| Abstract
| - Herein, we describe the structure−activity relationship study of a new 3-aryl-8H-thieno[2,3-b]pyrrolizin-8-one series of antitubulin agents. The pharmacological results from the NationalCancer Institute in vitro human disease oriented tumor cell line screening allowed us to identifycompound 1d (NSC 676693) as a very efficient antitumoral drug in all cancer cell lines tested.This prompted us to define the structural requirements essential for this antiproliferativeactivity. Among all analogues synthesized in this study, compound 1o was the most promising,being 10-fold more potent than compound 1d. Its activity over a panel of nine tumoral celllines was in the nanomolar range for all of the histological types tested, and surprisingly, theresistant KB-A1 cell line was also sensitive to this compound. Moreover, a flow cytometricstudy showed that L1210 cells treated by the most potent compounds were arrested in theG2/M phases of the cell cycle with a significant percentage of cells having reinitiated a cycle ofDNA synthesis without cell division. This interesting pharmacological profile, resulting frominhibition of tubulin polymerization, encouraged us to perform preliminary in vivo studies thatled to a new prodrug chemical approach.
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