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

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    Author
    Cheng , Chunwei; Liu, Yan; Balasis, Maria E.; Garner, Thomas P.; Li, Jerry; More... Simmons, Nicholas L.; Berndt, Norbert; Song, Hao; Pan, Lili; Qin, Yong; Nicolaou, K.C.; Gavathiotis, Evripidis; Sebti , Said M.; Li, Rongshi Less...
    Date
    2014
    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.
    Citation
    Cheng , Chunwei, Liu, Yan, Balasis, Maria E., et al.. "Marinopyrrole Derivatives with Sulfide Spacers as Selective Disruptors of Mcl-1 Binding to Pro-Apoptotic Protein Bim." Marine Drugs, 12, (2014) MDPI: 4311-4325. http://dx.doi.org/10.3390/md12084311.
    Published Version
    http://dx.doi.org/10.3390/md12084311
    Keyword
    marinopyrroles; protein-protein interaction disruptors; apoptosis; SAR
    Type
    Journal article
    Publisher
    MDPI
    Citable link to this page
    https://hdl.handle.net/1911/77133
    Rights
    This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
    Link to License
    http://creativecommons.org/licenses/by/3.0/
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    • Chemistry Publications [636]
    • Faculty Publications [4988]

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    Managed by the Digital Scholarship Services at Fondren Library, Rice University
    Physical Address: 6100 Main Street, Houston, Texas 77005
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