Design and application of a rigid quinazolone scaffold based on two-face Bim α-helix mimicking

Eur J Med Chem. 2013 Nov:69:711-8. doi: 10.1016/j.ejmech.2013.09.030. Epub 2013 Sep 21.

Abstract

Based on our previous discovery of an anthraquinone scaffold mimicking two faces of Bim α-helix, we derived a quinazolone scaffold through structure simplification and optimization. It was inferred that a rigid bicyclic ring was necessary and efficient to maintain the two-faced binding mode. A novel dual inhibitor 6c [6,7,8-trihydroxy-3-(2-hydroxy-5-methylbenzyl)-2-phenylquinazolin-4(3H)-one] was obtained based on this scaffold. 6c exhibited dual binding activity with K(i) values of 0.123 μM for Mcl-1 and 0.179 μM for Bcl-2.

Keywords: Bcl-2; JQFLKAJQKGNCSW-UHFFFAOYSA-N; Mcl-1; Quinazolone; RNUPWQDKOJAKGW-UHFFFAOYSA-N; SYEGIOUDEHFYQT-UHFFFAOYSA-N; Two-faced; UGGKGLCTXKBKQS-UHFFFAOYSA-N; α-Helix.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Models, Molecular
  • Molecular Mimicry*
  • Molecular Structure
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology*
  • Structure-Activity Relationship

Substances

  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • Quinazolines