Synthesis of sesquiterpene-inspired derivatives designed for covalent binding and their inhibition of the NF-κB pathway

Org Biomol Chem. 2014 Jan 14;12(2):370-5. doi: 10.1039/c3ob42049c.

Abstract

A significant portion of bioactive secondary metabolites are endowed with reactive functionalities that can engage in covalent interactions with their target. Sesquiterpene lactones in particular are rich in Michael acceptors that react with cysteines. Several polycyclic scaffolds derived from total synthesis or readily available polycyclic terpenes were used as the starting point in the synthesis of a library aiming to project mildly reactive functionalities (Michael acceptors or chloroacetates) with diverse geometries. Screening of the library for inhibition of the NF-κB pathway revealed several potent inhibitors that are chemically readily accessible.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Molecular Conformation
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Sesquiterpenes / chemical synthesis
  • Sesquiterpenes / chemistry
  • Sesquiterpenes / pharmacology*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • NF-kappa B
  • Sesquiterpenes
  • Small Molecule Libraries