Evaluating the effects of fluorine on biological properties and metabolic stability of some antitubulin 3-substituted 7-phenyl-pyrroloquinolinones

Eur J Med Chem. 2019 Sep 15:178:297-314. doi: 10.1016/j.ejmech.2019.05.092. Epub 2019 Jun 3.

Abstract

A small number of fluorinated 7-phenyl-pyrroloquinolinone (7-PPyQ) derivatives was synthesized in an attempt to improve the metabolic stability of 3N-ethyl-7-PPyQ and 3N-benzoyl-7-PPyQ. The possible impacts of the fluorine-hydrogen isosterism on both biological activity and metabolic stability were evaluated. Introduction of a fluorine atom in the 2 or 3 position of the 7-phenyl ring yielded the 7-PPyQ derivatives 12, 13 and 15, which showed potent cytotoxicity (low micromolar and sub-nanomolar GI50s) both in human leukemic and solid tumor cell lines. None of them induced significant cell death in quiescent and proliferating human lymphocytes. Moreover, 12, 13 and 15 exhibited remarkable cytotoxic activity in the multidrug-resistant cell line CEMVbl100, suggesting that they are not substrates for P-glycoprotein. All compounds inhibited tubulin assembly and the binding of [3H]colchicine to tubulin, with the best activity occurring with compound 15. Mechanistic studies carried out on compound 12 indicated that it caused (a) a strong G2/M arrest; (b) apoptosis in a time- and concentration-dependent manner; (c) a significant production of ROS (in good agreement with the observed mitochondrial depolarization); (d) caspase-3 and poly (ADP-ribose) polymerase activation; and (e) a decrease in the expression of anti-apoptotic proteins. In vivo experiments in a murine syngeneic tumor model demonstrated that compounds 12 and 15 significantly reduced tumor mass at doses four times lower than that required for the reference compound combretastatin A-4 phosphate. Neither monofluorination of the 7-phenyl ring of 3N-ethyl-7-PPyQ nor replacement of the benzoyl function of 3N-benzoyl-7-PPyQ with a 2-fluorobenzoyl moiety led to any improvement in the metabolic stability.

Keywords: Anti-tubulin; Apoptosis; Fluoro-phenylpyrroloquinolinone; Metabolic stability; Molecular docking; Structure-activity relationships.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Fluorine / chemistry
  • Fluorine / pharmacology*
  • Humans
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Molecular Structure
  • Quinolones / chemistry
  • Quinolones / metabolism
  • Quinolones / pharmacology*
  • Structure-Activity Relationship
  • Tubulin Modulators / chemistry
  • Tubulin Modulators / metabolism
  • Tubulin Modulators / pharmacology*

Substances

  • Antineoplastic Agents
  • Quinolones
  • Tubulin Modulators
  • Fluorine