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Marinopyrrole derivatives with sulfide spacers as selective disruptors of Mcl-1 binding to pro-apoptotic protein Bim

Academic Article
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Overview

related to degree

  • Simmons, Nicholas, Ph.D. in Chemistry, Scripps Research 2009 - 2015

authors

  • Cheng, C.
  • Liu, Y.
  • Balasis, M. E.
  • Garner, T. P.
  • Li, J.
  • Simmons, Nicholas
  • Berndt, N.
  • Song, H.
  • Pan, L.
  • Qin, Y.
  • Nicolaou, K.C.
  • Gavathiotis, E.
  • Sebti, S. M.
  • Li, R.

publication date

  • August 2014

journal

  • Marine Drugs  Journal

abstract

  • A series of novel marinopyrroles with sulfide and sulphone spacers 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-xL, was evaluated using ELISA assays. Fluorescence-quenching (FQ) assays confirmed the direct binding of marinopyrroles to Mcl-1. Benzyl- and benzyl methoxy-containing sulfide derivatives 4 and 5 were highly potent dual Mcl-1/Bim and Bcl-xL/Bim disruptors (IC50 values of 600 and 700 nM), whereas carboxylate-containing sulfide derivative 9 exhibited 16.4-fold more selectivity for disrupting Mcl-1/Bim over Bcl-xL/Bim binding. In addition, a nonsymmetrical marinopyrrole 12 is as equally potent as the parent marinopyrrole A (1) for disrupting both Mcl-1/Bim and Bcl-xL/Bim binding. Some of the derivatives were also active in intact human breast cancer cells where they reduced the levels of Mcl-1, induced programd cell death (apoptosis) and inhibited cell proliferation.

subject areas

  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Cell Line, Tumor
  • Humans
  • Membrane Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Protein Binding
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrroles
  • Sulfides
  • bcl-X Protein
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Research

keywords

  • SAR
  • apoptosis
  • marinopyrroles
  • protein-protein interaction disruptors
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Identity

PubMed Central ID

  • PMC4145318

International Standard Serial Number (ISSN)

  • 1660-3397

Digital Object Identifier (DOI)

  • 10.3390/md12084311

PubMed ID

  • 25076060
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Additional Document Info

start page

  • 4311

end page

  • 4325

volume

  • 12

issue

  • 8

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