Synthesis and structure-activity relationships of 3-aminobenzophenones as antimitotic agents.
A new series of 3-aminobenzophenone compounds as potent inhibitors of tubulin polymerization was discovered based on the mimic of the aminocombretastatin molecular skeleton. Lead compounds 5 and 11, with alkoxy groups at the C-4 position of B-ring, were potent cytotoxic agents and inhibitors of tubulin polymerization through the binding to the colchicine-binding site of tubulin. The corresponding antitubulin activities of 5 and 11 were similar to or greater than combretastatin A-4 and AVE-8063. Replacement of the methoxy group with a chloro group in the B ring of aminobenzopheneones (3, 8, and 9) caused drastic decrease in cytotoxic and antitubulin activity except in compounds 4 and 10, which could result from a unique alignment between chloro and amino groups located at the para position to each other. SAR information revealed that introduction of an amino group at the C-3 position in B ring of benzophenones, in addition to a methoxy group at the C-4 position, plays an important role for maximal cytotoxicity.
Liou
Jing-Ping
JP
Medicinal Synthetic Laboratory, Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Taipei, Taiwan, Republic of China.
Chang
Jang-Yang
JY
Chang
Chun-Wei
CW
Chang
Chi-Yen
CY
Mahindroo
Neeraj
N
Kuo
Fu-Ming
FM
Hsieh
Hsing-Pang
HP
D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001577:Benzophenones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001704:Biopolymers; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003078:Colchicine / Q000737:chemistry; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D011485:Protein Binding; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry
C000600729:AVE-8063; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001577:Benzophenones; D001704:Biopolymers; D013267:Stilbenes; D014404:Tubulin; D003078:Colchicine