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Discovery of Novel 2‐ N ‐Aryl‐Substituted Benzenesulfonamidoacetamides: Orally Bioavailable Tubulin Polymerization Inhibitors with Marked Antitumor Activities
Author(s) -
Liu Zulong,
Zhou Zuyu,
Tian Wei,
Fan Xing,
Xue Ding,
Yu Long,
Yu Qiang,
Long YaQiu
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100529
Subject(s) - pharmacophore , chemistry , apoptosis , cytotoxicity , hela , tubulin , acetamide , cell cycle checkpoint , stereochemistry , aryl , cell cycle , trifluoromethyl , microtubule , biochemistry , in vitro , biology , microbiology and biotechnology , alkyl , organic chemistry
The discovery and optimization of a series of 2‐ N ‐aryl‐substituted benzenesulfonamidoacetamides as novel tubulin polymerization inhibitors are described. Pharmacophore exploration of hit compound AH‐487 identified the optimal structure of N ‐heteroaryl‐2‐(4‐methoxy‐ N ‐(3‐(trifluoromethyl)phenyl)phenylsulfonamido)acetamide as a potent antimitotic agent. Subsequent lead compounds 4 b and 4 c , with N ‐4‐aminophenyl and N ‐1 H ‐indol‐5‐yl substitutions at the acetamide position, respectively, were shown to induce cell‐cycle arrest at the G 2 /M phase and lead to an accumulation of HeLa cells in the sub‐G 1 phase. More significantly, these lead compounds ( 3 c , 4 b , and 4 c ) exhibit impressive cytotoxicity against a panel of cancer cells including P‐glycoprotein‐overexpressing MDR‐positive cells, with potency greater than or equal to clinically studied benzenesulfonamide E7010. Mechanistic studies demonstrated that derivatives of AH‐487 disrupt mitotic spindles by inhibiting microtubule polymerization and induce apoptosis via induction of Bcl‐2 phosphorylation in tumor cells. The optimized leads 4 b and 4 c strongly inhibited the growth of human hepatocellular carcinoma cells in a mouse xenograft model.