Structure-activity relationship studies of 3-aroylindoles as potent antimitotic agents.
The concise synthesis and structure-activity relationship (SAR) studies of 3-aroylindoles were carried out in an effort to improve the potency and solubility of anticancer drug candidate BPR0L075 (8) by exploring structure modifications through three regimens: substitution of the B ring, at the N1 position, and of the 3-carbonyl linker. The SAR information revealed that the methoxy group of the B ring could be replaced with an electron-donating group such as methyl (in compound 9) or N,N-dimethylamino (in compound 13) while retaining both strong cytotoxic and antitubulin activities. The introduction of amide (compounds 30-33) and carbamate (compounds 34-37) functionalities at the N1 position of 8 gave analogues with potent antiproliferative activities. The cytotoxic potency of 8 was improved by replacing the carbonyl group with sulfide (compound 41) or oxygen (compound 43), indicating that the carbonyl moiety is important but not essential. The N,N-dimethylamino derivative 13 not only displayed potent cytotoxicity and antitubulin activity, but also showed a markedly improved physicochemical profile relative to the parent compound.
Liou
Jing-Ping
JP
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli County 350, Taiwan, Republic of China.
Mahindroo
Neeraj
N
Chang
Chun-Wei
CW
Guo
Fu-Ming
FM
Lee
Sandy Wen-Hsing
SW
Tan
Uan-Kang
UK
Yeh
Teng-Kuang
TK
Kuo
Ching-Chuan
CC
Chang
Yi-Wei
YW
Lu
Ping-Hsun
PH
Tung
Yen-Shih
YS
Lin
Ke-Ta
KT
Chang
Jang-Yang
JY
Hsieh
Hsing-Pang
HP
D000818:Animals; D050256:Antimitotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000187:drug effects; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C488735:6-methoxy-3-(3',4',5'-trimethoxybenzoyl)-1H-indole; D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D007211:Indoles; D014404:Tubulin; D050257:Tubulin Modulators