activated aromatic halides Ma,
Zhu 2004 copper-catalyzed reaction, EtOH / water Liang 2005 mild
conditions 27 Zhu, W.; Ma, D. Chem. Comm. 2004, 888. Andersen, J.;
Madsen, U.; Bjrkling, F.; Liang, X. Synlett 2005, 14, 2209.
- Slide 28
- synthesis of appropriate azides azidation and Suzuki-Miyaura
cross-coupling key steps 28 Preparation of target azides
- Slide 29
- azide with ortho-substituted pyridyl cycle 57 % overall yield
over 2 steps azide with meta-substituted pyridyl cycle 45 % overall
yield (2 steps) 29 Trokowski, R.; Akine, S.; Nabeshima, T. Dalton
Trans. 2009, 46, 10359. Li, W.; Nelson, D. P.; Jensen, M. S.;
Hoerrner, R. S.; Cai, D; Larsen, R. D. Org. Synth. 2005, 11,
393.
- Slide 30
- C-H palladium activated acetoxylation recently developed method
for heteroatom-directed functionalization Ph(IOAc) 2, Pd(OAc) 2 in
acetanhydride and benzene 30 Daugulis, O.; Zaitsev, V. G. Angew.
Chem., Int. Ed. 2005, 44, 4046.
- Slide 31
- Preparation of MOM- protected azidobiaryl V.47d and
unsuccessful preparation of hydroxylated azidobiarym V.40d 31
Doyagez, E. S. Synlett 2005, 10, 1636. Soni, A.; Dutt, A.;
Sattigeri, V.; Cliffe, I. A. Synth. Commun. 2011, 41, 1852.
- Slide 32
- Pyrrole azide V.43 traces after Suzuki coupling azidation not
performed 32 Gu, Z. ; Zakarian, A. Org. Lett. 2010, 12, 4224.
Morrison, M. D. ; Hanthorn, J. J. ; Pratt, D. A. Org. Lett. 2009,
11, 1051.
- Slide 33
- Proposed new retrosynthetical approach Prepared 2 new azides
V.78a and V.78b 33 14% over 3 steps 19% over 4 steps
- Slide 34
- Preparation of urea azide V.42 Overall yield 37 % over 7 steps
34 Kotha, S.; Shah, V. R. Eur. J. Org. Chem. 2008, 1054. Ganesh,
T.; Thepchatri, P.; Du, L. L. Y.; Fu, H; Snyder, J. P.; Sun, A.
Bio. Med. Chem. Lett. 2008, 4982. Chandrappa, S.; Vinaya, T.;
Ramakrishnappa, T.; Rangappa, K. S. Synlett 2010, 3019. Deng, Q.
H.; Wang, J. C.; Xu, Z. J.; Zhou, C. Y.; Che, C. M. Synthesis 2011,
18, 2959.
- Slide 35
- Preparation of pyrimidine azide V. 42 2 synthetical pathways
performed 35 Yaziji, V,; Rodriguez, D.; Guierrez-de-Terran, H.;
Coehlo, A. ; Caamano, O. ; Garcia-Mera, X. ; Brea, J. ; Loza, M. I.
; Cadavid, M. I. ; Sotelo, E. J. Med. Chem. 2011, 54, 457. Chang,
L. C. W.; Ijzerman, A. P.; Brussee, J. Oct. 1, 2004, United States
Patent US 2007/0032510. Ye, C.; Gao, H.; Boatz,Drake, G. W.;
Twamley, B.; Shreeve, J. M. Angew. Chem. Int. Ed. 2006, p.
7262.
- Slide 36
- Click Chemistry K. B. Sharpless, 2001 Requirements: modular and
wide in scope higly efficient and give high yields no or
inoffensive by-poducts stereospecific readily available reagents no
solvents or benign solvents simple purification non-chromatographic
techniques 36 K.B. Sharpless Kolb, H. C.; Finn, M. G.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2001, 40, 2004. Becer, C. R.;
Hoogenboom, R.; Schubert, U. S. Angew. Chem. Int. Ed. 2009, 48,
4900.
