Sudemycin K: a synthetic antitumor splicing inhibitor variant with improved activity and versatile chemistry

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• dc.contributor.author Makowski, Kamil
• dc.contributor.author Vigevani, Luisa, 1985-
• dc.contributor.author Albericio, Fernando
• dc.contributor.author Valcárcel, J. (Juan)
• dc.contributor.author Álvarez, Mercedes
• dc.date.accessioned 2018-11-16T10:38:35Z
• dc.date.available 2018-11-16T10:38:35Z
• dc.date.issued 2017
• dc.description.abstract Important links exist between the process of pre-mRNA splicing and cancer, as illustrated by the frequent mutation of splicing factors in tumors and the emergence of various families of antitumor drugs that target components of the splicing machinery, notably SF3B1, a protein subunit of spliceosomal U2 small nuclear ribonucleoprotein particle (snRNP). Sudemycins are synthetic compounds that harbor a pharmacophore common to various classes of splicing inhibitors. Here, we describe the synthesis and functional characterization of novel sudemycin analogues that functionally probe key chemical groups within this pharmacophore. Our results confirm the importance of a conjugated diene group and in addition reveal significant spatial flexibility in this region of the molecule. Sudemycin K, a derivative that replaces the pharmacophore's oxycarbonyl by an amide group, displays improved potency as an inhibitor of cancer cell proliferation, as a regulator of alternative splicing in cultured cells and as an inhibitor of in vitro spliceosome assembly. Sudemycin K displays higher stability, likely related to the replacement of the oxycarbonyl group, which can be a substrate of esterases, by an amide group. The activity and special reactivity of sudemycin K can pave the way to the synthesis and evaluation of a variety of novel sudemycin derivatives.
• dc.description.sponsorship This study was supported by Fundación Botín, Banco de Santander through its Santander Universities Global Division, Consolider RNAREG, AGAUR, MINECO and the European Research Council. We acknowledge support of the Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa 2013-2017.’ This work was partially funded by the CICYT (CTQ2015-67870P) and Generalitat de Catalunya (2014 SGR 137)
• dc.format.mimetype application/pdf
• dc.identifier.citation Makowski K, Vigevani L, Albericio F, Valcárcel J, Álvarez M. Sudemycin K: a synthetic antitumor splicing inhibitor variant with improved activity and versatile chemistry. ACS Chem Biol. 2017 Jan 20;12(1):163-73. DOI: 10.1021/acschembio.6b00562
• dc.identifier.doi http://dx.doi.org/10.1021/acschembio.6b00562
• dc.identifier.issn 1554-8929
• dc.identifier.uri http://hdl.handle.net/10230/35778
• dc.language.iso eng
• dc.publisher American Chemical Society (ACS)
• dc.relation.ispartof ACS Chemical Biology. 2017 Jan 20;12(1):163-73
• dc.rights This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical Biology, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/acschembio.6b00562
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.other Medicaments antineoplàstics
• dc.subject.other Empalmament (Genètica)
• dc.subject.other Medicaments -- Efectes secundaris
• dc.subject.other Compostos spiro
• dc.subject.other Química
• dc.title Sudemycin K: a synthetic antitumor splicing inhibitor variant with improved activity and versatile chemistry
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion