Design, synthesis and preliminary biological studies of pyrrolidine derivatives as Mcl-1 inhibitors

Bioorg Med Chem. 2015 Dec 15;23(24):7685-93. doi: 10.1016/j.bmc.2015.11.014. Epub 2015 Nov 14.

Abstract

Anti-apoptotic proteins, such as B-cell lymphoma (Bcl-2) protein, myeloid cell leukemia sequence 1 (Mcl-1) protein, are potential targets for cancer treatment. In the studies, a series of pyrrolidine derivatives were developed as potent Mcl-1 inhibitors. The preliminary biological studies suggested that most of target compounds exhibit good abilities for targeting Mcl-1 protein. Among them, compound 21 (Ki=0.53μM) exhibited equal inhibitory activities towards Mcl-1 protein compared to positive control gossypol (Ki=0.39μM). This compound also possessed good antiproliferative activities against MDA-MB-231 and PC-3 cancer cells.

Keywords: Anti-tumor; Apoptosis; Bcl-2; Mcl-1; Pyrrolidine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design
  • Humans
  • Molecular Docking Simulation
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacology*

Substances

  • Antineoplastic Agents
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Pyrrolidines
  • pyrrolidine