Concise synthesis and structure-activity relationships of combretastatin A-4 analogues, 1-aroylindoles and 3-aroylindoles, as novel classes of potent antitubulin agents

Jing Ping Liou, Yi Ling Chang, Fu Ming Kuo, Chun Wei Chang, Huan Yi Tseng, Chiung Chiu Wang, Yung Ning Yang, Jang Yang Chang, Shiow Ju Lee, Hsing Pang Hsieh

Research output: Contribution to journalArticle

164 Citations (Scopus)

Abstract

The synthesis and study of the structure-activity relationships of two new classes of synthetic antitubulin compounds based on 1-aroylindole and 3-aroylindole skeletons are described. Lead compounds 3, 10, and 14 displayed potent cytotoxicities with IC50 = 0.9-26 nM against human NUGC3 stomach, MKN45 stomach, MESSA uterine, A549 lung, and MCF-7 breast carcinoma cell lines. The inhibition of proliferation correlated with in vitro polymerization inhibitory activities. Structure-activity relationships revealed that 6-methoxy substitution of 3-aroylindoles and 5-methoxy substitution of 1-aroylindoles contribute to a significant extent for maximal activity by mimicking the para substitution of the methoxy group to the carbonyl group in the case of aminobenzophenones. Addition of a methyl group at the C-2 position on the indole ring exerts an increased potency. The 3,4,5-trimethoxybenzoyl moiety was necessary for better activity but not essential and can be replaced by 3,5-dimethoxybenzoyl and 3,4,5-trimethoxybenzyl moieties. We conclude that 1- and 3-aroylindoles constitute an interesting new class of antitubulin agents with the potential to be clinically developed for cancer treatment.

Original languageEnglish
Pages (from-to)4247-4257
Number of pages11
JournalJournal of Medicinal Chemistry
Volume47
Issue number17
DOIs
Publication statusPublished - Aug 12 2004
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

Fingerprint Dive into the research topics of 'Concise synthesis and structure-activity relationships of combretastatin A-4 analogues, 1-aroylindoles and 3-aroylindoles, as novel classes of potent antitubulin agents'. Together they form a unique fingerprint.

  • Cite this