These authors contributed equally to this work.
Discovery of Novel 2-N-Aryl-Substituted Benzenesulfonamidoacetamides: Orally Bioavailable Tubulin Polymerization Inhibitors with Marked Antitumor Activities
Article first published online: 6 FEB 2012
Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Volume 7, Issue 4, pages 680–693, April 2012
How to Cite
Liu, Z., Zhou, Z., Tian, W., Fan, X., Xue, D., Yu, L., Yu, Q. and Long, Y.-Q. (2012), Discovery of Novel 2-N-Aryl-Substituted Benzenesulfonamidoacetamides: Orally Bioavailable Tubulin Polymerization Inhibitors with Marked Antitumor Activities. ChemMedChem, 7: 680–693. doi: 10.1002/cmdc.201100529
- Issue published online: 27 MAR 2012
- Article first published online: 6 FEB 2012
- Manuscript Revised: 28 DEC 2011
- Manuscript Received: 17 NOV 2011
- National Natural Science Foundation of China. Grant Numbers: 81021062, 31129004, 31000619, 81102848
- Shanghai Science and Technology Research Grant. Grant Number: 08DZ1971403
- antitumor agents;
- bioactive compounds;
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-1H-indol-5-yl substitutions at the acetamide position, respectively, were shown to induce cell-cycle arrest at the G2/M phase and lead to an accumulation of HeLa cells in the sub-G1 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.