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Title: Review of cytotoxic cephalostatins and ritterazines: isolation and synthesis

item Moser, Bryan

Submitted to: Journal of Natural Products
Publication Type: Review Article
Publication Acceptance Date: 12/1/2007
Publication Date: 1/15/2008
Citation: Moser, B.R. 2008. Review of cytotoxic cephalostatins and ritterazines: isolation and synthesis. Journal of Natural Products. 71:487-491.

Interpretive Summary:

Technical Abstract: The cephalostatins are a family of 19 bis-steroidal pyrazine natural products reported by Professor Pettit and colleagues at Arizona State University from 1988-1998. Isolated from a marine worm, Cephalodiscus gilchristi, the cephalostatins exhibit extraordinarily potent cytotoxicity toward the murine P388 lymphocytic leukemia cell line. In fact, cephalostatin 1, with an ED50 of 10-7 - 10-9 ug/mL (P388), proved to be one of the most powerful cancer cell growth inhibitors ever tested by the U.S. National Cancer Institute, which is 400-fold more active in vitro than taxol. Related in structure and biochemical mode of action are the ritterazines, which are a family of 26 trisdecacyclic pyrazines reported by Professor Fusetani and coworkers at the University of Tokyo from 1994-1997. Also isolated from an invertebrate marine chordate, Ritterella tokioka, the ritterazines demonstrated excellent cytotoxicity, but inferior to the cephalostatins (ritterazine B, P388 ED50 0.00015 ug/mL). The ritterazines and cephalostatins share many common structural features in which two highly oxygenated steroidal units are fused via a pyrazine core and the side chains of the steroidal units form either 5/5 or 5/6 spiroketals. The cephalostatins in general are more oxygenated on the right side whereas the ritterazines have the more oxygenated left side. Both cephalostatin 1 and ritterazine B induce apoptosis in cancerous cells through caspase activation. Professor Fuchs and colleagues of Purdue University reported the total syntheses of cephalostatins 1, 7, and 12 and ritterazines K and M. The synthesis of cephalostatin 1, reported in 1998, required an amazing 65 synthetic operations to complete.