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ChemMedChem. 2012 Apr;7(4):680-93. doi: 10.1002/cmdc.201100529. Epub 2012 Feb 6.

Discovery of novel 2-N-aryl-substituted benzenesulfonamidoacetamides: orally bioavailable tubulin polymerization inhibitors with marked antitumor activities.

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1
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.

Abstract

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 4b and 4c, with N-4-aminophenyl and N-1H-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 (3c, 4b, and 4c) 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 4b and 4c strongly inhibited the growth of human hepatocellular carcinoma cells in a mouse xenograft model.

PMID:
22311585
DOI:
10.1002/cmdc.201100529
[Indexed for MEDLINE]
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