Improved synthesis, resolution, absolute configuration determination and biological evaluation of HLM006474 enantiomers

Bioorg Med Chem Lett. 2019 Feb 1;29(3):380-382. doi: 10.1016/j.bmcl.2018.12.037. Epub 2018 Dec 17.

Abstract

An improved green synthesis of the E2F inhibitor HLM0066474 is described, using solvent-free and microwave irradiation conditions. The two enantiomers are separated using semi-preparative separation on Chiralpak ID and their absolute configuration is determined by vibrational circular dichroism (VCD) analysis. Biological evaluation of both enantiomers on E2F1 transcriptional activity reveals that the (+)-R, but not the (-)-S enantiomer is biologically active in repressing E2F1 transcriptional activity.

Keywords: Absolute configuration determination; Betti reaction; Biological activity; HLM006474 enantiomers; Microwave assisted synthesis; Solvent-free reaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology*
  • Circular Dichroism
  • Dose-Response Relationship, Drug
  • E2F1 Transcription Factor / antagonists & inhibitors*
  • E2F1 Transcription Factor / metabolism
  • HEK293 Cells
  • Humans
  • Hydroxyquinolines / chemistry
  • Hydroxyquinolines / pharmacology*
  • Molecular Structure
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Aminopyridines
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • HLM006474
  • Hydroxyquinolines