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

  • J Med Chem. 2009 Aug 13;52(15):4941-5. doi: 10.1021/jm900060s.
Yu-Shan Wu  1 ,  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
Affiliations
  • 1. Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, Republic of China.
PMID: 19586033 DOI: 10.1021/jm900060s
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.