The synthesis and study of structure-activity relationship of two new classes of synthetic antitubulin compounds based on 1-aroylindole and 3-aroylindole skeleton are described. Lead compounds 3, 10 and 14 displayed potent cytotoxicity with IC50 = 0.9 to 22 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 contributes to a significant extent for maximal activity by mimicking the para substitution of the methoxy group to the carbonyl group in case of aminobenzophenones. Addition of a methyl group at the C-2 position on indole ring exerts increased potency. 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.
Date:
2004-08-22
Relation:
Abstracts of Papers - American Chemical Society. 2004 Aug 22;228:U924.
