Fluorinated derivatives of 2-phenyl-3-hydroxy-4(1H)-quinolinone as tubulin polymerization inhibitors

Eur J Med Chem. 2020 Apr 15;192:112176. doi: 10.1016/j.ejmech.2020.112176. Epub 2020 Feb 21.

Abstract

We have synthesized a series of 2-phenyl-3-hydroxy-4(1H)-quinolinone derivatives substituted with one or more fluorine atoms on the quinolone backbone as well as on phenyl ring. The derivatives bearing more fluorine atoms were subjected to modification by nucleophilic substitutions by thiophenol, morpholine, and piperazine derivative. We have tested the prepared compounds in cytotoxic activity assay against cancer cell lines. Four derivatives exhibited micromolar values of IC50 against some of the cancer cell lines, and we have subjected them to cell cycle analysis on CCRF-CEM. Moreover, most active 7-fluoro-3-hydroxy-2-phenyl-6-(phenylthio)quinolin-4(1H)-one inhibits mitosis progression. Cell cycle analysis, in vitro tubulin polymerization assay, and tubulin imaging in cells indicated that the anticancer activity of thiophenol derivative is associated with its ability to inhibit microtubule formation.

Keywords: 2-Phenyl-3-hydroxy-4(1H)-Quinolinone; Cytotoxic activity; Fluorine implementation; Tubulin.

MeSH terms

  • Dose-Response Relationship, Drug
  • HCT116 Cells
  • Halogenation
  • Humans
  • Molecular Structure
  • Polymerization / drug effects
  • Quinolones / chemical synthesis
  • Quinolones / chemistry
  • Quinolones / pharmacology*
  • Structure-Activity Relationship
  • Tubulin / metabolism*
  • Tubulin Modulators / chemical synthesis
  • Tubulin Modulators / chemistry
  • Tubulin Modulators / pharmacology*

Substances

  • Quinolones
  • Tubulin
  • Tubulin Modulators