Synthesis and structure-activity relationships of carbazole sulfonamides as a novel class of antimitotic agents against solid tumors.
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.
Hu
Laixing
L
Department of Chemistry, Georgia State University, Atlanta, Georgia 30303-3083, USA.
Li
Zhuo-Rong
ZR
Li
Yan
Y
Qu
Jinrong
J
Ling
Yi-He
YH
Jiang
Jian-Dong
JD
Boykin
David W
DW
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
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