Synthesis and evaluation of 3-aroylindoles as anticancer agents: metabolite approach.
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.
Wu
Yu-Shan
YS
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, Republic of China.
Coumar
Mohane Selvaraj
MS
Chang
Jang-Yang
JY
Sun
Hsu-Yi
HY
Kuo
Fu-Ming
FM
Kuo
Ching-Chuan
CC
Chen
Ying-Jun
YJ
Chang
Chi-Yen
CY
Hsiao
Chia-Ling
CL
Liou
Jing-Ping
JP
Chen
Ching-Ping
CP
Yao
Hsien-Tsung
HT
Chiang
Yi-Kun
YK
Tan
Uan-Kang
UK
Chen
Chiung-Tong
CT
Chu
Chang-Ying
CY
Wu
Su-Ying
SY
Yeh
Teng-Kuang
TK
Lin
Chin-Yu
CY
Hsieh
Hsing-Pang
HP
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D003078:Colchicine / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology
C488735:6-methoxy-3-(3',4',5'-trimethoxybenzoyl)-1H-indole; D000970:Antineoplastic Agents; D007211:Indoles; D050257:Tubulin Modulators; D003078:Colchicine