Discovery of potent cytotoxic ortho-aryl chalcones as new scaffold targeting tubulin and mitosis with affinity-based fluorescence

J Med Chem. 2014 Aug 14;57(15):6364-82. doi: 10.1021/jm500024v. Epub 2014 Jul 25.


A series of new ortho-aryl chalcones have been designed and synthesized. Many of these compounds were found to exhibit significant antiproliferation activity toward a panel of cancer cell lines. Selected compounds show potent cytotoxicity against several drug resistant cell lines including paclitaxel (Taxol) resistant human ovarian carcinoma cells, vincristine resistant human ileocecum carcinoma cells, and doxorubicin resistant human breast carcinoma cells. Further investigation revealed that active analogues could inhibit the microtubule polymerization by binding to colchicine site and thus induce multipolar mitosis, G2/M phase arrest, and apoptosis of cancer cells. Furthermore, affinity-based fluorescence enhancement was observed during the binding of active compounds with tubulin, which greatly facilitated the determination of tubulin binding site of the compounds. Finally, selected compound 26 was found to exhibit obvious in vivo antitumor activity in A549 tumor xenografts model. Our systematic studies implied a new scaffold targeting tubulin and mitosis for novel antitumor drug discovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Binding Sites
  • Chalcones / chemical synthesis
  • Chalcones / chemistry*
  • Chalcones / pharmacology
  • Colchicine / metabolism
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Female
  • Fluorescence
  • G2 Phase Cell Cycle Checkpoints
  • Heterografts
  • Humans
  • Mice, Nude
  • Microtubules / drug effects
  • Microtubules / ultrastructure
  • Mitosis / drug effects*
  • Neoplasm Transplantation
  • Polymerization
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tubulin / metabolism
  • Tubulin Modulators / chemical synthesis
  • Tubulin Modulators / chemistry*
  • Tubulin Modulators / pharmacology


  • 3-(4-(dimethylamino)phenyl)-1-(4'-fluoro(1,1'-biphenyl)-2-yl)prop-2-en-1-one
  • Aniline Compounds
  • Antineoplastic Agents
  • Chalcones
  • Tubulin
  • Tubulin Modulators
  • Colchicine