Design, synthesis and preliminary biological evaluation of indole-3-carboxylic acid-based skeleton of Bcl-2/Mcl-1 dual inhibitors

Bioorg Med Chem. 2017 Mar 15;25(6):1939-1948. doi: 10.1016/j.bmc.2017.02.014. Epub 2017 Feb 11.

Abstract

The B-cell lymphoma-2 (Bcl-2) family proteins are attractive targets for cancer therapy. In our previous work, the structure-activity relationship of WL-276 was studied. According to the results, rhodanine derivatives show potent binding affinity for Bcl-2 and Mcl-1 protein and show weaker activity against Bcl-XL protein. Based on the previous results, a new class of indole-3-carboxylic acid-based derivatives were designed and synthesized as Bcl-2/Mcl-1 dual inhibitors. Among them, compound 17 has a Ki value of 0.26μM for Bcl-2 protein and is better than WL-276. Furthermore, it inhibits the myeloid cell leukemia sequence 1 (Mcl-1) protein with a Ki value of 72nM. Especially, compound 31 can selectively acting on Bcl-2 and Mcl-1 protein but not Bcl-XL protein, which has great significance for developing dual inhibitors targeting Bcl-2 and Mcl-1 protein, as well as specific antitumor abilities in cells.

Keywords: Anti-tumor; Bcl-2/Mcl-1; Indole-3-carboxylic acid-based derivatives; Inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbon-13 Magnetic Resonance Spectroscopy
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Fluorescence Polarization
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proton Magnetic Resonance Spectroscopy
  • Spectrometry, Mass, Electrospray Ionization

Substances

  • Indoles
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • indole-3-carboxylic acid