Bioorganic & Medicinal Chemistry Letters 2010-11-15

Catharanthine C16 substituent effects on the biomimetic coupling with vindoline: preparation and evaluation of a key series of vinblastine analogues.

Annie Tam, Hiroaki Gotoh, William M Robertson, Dale L Boger, Annie Tam, Hiroaki Gotoh, William M. Robertson, Dale L. Boger, Annie Tam, Hiroaki Gotoh, William M. Robertson, Dale L. Boger, Annie Tam, Hiroaki Gotoh, William M. Robertson, Dale L. Boger, Annie Tam, Hiroaki Gotoh, William M. Robertson, Dale L. Boger

Index: Bioorg. Med. Chem. Lett. 20(22) , 6408-10, (2010)

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Abstract

The examination of the catharanthine C16 substituent effects on the Fe(III)-promoted biomimetic coupling reaction with vindoline is detailed, confirming the importance of the presence of a C16 electron-withdrawing substituent, and establishing an unanticipated unique role (>10-fold) that the C16 methyl ester plays in the expression of the natural product properties. Thus, replacement of the vinblastine C16' methyl ester with an ethyl ester (10-fold), a cyano group (100-fold), an aldehyde (100-fold), a hydroxymethyl group (1000-fold) or a primary carboxamide (>1000-fold) led to surprisingly large reductions in cytotoxic activity.Copyright © 2010 Elsevier Ltd. All rights reserved.