Presentation is loading. Please wait.

Presentation is loading. Please wait.

Margaréta VOJTIČKOVÁ under the direction of: Assoc. Prof. Andrej BOHÁČ Dr. Gilles HANQUET 27 th September 2013, Strasbourg.

Similar presentations


Presentation on theme: "Margaréta VOJTIČKOVÁ under the direction of: Assoc. Prof. Andrej BOHÁČ Dr. Gilles HANQUET 27 th September 2013, Strasbourg."— Presentation transcript:

1 Margaréta VOJTIČKOVÁ under the direction of: Assoc. Prof. Andrej BOHÁČ Dr. Gilles HANQUET 27 th September 2013, Strasbourg

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

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

4 Angiogenesis 4

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.

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

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

8  docking scores and ligand possess in VEGFR2 are less interesting  significantly higher price of ruthenium catalyst 8 1,5-regioisomers

9  Retrosynthetic approach 9

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.

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.

12  expansion of chemistry of ynamides – Witulski, Rainer 12 Witulski, B.; Stengel, T. Angew. Chem. Int. Ed. 1998, 37, 489. Witulski, B.; Gößmann, 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.

13  Elimination protocols  Zemlicka, 1994 – preparation of ynamides via lithium-halogen exchange  Brückner, 2000 – preparation of ynamides from formamides via lithium- halogen exchange 13 Brückner, D. Synlett 2000, 1402. Brückner,D. Tetrahedron 2006, 62, 3809. Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125.

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 Hsung’s 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

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.

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.

17 Ynamides - Proposed synthesis 17

18 Preparation of model ynamide  A) Corey-Fuchs approach – published by Brückner  crucial step - selection of EWG (Boc, Piv, Ts)  B) Bestmann-Ohira reaction – one step synthesis, all the attempts failed 18 Brückner, D. Synlett 2000, 1402. Brückner,D. Tetrahedron 2006, 62, 3809.

19 Preparation of target ynamide Pathway A: via Corey-Fuchs approach  problematic preparation of Corey-Fuchs precursor 19

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

21 21  Application of Corey-Fuchs approach on tosylated N-formamide.

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.

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

24  using bromoalkynes  2 possible reagents:   Tam’s 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

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.

26 Azides  synthesis of several aromatic azides as partners for Click Chemistry  discovered 140 years ago by Grieβ  polar mesomeric structures  Preparation:  from diazonium salts 26 Grieß, P. Philos. Trans. R. Soc. London 1864, 13, 377. Grieß, P. Justus Liebigs Ann. Chem. 1865, 135, 131. Capitosti, S. M.; Hansen, T. P.; Brown, M. L. Org. Lett. 2003, 5, 2865.

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.; Björkling, F.; Liang, X. Synlett 2005, 14, 2209.

28  synthesis of appropriate azides  azidation and Suzuki-Miyaura cross-coupling – key steps 28 Preparation of target azides

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.

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.

31  Preparation of MOM- protected azidobiaryl V.47d and unsuccessful preparation of hydroxylated azidobiarym V.40d 31 Doyagüez, E. S. Synlett 2005, 10, 1636. Soni, A.; Dutt, A.; Sattigeri, V.; Cliffe, I. A. Synth. Commun. 2011, 41, 1852.

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.

33  Proposed new retrosynthetical approach  Prepared 2 new azides V.78a and V.78b 33 14% over 3 steps 19% over 4 steps

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.

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.

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.

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.

38 Preparation of In Silico predicted triazoles  via CuAAC in mild conditions  using the prepared azides and ynamides  Classical retrosynthetical approach 38

39 39

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

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.; O’Shea; D. F. J. Am. Chem. Soc. 2003, 4054. Englund, E. A.; Gopi, H. N.; Appella; D. H. Org. Lett. 2004, 213

42  Alternative retrosynthetical approach  preparation of triazole III.24 42

43  preparation of triazole III.23  problem with solubility and purification of the resulting triazole 43 not prepared

44 44 Prepared triazoles

45 Biological assays  IC 50 biological activity – radiometric protein kinase assay  3 active  2 not active 45

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

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)

48 General conclusion  study towards preparation of target ynamides  prepared 7 azides suitable for Click Chemistry approach 48

49  prepared 5 desired 1,2,3-triazoles  3 active VEGFR-2 inhibitors  2 not active inhibitors 49

50 Acknowledgement  To my supervisors Assoc. Prof. Andrej BOHÁČ 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


Download ppt "Margaréta VOJTIČKOVÁ under the direction of: Assoc. Prof. Andrej BOHÁČ Dr. Gilles HANQUET 27 th September 2013, Strasbourg."

Similar presentations


Ads by Google