Design and synthesis of formononetin-dithiocarbamate hybrids that inhibit growth and migration of PC-3 cells via MAPK/Wnt signaling pathways

Eur J Med Chem. 2017 Feb 15:127:87-99. doi: 10.1016/j.ejmech.2016.12.027. Epub 2016 Dec 14.

Abstract

A series of novel formononetin-dithiocarbamate derivatives were designed, synthesized and evaluated for antiproliferative activity against three selected cancer cell line (MGC-803, EC-109, PC-3). The first structure-activity relationship (SAR) for this formononetin-dithiocarbamate scaffold is explored in this report with evaluation of 14 variants of the structural class. Among these analogues, tert-butyl 4-(((3-((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl)oxy)propyl)thio)carbonothioyl)piperazine-1-carboxylate (8i) showed the best inhibitory activity against PC-3 cells (IC50 = 1.97 μM). Cellular mechanism studies elucidated 8i arrests cell cycle at G1 phase and regulates the expression of G1 checkpoint-related proteins in concentration-dependent manners. Furthermore, 8i could inhibit cell growth via MAPK signaling pathway and inhibit migration via Wnt pathway in PC-3 cells.

Keywords: Dithiocarbamate; Formononetin; Growth; Migration.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects
  • Chemistry Techniques, Synthetic
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Isoflavones / chemical synthesis
  • Isoflavones / chemistry*
  • Isoflavones / pharmacology*
  • MAP Kinase Signaling System / drug effects*
  • Structure-Activity Relationship
  • Thiocarbamates / chemistry*
  • Wnt Signaling Pathway / drug effects*

Substances

  • Antineoplastic Agents
  • Isoflavones
  • Thiocarbamates
  • formononetin