Concise synthesis and structure-activity relationships of combretastatin A-4 analogues, 1-aroylindoles and 3-aroylindoles, as novel classes of potent antitubulin agents.
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.
Medicinal Synthetic Laboratory, Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Taipei 114, Taiwan, Republic of China.
Jing-Ping
JP
Liou
Yi-Ling
YL
Chang
Fu-Ming
FM
Kuo
Chun-Wei
CW
Chang
Huan-Yi
HY
Tseng
Chiung-Chiu
CC
Wang
Yung-Ning
YN
Yang
Jang-Yang
JY
Chang
Shiow-Ju
SJ
Lee
Hsing-Pang
HP
Hsieh
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001704:Biopolymers / Q000737:chemistry; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators
D000970:Antineoplastic Agents; D001704:Biopolymers; D007211:Indoles; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; C058728:fosbretabulin