Synthesis and biological evaluation of thielocin B1 analogues as protein-protein interaction inhibitors of PAC3 homodimer

Bioorg Med Chem. 2018 Dec 15;26(23-24):6023-6034. doi: 10.1016/j.bmc.2018.11.001. Epub 2018 Nov 7.

Abstract

The synthesis and biological evaluation of thielocin B1 analogues have been demonstrated. Fourteen analogues modified in the central core and terminal carboxylic acid moiety were concisely synthesized by simple esterification or etherification reaction. The evaluation of synthetic analogues as inhibitors of proteasome assembling chaperone (PAC) complexes (the PAC3 homodimer and PAC1/PAC2) revealed that the natural product-like bending structure and terminal carboxylic acid groups were crucial for its biological activity. Moreover, SAR and in silico docking studies indicated that all methyl groups on the diphenyl ether moiety of thielocin B1 contribute to the potent and selective inhibition of the PAC3 homodimer via hydrophobic interactions.

Keywords: Multi-substituted benzene; Natural product analogues; Protein assembling chaperon 3 (PAC3); Protein-protein interaction inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzoates / chemical synthesis
  • Benzoates / chemistry
  • Benzoates / pharmacology*
  • Carboxylic Acids / chemical synthesis
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology*
  • Dimerization
  • Dose-Response Relationship, Drug
  • Esters / chemical synthesis
  • Esters / chemistry
  • Esters / pharmacology*
  • Hydrophobic and Hydrophilic Interactions
  • Molecular Chaperones / antagonists & inhibitors*
  • Molecular Chaperones / metabolism
  • Molecular Structure
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Binding / drug effects
  • Structure-Activity Relationship

Substances

  • Benzoates
  • Carboxylic Acids
  • Esters
  • Molecular Chaperones
  • thielocin B1
  • Proteasome Endopeptidase Complex