Synthesis and biological characterization of argyrin F, a proteasome inhibitor with improved in vitro and in vivo activities

In the quest for new targets in anti-tumor therapy the proteasome and its inhibitors have been in the focus of academic and industrial research. In this context, we recently reported on the p27 stabilization effect of argyrin A through selective inhibition of the proteasome1. The talk will cover the synthesis of novel argyrines through a route that takes advantage of modern synthetic transformations and thus allows medicinal application by avoiding pharmacologically problematic functional group manipulations such as the incorporation of selenium compounds2.

[1] a) F. Sasse, H. Steinmetz, T. Schupp, F. Petersen, K. Memmert, H. Hofmann, C. Heusser, V. Brinkmann, P. von Matt, G. Höfle, H. Reichenbach, J. Antibiot. 2002, 55, 543-551; b) Compound A21459 isolated by the Zerilli and Serva group exhibits identical chemical shifts and coupling constants compared to argyrin; b) P. Ferrari, K. Vékey, M. Galimberti, G. G. Gallo, E. Selva, L. F. Zerilli, J. Antibiot. 1996, 49, 150-154; c) E. Selva, G. Gastaldo, G. S. Saddler, G. Toppo, P. Ferrari, G. Carniti, B. P. Goldstein, J. Antibiot. 1996, 49, 145-149. 
[2] Nickeleit, S. Zender, F. Sasse, R. Geffers, G. Brandes, I. Soerensen, H. Steinmetz, S. Kubicka, T. Carlomagno, D. Menche, I. Guetgemann, J. Buer, A. Gossler, M. P. Manns, M. Kalesse, R. Frank, N. P. Malek, Cancer Cell 2008, 14, 23-35.

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