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.
Highlights
Marinopyrroles were first reported to show antibiotic activity against methicillin-resistantStaphylococcus aureus (MRSA) in 2008 by the Fenical group [1]
To determine if the marinopyrroles are active in intact cells, the human breast cancer MDA-MB-468 cells were treated with the marinopyrrole derivatives (40 μM for 16 h)
We evaluated the effects of the compounds on programed cell death by determining their ability to induce cleaved caspase
Summary
Marinopyrroles were first reported to show antibiotic activity against methicillin-resistant. Staphylococcus aureus (MRSA) in 2008 by the Fenical group [1] Due to their novel molecular structures and promising biological properties, marinopyrroles have attracted considerable attention [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16]. Following our finding that (±)-marinopyrrole A (1) antagonizes Mcl-1 and overcomes resistance of human cancer cells to the Bcl-xL antagonist ABT-737 [10], we recently reported a series. We report on the design of a series of marinopyrroles with sulfide and sulphone spacers, some as dual Mcl-1 and Bcl-xL antagonists and others as selective disruptors of Mcl-1 binding to Bim
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