Synthesis and biological evaluation of dimeric furanoid macroheterocycles: discovery of new anticancer agents

J Am Chem Soc. 2015 Apr 15;137(14):4766-70. doi: 10.1021/jacs.5b00141. Epub 2015 Apr 1.

Abstract

A recently developed dimerization/macrocyclization was employed to synthesize a series of macroheterocycles which were biologically evaluated, leading to the discovery of a number of potent cytotoxic agents (e.g., 27: GI50 = 51 nM against leukemia CCRF-CEM cell line; 29: GI50 = 99 nM against melanoma MDA-MB-435 cell line). Further biological studies support an apoptosis mechanism of action for these compounds involving deregulation of the tricarboxylic acid cycle activity and suppression of mitochondrial function in cancer cells.

Publication types

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

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Chemistry Techniques, Synthetic
  • Dimerization*
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Furans / chemistry*
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Humans

Substances

  • Antineoplastic Agents
  • Furans
  • Heterocyclic Compounds
  • furan