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Towards New Drugs to Fight Cancer and Cancer-Induced Acute-Pain Through a Common Novel Annulation Methodology Krzysztof Kierus, Fernando Cagide-Fagin,

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Presentation on theme: "Towards New Drugs to Fight Cancer and Cancer-Induced Acute-Pain Through a Common Novel Annulation Methodology Krzysztof Kierus, Fernando Cagide-Fagin,"— Presentation transcript:

1 Towards New Drugs to Fight Cancer and Cancer-Induced Acute-Pain Through a Common Novel Annulation Methodology Krzysztof Kierus, Fernando Cagide-Fagin, Patricia Martínez-Bescos, Ricardo Alonso University of Santiago de Compostela Galicia, Spain

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3 Towards New Drugs to Fight Cancer and Cancer-Induced Acute-Pain Through a Common Novel Annulation Methodology Krzysztof Kierus, Fernando Cagide-Fagin, Patricia Martínez-Bescos, Ricardo Alonso University of Santiago de Compostela Galicia, Spain

4 Biological importance of pancratistatin
Antineoplastic activity Specific to wide range of cancer cells Induce apoptosis Natural sources: Pancratium littorale Hymenocallis pedalis

5 Isolation from natural sources has its drawbacks:
Difficult separations and purifications Variability on the content with the species, crop, recollection time, etc. Expensive: very demanding in terms of time, effort, facilities, solvents, chromatography – normal and HPLC. It is very difficult to prepare new analogs

6 Total syntheses of pancratistatin
year group leader steps overall yield (%) ref. 1989 Danishefsky 26 0.13 racemic J. Am. Chem. Soc. 1989; 111, 4829 1995 Hudlicky 14 2 enantiopure J. Am. Chem. Soc. 1995; 117, 3643 Trost 15 11 J. Am. Chem. Soc. 1995; 117, 10143 1997 Haseltine >15 1.2 Tetrahedron 1997, 53, 11153 1998 Magnus 19 J. Am. Chem. Soc. 1998, 120, 5341 2000 Rigby 22 0.16 J. Am. Chem. Soc. 2000, 122, 6624 2001 Pettit 10 3.6 from narciclasine J. Org. Chem. 2001, 66, 2583 2002 Kim 17 5.8 Org. Lett. 2002, 4, 1343 2004 18 3.8 J. Org. Chem. 2004, 69, 112

7 Biological importance of tetrodotoxin
Voltage-gated, sodium channel blocker Potential analgesic for cancer pain Natural sources: pufferfish (Fugu fish) Bacteria: Pseudoalteromonas tetraodonis

8 Total syntheses of tetrodotoxin
year group leader steps overall yield ref. 1972 Kishi 30 0.65 racemic J. Am. Chem. Soc. 1972, 94, 9217 2003 Isobe 69 0.17 enantiopure J. Am. Chem. Soc. 2003, 125, 8798 Du Bois 33 1.09 J. Am. Chem. Soc. 2003, 125, 11510 2004 39 0.13 Angew. Chem. Int. Ed. 2004, 43, 4782 2005 Sato 32 0.1 J. Org. Chem. 2005, 70, 7496 2006 22 0.22 Chem. Asian. J. 2006, 1-2, 125

9 Formation of main carbon ring

10 β-aryl-α-nitro-α,β-enals
Synthesis by: nitration of 3-(2-furyl)-propenal and 3-(5-methyl-2-furyl)-propenal condensation of guaiazulene with nitromalondi-aldehyde a) Sitkin, A. I.; Klimenko, V. I.; Fridman, A. L. Zh. Org. Khim. 1975, 11, b) Klimenko, V. I.; Sitkin, A. I.; Fridman, A. L. Vses. Nauchn. Konf. Khim. Tekhnol. Furanovykh Soedin., [Tezisy Dokl.], 3rd, Riga, USSR, 1978; Stradyn, Y. P., Ed. pp c) Kirby, E. C.; Reid, D. H. J. Chem. Soc. 1961, d) S. Goldmann, M. Bechem, Ger. Offen. (1994), DE A1

11 New strategy Morita–Baylis–Hillman

12 Annulation reactions

13 Tetrodotoxin, the synthetic challenge

14 Path to pancratistatin analog
pyrrolidine 30% 6 3 7

15 7 8 Yield 49% for 3 steps 9

16 10 9 11 Yield 74% for 2 steps

17 12 11

18 Enantioselective annulation reaction
93% e.e. >99% e.e. (after crystallization) 80% e.e.

19 Summary We have successfully elaborated a new route to nitroenals
We have developed a new annulation methodology to aminocyclohexitols We proved the utility of the annulation methodology in a 0.8g scale synthesis of a pancratistatin analog Enantiopure synthesis is possible by use of chiral inducer combined with crystallization.

20 Prof. Ricardo Alonso Alonso Dr Umadevi Bhoga
M.Sc. Patricia Martínez Bescos M.Sc. Fernando Cagide Fagin Olaia Nieto García Hugo Lago Santomé Dr Juan Carlos Ortiz Dr Lidia Ozores Dr Luis Fernando Roa de la Fuente M.Sc. Marta Fernández González Project suported by: Xunta de Galicia through Project PGIDIT05BTF20901PR Spanish Ministries of Science and Technology BQU Fellowship awarded to L.O.


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