- Slide 37
- Huisgen thermal 1,3-dipolar cycloaddition of alkynes and azides
Click Chemistry CuAAC, RuAAC MW accelerated Click Chemistry Cintrat
and Ijsselstijn, 2006 Click Chemistry with ynamides 2004 Eycken
3-component MW accelerated Click chemistry reaction 37 Huisgen, R.
Angew. Chem., Int. Ed. 1963, 2, 633. Lovell, T.; Hilgraf, R.;
Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J.
Am. Chem. Soc., 2005, 127, 210. Cintrat, J.C.; IJsselstijn, M.
Tetrahedron 2006, 62, 3837. Appakkuttan, P.; Dehaen, W.; Fokin, V.
V.; Eycken, E. V. Org. Lett. 2004, 6, 4223.
- Slide 38
- Preparation of In Silico predicted triazoles via CuAAC in mild
conditions using the prepared azides and ynamides Classical
retrosynthetical approach 38
- Slide 39
- 39
- Slide 40
- Preparation of triazole III.26 with MeCOO- protecting group 40
Problematic deprotection of EWG EntryConditionsResults 11 M KOH in
MeOH, rt, overnight Starting material VI.12 + products of
decomposition VI.14 + VI.15 21 M KOH in MeOH, rt, 20 minStarting
material VI.12 31 M KOH in MeOH, reflux, 20 minProducts of
decomposition VI.14 + VI.15 4 0.5 M KOH in ethylene glycol + water,
rt, 20 min Starting material VI.12 50.5 M KOH in ethylene glycol +
water, reflux, 20 min Starting material VI.12 + products of
decomposition VI.14 + VI.15
- Slide 41
- with Boc- protecting group 41 EntryConditionsResults 15 equiv
TBAF, THF, rt, overnightStarting material VI.16 25 equiv TBAF, THF,
reflux, 30 minProducts of decomposition 312 M HCl / EtOAc = 1 /
2.3, rt, 1 hour Expected product III.26 + Starting material VI.16 +
Products of decomposition 4TFA, rt, 1 hExpected product III.26 +
products of decomposition [.[. Coleman, C. M.; OShea; D. F. J. Am.
Chem. Soc. 2003, 4054. Englund, E. A.; Gopi, H. N.; Appella; D. H.
Org. Lett. 2004, 213
- Slide 42
- Alternative retrosynthetical approach preparation of triazole
III.24 42
- Slide 43
- preparation of triazole III.23 problem with solubility and
purification of the resulting triazole 43 not prepared
- Slide 44
- 44 Prepared triazoles
- Slide 45
- Biological assays IC 50 biological activity radiometric protein
kinase assay 3 active 2 not active 45
- Slide 46
- redocking biological activities not corresponded to docking
score newer version Dock 3.6 with PDB : 1Y6A triazolic compounds
much more worse binding energies than oxazolic predicted energies
of triazoles ca 21 % less favorable compare to oxazolic isosters
46
- Slide 47
- influence of isosteric oxazole / triazole replacement oxazolic
core in PDB : 1Y6A surronded by liphophilic amino acid residues
less favourable to bind triazole dipole moment 47 Discovery Studio
http://accelrys.com/products/discovery-studio/visualization-download.php
(visited 2 nd August 2013)
- Slide 48
- General conclusion study towards preparation of target ynamides
prepared 7 azides suitable for Click Chemistry approach 48
- Slide 49
- prepared 5 desired 1,2,3-triazoles 3 active VEGFR-2 inhibitors
2 not active inhibitors 49
- Slide 50
- Acknowledgement To my supervisors Assoc. Prof. Andrej BOH Dr.
Gilles. HANQUET To members of jury my co-workers from ECPM and
Faculty of Natural Sciences in Bratislava Financial support
Comenius University COST STSM 0602 French Embassy in Bratislava my
parents and all my friends 50