Synthesis and Structure−Activity Relationships of Carbazole Sulfonamides as a Novel Class of Antimitotic Agents Against Solid Tumors

• Published in: Journal of medicinal chemistry Vol. 49; no. 21; pp. 6273 - 6282
• Main Authors: Hu, Laixing, Li, Zhuo-rong, Li, Yan, Qu, Jinrong, Ling, Yi-He, Jiang, Jian-dong, Boykin, David W
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 19-10-2006
• Subjects: Animals; Antimitotic Agents - chemical synthesis; Antimitotic Agents - chemistry; Antimitotic Agents - pharmacology; Antineoplastic agents; Apoptosis; Biological and medical sciences; Breast Neoplasms - drug therapy; Carbazoles - chemical synthesis; Carbazoles - chemistry; Carbazoles - pharmacology; Carcinoma, Hepatocellular - drug therapy; Cell Division - drug effects; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; General aspects; Humans; Liver Neoplasms - drug therapy; Medical sciences; Mice; Mice, Nude; Neoplasm Transplantation; Pharmacology. Drug treatments; Phosphorylation; Proto-Oncogene Proteins c-bcl-2 - metabolism; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Transplantation, Heterologous; Tumor Suppressor Protein p53 - biosynthesis; Antineoplastic agent; Human; Solid tumor; Sulfonamide; Carbazole derivatives; Liver; Rodentia; Malignant tumor; In vitro; In vivo; Vertebrata; Mammalia; Cell line; Structure activity relation; Mouse; Animal; Mammary gland; Mechanism of action; Chemical synthesis; Antimitotic; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060546h

Two series of carbazole sulfonamides related to Combretastatin A4 (1) were synthesized and evaluated for antiproliferative activity. Thirteen of the 26 new sulfonamides exhibited IC50 values of <1 μM against CEM 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 in two human xenograft models (MCF-7 and Bel-7402). Preliminary studies with 11a showed that the mode of action involves arrest of M-phase cell cycle and induction of apoptosis by increasing expression of p53 and promoting bcl-2 phosphorylation. Unexpectedly, 11a only weakly inhibits tubulin polymerization, which suggests that the mode of action of 11a differs from 1 and involves an unidentified target(s). Also, the SAR information gleaned from ring A-substituted analogues varies significantly from that of 1. Carbazole sulfonamides are a novel promising class of antimitotic agents with clinical development potential.