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

Key Laboratory of Drug Targeting and Drug Delivery Systems of the Ministry of Education and State Key Laboratory of Biotherapy, Department of Medicinal Natural Products, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
Department of Drug Discovery and Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA
Department of Pharmaceutical Sciences, Center for Drug Discovery, College of Pharmacy, and Cancer Genes and Molecular Regulation Program, Buffett Cancer Center, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198, USA
Departments of Biochemistry and Medicine, Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, 1300 Morris Park Avenue, Forchheimer G46, Bronx, NY 10461, USA
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
The Innovative Drug Research Center, Chongqing University, Chongqing 400000, China
Department of Chemistry, BioScience Research Collaborative, Rice University, 6500 Main Street, Houston, TX 77030, USA
Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs, Tampa, FL 33612, USA
Authors to whom correspondence should be addressed.
Mar. Drugs 2014, 12(8), 4311-4325;
Received: 8 April 2014 / Revised: 23 May 2014 / Accepted: 14 July 2014 / Published: 29 July 2014
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. View Full-Text
Keywords: marinopyrroles; protein-protein interaction disruptors; apoptosis; SAR marinopyrroles; protein-protein interaction disruptors; apoptosis; SAR
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Cheng, C.; Liu, Y.; Balasis, M.E.; Garner, T.P.; Li, J.; Simmons, N.L.; Berndt, N.; Song, H.; Pan, L.; Qin, Y.; Nicolaou, K.C.; Gavathiotis, E.; Sebti, S.M.; Li, R. Marinopyrrole Derivatives with Sulfide Spacers as Selective Disruptors of Mcl-1 Binding to Pro-Apoptotic Protein Bim. Mar. Drugs 2014, 12, 4311-4325.

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