Cyclic marinopyrrole derivatives as disruptors of Mcl-1 and Bcl-x(L) binding to Bim

Mar Drugs. 2014 Mar 7;12(3):1335-48. doi: 10.3390/md12031335.

Abstract

A series of novel cyclic marinopyrroles were designed and synthesized. Their activity to disrupt the binding of the pro-apoptotic protein, Bim, to the pro-survival proteins, Mcl-1 and Bcl-x(L), was evaluated using ELISA assays. Both atropisomers of marinopyrrole A (1) show similar potency. A tetrabromo congener 9 is two-fold more potent than 1. Two novel cyclic marinopyrroles (3 and 4) are two- to seven-fold more potent than 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / chemistry*
  • Bcl-2-Like Protein 11
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Catalysis
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • Indicators and Reagents
  • Isomerism
  • Magnetic Resonance Spectroscopy
  • Marine Toxins / pharmacology*
  • Membrane Proteins / chemistry*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins / chemistry*
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry*
  • Pyrroles / pharmacology*
  • Spectrophotometry, Ultraviolet
  • Structure-Activity Relationship
  • bcl-X Protein / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Indicators and Reagents
  • MCL1 protein, human
  • Marine Toxins
  • Membrane Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins
  • Pyrroles
  • bcl-X Protein