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

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dc.citation.firstpage4311
dc.citation.journalTitleMarine Drugs
dc.citation.lastpage4325
dc.citation.volumeNumber12
dc.contributor.authorCheng , Chunwei
dc.contributor.authorLiu, Yan
dc.contributor.authorBalasis, Maria E.
dc.contributor.authorGarner, Thomas P.
dc.contributor.authorLi, Jerry
dc.contributor.authorSimmons, Nicholas L.
dc.contributor.authorBerndt, Norbert
dc.contributor.authorSong, Hao
dc.contributor.authorPan, Lili
dc.contributor.authorQin, Yong
dc.contributor.authorNicolaou, K.C.
dc.contributor.authorGavathiotis, Evripidis
dc.contributor.authorSebti , Said M.
dc.contributor.authorLi, Rongshi
dc.contributor.orgBioScience Research Collaborative
dc.date.accessioned2014-08-29T20:22:43Z
dc.date.available2014-08-29T20:22:43Z
dc.date.issued2014
dc.description.abstractA 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.
dc.identifier.citationCheng , 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." <i>Marine Drugs,</i> 12, (2014) MDPI: 4311-4325. http://dx.doi.org/10.3390/md12084311.
dc.identifier.doihttp://dx.doi.org/10.3390/md12084311
dc.identifier.urihttps://hdl.handle.net/1911/77133
dc.language.isoeng
dc.publisherMDPI
dc.rightsThis is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/
dc.subject.keywordmarinopyrroles
dc.subject.keywordprotein-protein interaction disruptors
dc.subject.keywordapoptosis
dc.subject.keywordSAR
dc.titleMarinopyrrole Derivatives with Sulfide Spacers as Selective Disruptors of Mcl-1 Binding to Pro-Apoptotic Protein Bim
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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