Lead identification of conformationally restricted benzoxepin type combretastatin analogs: synthesis, antiproliferative activity, and tubulin effects

J Enzyme Inhib Med Chem. 2010 Apr;25(2):180-94. doi: 10.3109/14756360903169659.

Abstract

We have synthesized a series of polymethoxylated rigid analogs of combretastatin A-4 which contain a benzoxepin ring in place of the usual ethylene bridge present in the natural combretastatin products. The compounds display antiproliferative activity when evaluated against the MCF-7 and MDA human breast carcinoma cell lines. 5-(3-Hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-2,3-dihydro-benzoxepine (11g) was found to be the most potent product when evaluated against the MCF-7 breast cancer cell line. A brief computational study of the structure-activity relationship for the synthesized compounds is presented. These 4,5-diarylbenzoxepins are identified as potentially useful scaffolds for the further development of antitumor agents which target tubulin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic* / chemical synthesis
  • Antineoplastic Agents, Phytogenic* / chemistry
  • Antineoplastic Agents, Phytogenic* / pharmacology
  • Benzoxepins* / chemical synthesis
  • Benzoxepins* / chemistry
  • Benzoxepins* / pharmacology
  • Binding Sites
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Drug Design*
  • Female
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Stilbenes / chemistry*
  • Structure-Activity Relationship
  • Tubulin / metabolism*

Substances

  • Antineoplastic Agents, Phytogenic
  • Benzoxepins
  • Stilbenes
  • Tubulin
  • fosbretabulin