Pro-apoptotic carboxamide analogues of natural fislatifolic acid targeting Mcl-1 and Bcl-2

Bioorg Med Chem Lett. 2020 Apr 1;30(7):127003. doi: 10.1016/j.bmcl.2020.127003. Epub 2020 Feb 3.

Abstract

A library of 26 novel carboxamides deriving from natural fislatifolic acid has been prepared. The synthetic strategy involved a bio-inspired Diels-Alder cycloaddition, followed by functionalisations of the carbonyl moiety. All the compounds were evaluated on Bcl-xL, Mcl-1 and Bcl-2 proteins. In this series of cyclohexenyl chalcone analogues, six compounds behaved as dual Bcl-xL/Mcl-1 inhibitors in micromolar range and one exhibited sub-micromolar affinities toward Mcl-1 and Bcl-2. The most potent compounds evaluated on A549 and MCF7 cancer cell lines showed moderate cytotoxicities.

Keywords: Carboxamide; Diels-Alder; Mcl-1; Natural product; Pro-apoptotic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / pharmacology*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cyclohexanecarboxylic Acids / chemical synthesis
  • Cyclohexanecarboxylic Acids / pharmacology*
  • Drug Screening Assays, Antitumor
  • Humans
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / pharmacology
  • Stereoisomerism
  • bcl-X Protein / antagonists & inhibitors*

Substances

  • Amides
  • Antineoplastic Agents
  • BCL2L1 protein, human
  • Cyclohexanecarboxylic Acids
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Small Molecule Libraries
  • bcl-X Protein