Design, synthesis and anticancer properties of IsoCombretaQuinolines as potent tubulin assembly inhibitors

Eur J Med Chem. 2017 Feb 15:127:1025-1034. doi: 10.1016/j.ejmech.2016.11.012. Epub 2016 Nov 9.

Abstract

The synthesis and evaluation of a new series of IsoCombretaQuinolines (IsoCoQuines) 2 with a 2-substituted-quinoline in place of the 3,4,5-trimethoxyphenyl ring present in isoCA-4 and CA-4 are described. Most of these compounds displayed a potent cytotoxic activity (IC50 < 10 nM) against a panel of five human cancer cell lines and inhibited tubulin assembly at a micromolar level. The most potent analogue 2b, having a 3-hydroxy-4-methoxyphenyl as B-ring, led to cell cycle arrest in G2/M phase. Docking studies indicate that 2b showed a binding mode comparable to those previously observed with quinazoline analogous (IsoCoQ) and with isoCA-4 at the colchicine binding site of tubulin.

Keywords: Binding; Cancer; Cytotoxicity; Quinoline; Tubulin; isoCA-4.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chemistry Techniques, Synthetic
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • M Phase Cell Cycle Checkpoints / drug effects
  • Molecular Docking Simulation
  • Protein Multimerization / drug effects*
  • Protein Structure, Quaternary
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry
  • Quinazolines / metabolism
  • Quinazolines / pharmacology*
  • Tubulin / chemistry*
  • Tubulin / metabolism
  • Tubulin Modulators / chemical synthesis*
  • Tubulin Modulators / chemistry
  • Tubulin Modulators / metabolism
  • Tubulin Modulators / pharmacology*

Substances

  • Antineoplastic Agents
  • Quinazolines
  • Tubulin
  • Tubulin Modulators