Marinopyrrole Derivatives with Sulfide Spacers As Selective Disruptors of Mcl-1 Binding to Pro-apoptotic Protein Bim

Overview

Journal Mar Drugs

Publisher MDPI

Specialties Biology
Pharmacology

Date 2014 Jul 31

PMID 25076060

Citations 3

Authors

Chunwei Cheng

Yan Liu

Maria E Balasis

Thomas P Garner

Jerry Li

Nicholas L Simmons

Norbert Berndt

Hao Song

Lili Pan

Yong Qin

K C Nicolaou

Evripidis Gavathiotis

Said M Sebti

Rongshi Li

Affiliations

Soon will be listed here.

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.

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