Structure-activity relationship and antitumor activity of thio-benzodiazepines as p53-MDM2 protein-protein interaction inhibitors

Eur J Med Chem. 2012 Oct;56:10-6. doi: 10.1016/j.ejmech.2012.08.003. Epub 2012 Aug 10.

Abstract

In order to discuss the structure-activity relationship (SAR) of the thio-benzodiazepine compounds which showed excellent activity against p53-MDM2 protein-protein interaction, we designed and synthesized twenty compounds with electrophilic and nucleophilic groups on the benzene ring. Among them, compounds 8i (K(i) = 91 nM) and 8n (K(i) = 89 nM) showed better binding activity than that of the reference drug Nutlin-3a (K(i) = 121 nM). In addition, in vitro antitumor activity against Saos-2, U-2 OS, A549 and NCI-H1299 cell-lines were assayed by the MTT method. Especially, compounds 8i and 8n possessed excellent biological activity and good selectivity comparable to Nutlin-3a, which were promising candidates for further evaluation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzodiazepines / chemical synthesis
  • Benzodiazepines / chemistry
  • Benzodiazepines / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / chemistry
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / chemical synthesis
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / pharmacology*
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / chemistry

Substances

  • Antineoplastic Agents
  • Ligands
  • Sulfhydryl Compounds
  • Tumor Suppressor Protein p53
  • Benzodiazepines
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2