Synthesis and biological evaluation of novel withangulatin A derivatives as potential anticancer agents

Bioorg Chem. 2021 Mar:108:104690. doi: 10.1016/j.bioorg.2021.104690. Epub 2021 Feb 2.

Abstract

Novel withangulatin A (WA) derivatives were synthesized and evaluated for antiproliferative activity against four human cancer cell lines (U2OS, MDA-MB-231, HepG2, and A549). Among these derivatives, 10 exhibited the most potent antiproliferative activity, with an IC50 value of 74.0 nM against the human breast cancer cell line MDA-MB-231 and potency that was 70-fold that of WA (IC50 = 5.22 µM). Moreover, 10 caused G2-phase cell cycle arrest in a concentration-dependent manner and induced the apoptosis of MDA-MB-231 cells by increasing intracellular reactive oxygen species (ROS). Compound 10 showed a high selectivity index (SI = 267.03) for breast cancer MDA-MB-231 cells. These results suggest that 10 is a promising anticancer agent.

Keywords: Anticancer; Apoptosis; Cell cycle; Reactive oxygen species; Withangulatin A derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Membrane Potential, Mitochondrial
  • Pregnenes / chemical synthesis*
  • Pregnenes / pharmacology
  • Reactive Oxygen Species / metabolism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Pregnenes
  • Reactive Oxygen Species
  • withangulatin A