title: Synthesis and structure-activity relationships of carbazole sulfonamides as a novel class of antimitotic agents against solid tumors.
abstract: Two series of carbazole sulfonamides related to Combretastatin A4 (1) were synthesized and evaluated for antiproliferative activity. Thirteen of the 26 new sulfonamides exhibited IC(50) values of <1 muM 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.
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia 30303-3083, USA.
authors.forename: Laixing
authors.initials: L
authors.lastname: Hu
authors.forename: Zhuo-Rong
authors.initials: ZR
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Jinrong
authors.initials: J
authors.lastname: Qu
authors.forename: Yi-He
authors.initials: YH
authors.lastname: Ling
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
mesh_terms: D000818:Animals; D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: C515134:9-ethyl-N-(3,4,5-trimethoxyphenyl)carbazole-3-sulfonamide; D050256:Antimitotic Agents; D002227:Carbazoles; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53