Synthesis and evaluation of 3-aroylindoles as anticancer agents: metabolite approach.

Yu-Shan Wu, Mohane Selvaraj Coumar, Jang-Yang Chang, Hsu-Yi Sun, Fu-Ming Kuo, Ching-Chuan Kuo, Ying-Jun Chen, Chi-Yen Chang, Chia-Ling Hsiao, Jing-Ping Liou, Ching-Ping Chen, Hsien-Tsung Yao, Yi-Kun Chiang, Uan-Kang Tan, Chiung-Tong Chen, Chang-Ying Chu, Su-Ying Wu, Teng-Kuang Yeh, Chin-Yu Lin, Hsing-Pang Hsieh

Index: J. Med. Chem. 52 , 4941, (2009)

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Abstract

BPR0L075 (2) is a potential anticancer drug candidate designed from Combretastatin A-4 (1) based on the bioisosterism principle. Metabolites of 2, proposed from in vitro human microsome studies, were synthesized, leading to the identification of metabolite-derived analogue 10 with 40-350 pM potency against various cancer cell lines. Insights gained from the major inactive metabolite of 2 led to the development of 29, with better pharmacokinetics and improved potency in the tumor xenograft model than 2.