title: Structure-activity relationship studies of 3-aroylindoles as potent antimitotic agents.
abstract: 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.
authors.affiliation: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli County 350, Taiwan, Republic of China.
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Liou
authors.forename: Neeraj
authors.initials: N
authors.lastname: Mahindroo
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Chang
authors.forename: Fu-Ming
authors.initials: FM
authors.lastname: Guo
authors.forename: Sandy Wen-Hsing
authors.initials: SW
authors.lastname: Lee
authors.forename: Uan-Kang
authors.initials: UK
authors.lastname: Tan
authors.forename: Teng-Kuang
authors.initials: TK
authors.lastname: Yeh
authors.forename: Ching-Chuan
authors.initials: CC
authors.lastname: Kuo
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Chang
authors.forename: Ping-Hsun
authors.initials: PH
authors.lastname: Lu
authors.forename: Yen-Shih
authors.initials: YS
authors.lastname: Tung
authors.forename: Ke-Ta
authors.initials: KT
authors.lastname: Lin
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Hsieh
mesh_terms: 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
chemical_list: C488735:6-methoxy-3-(3',4',5'-trimethoxybenzoyl)-1H-indole; D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D007211:Indoles; D014404:Tubulin; D050257:Tubulin Modulators