Design, synthesis, and biological evaluation of (E)-N-aryl-2-arylethenesulfonamide analogues as potent and orally bioavailable microtubule-targeted anticancer agents

J Med Chem. 2013 Jul 11;56(13):5562-86. doi: 10.1021/jm400575x. Epub 2013 Jun 25.


A series of novel (E)-N-aryl-2-arylethenesulfonamides (6) were synthesized and evaluated for their anticancer activity. Some of the compounds in this series showed potent cytotoxicity against a wide spectrum of cancer cell-lines (IC50 values ranging from 5 to 10 nM) including all drug resistant cell-lines. Nude mice xenograft assays with compound (E)-N-(3-amino-4-methoxyphenyl)-2-(2',4',6'-trimethoxyphenyl)ethenesulfonamide (6t) showed dramatic reduction in tumor size, indicating their in vivo potential as anticancer agents. A preliminary drug development study with compound 6t is predicted to have increased blood-brain barrier permeability relative to many clinically used antimitotic agents. Mechanistic studies indicate that 6t and some other analogues disrupted microtubule formation, formation of mitotic spindles, and arrest of cells in mitotic phase. Compound 6t inhibited purified tubulin polymerization in vitro and in vivo and circumvented drug resistance mediated by P-glycoprotein. Compound 6t specifically competed with colchicine binding to tubulin and with similar avidity as podophylltoxin, indicating its binding site on tubulin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Biological Availability
  • Blood-Brain Barrier / metabolism
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Design*
  • Drug Resistance, Neoplasm / drug effects
  • HCT116 Cells
  • Humans
  • K562 Cells
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • Microtubules / drug effects*
  • Microtubules / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Polymerization / drug effects
  • Sulfonamides / chemical synthesis
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology*
  • Tubulin / metabolism
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays*


  • Antineoplastic Agents
  • N-(3-amino-4-methoxyphenyl)-2-(2',4',6'-trimethoxyphenyl)ethenesulfonamide
  • Sulfonamides
  • Tubulin