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Discovery of Novel 2-N-Aryl-Substituted Benzenesulfonamidoacetamides: Orally Bioavailable Tubulin Polymerization Inhibitors with Marked Antitumor Activities

  1. Dr. Zulong Liu1,†,
  2. Dr. Zuyu Zhou1,†,
  3. Dr. Wei Tian2,
  4. Dr. Xing Fan1,
  5. Ding Xue1,
  6. Prof. Long Yu3,
  7. Prof. Qiang Yu1,*,
  8. Prof. Ya-Qiu Long1,*

Article first published online: 6 FEB 2012

DOI: 10.1002/cmdc.201100529

Issue

ChemMedChem

ChemMedChem

Volume 7, Issue 4, pages 680–693, April 2012

Additional Information

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

Author Information

  1. 1

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

  2. 2

    The School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Liaoning 110016 (China)

  3. 3

    State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433 (China)

  1. †

    These authors contributed equally to this work.

*State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203 (China)

Publication History

  1. Issue published online: 27 MAR 2012
  2. Article first published online: 6 FEB 2012
  3. Manuscript Revised: 28 DEC 2011
  4. Manuscript Received: 17 NOV 2011

Funded by

  • National Natural Science Foundation of China. Grant Numbers: 81021062, 31129004, 31000619, 81102848
  • Shanghai Science and Technology Research Grant. Grant Number: 08DZ1971403

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Keywords:

  • antitumor agents;
  • benzenesulfonamidoacetamides;
  • bioactive compounds;
  • screening;
  • tubulin

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 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.

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