Synthesis and Structure-Activity Relationships of Carbazole Sulfonamides as a Novel Class of Antimitotic Agents Against Solid Tumors
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- 作者：Laixing Hu ; Zhuo-rong Li ; Yan Li ; Jinrong Qu ; Yi-He Ling ; Jian-dong Jiang ; David W. Boykin
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：October 19, 2006
- 年：2006
- 卷：49
- 期：21
- 页码：6273 - 6282
- 全文大小：404K
- 年卷期：v.49,no.21(October 19, 2006)
- ISSN：1520-4804
文摘
Two series of carbazole sulfonamides related to Combretastatin A4 (1) were synthesized and evaluated forantiproliferative activity. Thirteen of the 26 new sulfonamides exhibited IC50 values of <1 
M againstCEM leukemia cells. Five compounds were evaluated against a panel of eight human tumor cell lines.9-Ethyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulfonamide (11a) showed significant antitumor activity intwo human xenograft models (MCF-7 and Bel-7402). Preliminary studies with 11a showed that the modeof action involves arrest of M-phase cell cycle and induction of apoptosis by increasing expression of p53and promoting bcl-2 phosphorylation. Unexpectedly, 11a only weakly inhibits tubulin polymerization, whichsuggests that the mode of action of 11a differs from 1 and involves an unidentified target(s). Also, the SARinformation gleaned from ring A-substituted analogues varies significantly from that of 1. Carbazolesulfonamides are a novel promising class of antimitotic agents with clinical development potential.
M againstCEM leukemia cells. Five compounds were evaluated against a panel of eight human tumor cell lines.9-Ethyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulfonamide (11a) showed significant antitumor activity intwo human xenograft models (MCF-7 and Bel-7402). Preliminary studies with 11a showed that the modeof action involves arrest of M-phase cell cycle and induction of apoptosis by increasing expression of p53and promoting bcl-2 phosphorylation. Unexpectedly, 11a only weakly inhibits tubulin polymerization, whichsuggests that the mode of action of 11a differs from 1 and involves an unidentified target(s). Also, the SARinformation gleaned from ring A-substituted analogues varies significantly from that of 1. Carbazolesulfonamides are a novel promising class of antimitotic agents with clinical development potential.