Xanthone derivatives as phosphoglycerate mutase 1 inhibitors: Design, synthesis, and biological evaluation

Bioorg Med Chem. 2018 May 1;26(8):1961-1970. doi: 10.1016/j.bmc.2018.02.044. Epub 2018 Feb 24.

Abstract

Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that dynamically converts 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG), which was upregulated to coordinate glycolysis, pentose phosphate pathway (PPP) and serine biosynthesis to promote cancer cell proliferation and tumor growth in a variety of cancers. However, only a few inhibitors of PGAM1 have been reported with poor molecular or cellular efficacy. In this paper, a series of xanthone derivatives were discovered as novel PGAM1 inhibitors through scaffold hopping and sulfonamide reversal strategy based on the lead compound PGMI-004A. Most xanthone derivatives showed higher potency against PGAM1 than PGMI-004A and exhibited moderate anti-proliferation activity on different cancer cell lines.

Keywords: Cancer cell metabolism; Inhibitors; Phosphoglycerate mutase 1; Xanthone derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Molecular Docking Simulation
  • Phosphoglycerate Mutase / antagonists & inhibitors
  • Phosphoglycerate Mutase / metabolism*
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Xanthones / chemistry*
  • Xanthones / metabolism
  • Xanthones / pharmacology

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Xanthones
  • Phosphoglycerate Mutase
  • phosphoglycerate mutase 1, human