Presentation is loading. Please wait.

Presentation is loading. Please wait.

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

Similar presentations


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

2 o

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 yeargroup leaderstepsoverall yield (%)ref. 1989Danishefsky260.13racemic J. Am. Chem. Soc. 1989; 111, Hudlicky142enantiopure J. Am. Chem. Soc. 1995; 117, Trost1511enantiopure J. Am. Chem. Soc. 1995; 117, Haseltine>151.2enantiopure Tetrahedron 1997, 53, Magnus191.2enantiopure J. Am. Chem. Soc. 1998, 120, Rigby220.16enantiopure J. Am. Chem. Soc. 2000, 122, Pettit103.6from narciclasine J. Org. Chem. 2001, 66, Kim175.8racemic Org. Lett. 2002, 4, Kim183.8racemic 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 yeargroup leaderstepsoverall yieldref. 1972Kishi300.65racemic J. Am. Chem. Soc. 1972, 94, Isobe690.17enantiopure J. Am. Chem. Soc. 2003, 125, Du Bois331.09enantiopure J. Am. Chem. Soc. 2003, 125, Isobe390.13enantiopure Angew. Chem. Int. Ed. 2004, 43, Sato320.1racemic J. Org. Chem. 2005, 70, Isobe220.22enantiopure 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

12 Annulation reactions

13 Tetrodotoxin, the synthetic challenge

14 Path to pancratistatin analog pyrrolidine 30% 3 6 7

15 Yield 49% for 3 steps 7 8 9

16 Yield 74% for 2 steps

17 12

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.


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

Similar presentations


Ads by Google