A synthetic 2,3-diarylindole induces microtubule destabilization and G2/M cell cycle arrest in lung cancer cells

Bioorg Med Chem Lett. 2020 Jan 1;30(1):126777. doi: 10.1016/j.bmcl.2019.126777. Epub 2019 Oct 26.

Abstract

The anticancer potential of a synthetic 2,3-diarylindole (PCNT13) has been demonstrated in A549 lung cancer cells by inducing both apoptosis and autophagic cell death. In this report, we designed to connect a fluorophore to the compound via a hydrophilic linker for monitoring intracellular localization. The best position for linker attachment was identified from cytotoxicity and effect on cell morphology of newly synthesized PCNT13 derivatives bearing hydrophilic linker. Cytotoxicity and effect on cell morphology related to the parental compound were used to identify the optimum position for linker attachment in the PCNT13 chemical structure. The fluorophore-PCNT13 conjugate was found to localize in the cytoplasm. Microtubules were found to be one of the cytosolic target proteins of PCNT13, as the compound could inhibit tubulin polymerization in vitro. A molecular docking study revealed that PCNT13 binds at the colchicine binding site on the α/β-tubulin heterodimer. The effect of PCNT13 on microtubule dynamics caused cell cycle arrest in the G2/M phase as analyzed by flow cytometric analysis.

Keywords: 2,3-Diarylindole; Cell cycle arrest; Lung cancer; Tubulin polymerization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • M Phase Cell Cycle Checkpoints / drug effects
  • Microtubules / drug effects
  • Models, Molecular
  • Tubulin / chemistry
  • Tubulin / metabolism

Substances

  • Antineoplastic Agents
  • Indoles
  • PCNT13
  • Tubulin