Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1-Activated Prodrugs as Antiviral Agents

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dc.contributor.authorRichter, Michael
dc.contributor.authorBoldescu, Veaceslav
dc.contributor.authorGraf, Dominik
dc.contributor.authorStreicher, Felix
dc.contributor.authorDimoglo, Anatoli
dc.contributor.authorBartenschlager, Ralf
dc.contributor.authorKlein, Christian D.
dc.date.accessioned2020-04-30T23:32:28Z
dc.date.available2020-04-30T23:32:28Z
dc.date.issued2019
dc.departmentDÜ, Mühendislik Fakültesien_US
dc.descriptionStreicher, Felix/0000-0002-8375-2958; Klein, Christian/0000-0003-3522-9182; Richter, Michael/0000-0002-8227-0543; Bartenschlager, Ralf/0000-0001-5601-9307en_US
dc.descriptionWOS: 000458933200005en_US
dc.descriptionPubMed: 30605241en_US
dc.description.abstractRecent studies indicate that tubulin can be a host factor for vector-borne flaviviruses like dengue (DENV) and Zika (ZIKV), and inhibitors of tubulin polymerization such as colchicine have been demonstrated to decrease virus replication. However, toxicity limits the application of these compounds. Herein we report prodrugs based on combretastatin and colchicine derivatives that contain an ester cleavage site for human carboxylesterase, a highly abundant enzyme in monocytes and hepatocytes targeted by DENV. Relative to their parent compounds, the cytotoxicity of these prodrugs was reduced by several orders of magnitude. All synthesized prodrugs containing a leucine ester were hydrolyzed by the esterase in vitro. In contrast to previous reports, the phenylglycine esters were not cleaved by human carboxylesterase. The antiviral activity of combretastatin, colchicine, and selected prodrugs against DENV and ZIKV in cell culture was observed at low micromolar and sub-micromolar concentrations. In addition, docking studies were performed to understand the binding mode of the studied compounds to tubulin.en_US
dc.description.sponsorshipAlexander vonHumboldt FoundationAlexander von Humboldt Foundationen_US
dc.description.sponsorshipV.B. is grateful for generous funding under the Georg Forster Research Fellowship received from the Alexander vonHumboldt Foundation. The authors acknowledge the technical assistance of Stephanie Kallis for the ZIKV antiviral assay, Natascha Stefan for the help in cell culture, and Heiko Rudy for the mass spectrometry data. M.R. thanks Torben LangHeinrich for his assistance in the synthesis of compound 9 a.en_US
dc.identifier.doi10.1002/cmdc.201800641en_US
dc.identifier.endpage483en_US
dc.identifier.issn1860-7179
dc.identifier.issn1860-7187
dc.identifier.issue4en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage469en_US
dc.identifier.urihttps://doi.org/10.1002/cmdc.201800641
dc.identifier.urihttps://hdl.handle.net/20.500.12684/4730
dc.identifier.volume14en_US
dc.identifier.wosWOS:000458933200005en_US
dc.identifier.wosqualityQ2en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakPubMeden_US
dc.indekslendigikaynakScopusen_US
dc.language.isoenen_US
dc.publisherWiley-V C H Verlag Gmbhen_US
dc.relation.ispartofChemmedchemen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectantiviral agentsen_US
dc.subjectcolchicineen_US
dc.subjectcombretastatinen_US
dc.subjectdengueen_US
dc.subjectprodrugsen_US
dc.subjecttubulin ligandsen_US
dc.subjectZikaen_US
dc.titleSynthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1-Activated Prodrugs as Antiviral Agentsen_US
dc.typeArticleen_US

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