Comprehensive Structure–Activity Relationship Studies of Cepafungin Enabled by Biocatalytic C–H Oxidations

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dc.citation.firstpage239en_US
dc.citation.issueNumber2en_US
dc.citation.journalTitleACS Central Scienceen_US
dc.citation.lastpage251en_US
dc.citation.volumeNumber9en_US
dc.contributor.authorAmatuni, Alexanderen_US
dc.contributor.authorShuster, Antonen_US
dc.contributor.authorAbegg, Danielen_US
dc.contributor.authorAdibekian, Alexanderen_US
dc.contributor.authorRenata, Hansen_US
dc.date.accessioned2023-03-10T19:04:11Zen_US
dc.date.available2023-03-10T19:04:11Zen_US
dc.date.issued2023en_US
dc.description.abstractThe cepafungins are a class of highly potent and selective eukaryotic proteasome inhibitor natural products with potential to treat refractory multiple myeloma and other cancers. The structure–activity relationship of the cepafungins is not fully understood. This Article chronicles the development of a chemoenzymatic approach to cepafungin I. A failed initial route involving derivatization of pipecolic acid prompted us to examine the biosynthetic pathway for the production of 4-hydroxylysine, which culminated in the development of a 9-step synthesis of cepafungin I. An alkyne-tagged analogue enabled chemoproteomic studies of cepafungin and comparison of its effects on global protein expression in human multiple myeloma cells to the clinical drug bortezomib. A preliminary series of analogues elucidated critical determinants of potency in proteasome inhibition. Herein we report the chemoenzymatic syntheses of 13 additional analogues of cepafungin I guided by a proteasome-bound crystal structure, 5 of which are more potent than the natural product. The lead analogue was found to have 7-fold greater proteasome β5 subunit inhibitory activity and has been evaluated against several multiple myeloma and mantle cell lymphoma cell lines in comparison to the clinical drug bortezomib.en_US
dc.identifier.citationAmatuni, Alexander, Shuster, Anton, Abegg, Daniel, et al.. "Comprehensive Structure–Activity Relationship Studies of Cepafungin Enabled by Biocatalytic C–H Oxidations." <i>ACS Central Science,</i> 9, no. 2 (2023) American Chemical Society: 239-251. https://doi.org/10.1021/acscentsci.2c01219.en_US
dc.identifier.digitalacscentsci-2c01219en_US
dc.identifier.doihttps://doi.org/10.1021/acscentsci.2c01219en_US
dc.identifier.urihttps://hdl.handle.net/1911/114497en_US
dc.language.isoengen_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsThis is an open access article under the Creative Commons CC BY 4.0 license.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleComprehensive Structure–Activity Relationship Studies of Cepafungin Enabled by Biocatalytic C–H Oxidationsen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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