Second generation benzofuranone ring substituted noscapine analogs: synthesis and biological evaluation

Biochem Pharmacol. 2011 Jul 15;82(2):110-21. doi: 10.1016/j.bcp.2011.03.029. Epub 2011 Apr 8.

Abstract

Microtubules, composed of α/β tubulin heterodimers, represent a validated target for cancer chemotherapy. Thus, tubulin- and microtubule-binding antimitotic drugs such as taxanes and vincas are widely employed for the chemotherapeutic management of various malignancies. Although quite successful in the clinic, these drugs are associated with severe toxicity and drug resistance problems. Noscapinoids represent an emerging class of microtubule-modulating anticancer agents based upon the parent molecule noscapine, a naturally occurring non-toxic cough-suppressant opium alkaloid. Here we report in silico molecular modeling, chemical synthesis and biological evaluation of novel analogs derived by modification at position-7 of the benzofuranone ring system of noscapine. The synthesized analogs were evaluated for their tubulin polymerization activity and their biological activity was examined by their antiproliferative potential using representative cancer cell lines from varying tissue-origin [A549 (lung), CEM (lymphoma), MIA PaCa-2 (pancreatic), MCF-7 (breast) and PC-3 (prostate)]. Cell-cycle studies were performed to explore their ability to halt the cell-cycle and induce subsequent apoptosis. The varying biological activity of these analogs that differ in the nature and bulk of substituent at position-7 was rationalized utilizing predictive in silico molecular modeling.

Publication types

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

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Benzofurans / chemical synthesis*
  • Benzofurans / pharmacology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Computer Simulation
  • Humans
  • Models, Molecular
  • Noscapine / analogs & derivatives*
  • Noscapine / chemical synthesis
  • Noscapine / pharmacology
  • Protein Structure, Quaternary
  • Structure-Activity Relationship
  • Tubulin / chemistry
  • Tubulin Modulators / chemical synthesis*
  • Tubulin Modulators / pharmacology

Substances

  • Antineoplastic Agents
  • Benzofurans
  • Tubulin
  • Tubulin Modulators
  • Noscapine