Synthesis and biological evaluation of cis-restrained carbocyclic combretastatin A-4 analogs: Influence of the ring size and saturation on cytotoxic properties

Bioorg Med Chem. 2019 Oct 1;27(19):115032. doi: 10.1016/j.bmc.2019.07.048. Epub 2019 Jul 29.

Abstract

Combretastatin A-4 (CA-4) is a highly cytotoxic natural product and several derivatives have been prepared which underwent clinical trial. These investigations revealed that the cis-stilbene moiety of the natural product is prone to undergo cis/trans isomerization under physiological conditions, reducing the overall activity of the drug candidates. Herein, we report the preparation of cis-restrained carbocyclic analogs of CA-4. The compounds, which differ by the size and hybridization of the carbocyclic ring have been evaluated for their cytotoxic properties and their ability to inhibit tubulin polymerization. Biological data, supported by molecular docking studies, identified cyclobutenyl and cyclobutyl derivatives of the natural product as highly promising drug candidates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Binding
  • Stilbenes / chemical synthesis
  • Stilbenes / metabolism
  • Stilbenes / pharmacology*
  • Tubulin / metabolism
  • Tubulin Modulators / chemical synthesis
  • Tubulin Modulators / metabolism
  • Tubulin Modulators / pharmacology

Substances

  • Antineoplastic Agents
  • Stilbenes
  • Tubulin
  • Tubulin Modulators
  • fosbretabulin