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

[Image: see text] The 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...

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Autores principales: Amatuni, Alexander, Shuster, Anton, Abegg, Daniel, Adibekian, Alexander, Renata, Hans
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9951290/
https://www.ncbi.nlm.nih.gov/pubmed/36844499
http://dx.doi.org/10.1021/acscentsci.2c01219
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author Amatuni, Alexander
Shuster, Anton
Abegg, Daniel
Adibekian, Alexander
Renata, Hans
author_facet Amatuni, Alexander
Shuster, Anton
Abegg, Daniel
Adibekian, Alexander
Renata, Hans
author_sort Amatuni, Alexander
collection PubMed
description [Image: see text] The 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.
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spelling pubmed-99512902023-02-25 Comprehensive Structure–Activity Relationship Studies of Cepafungin Enabled by Biocatalytic C–H Oxidations Amatuni, Alexander Shuster, Anton Abegg, Daniel Adibekian, Alexander Renata, Hans ACS Cent Sci [Image: see text] The 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. American Chemical Society 2023-01-27 /pmc/articles/PMC9951290/ /pubmed/36844499 http://dx.doi.org/10.1021/acscentsci.2c01219 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Amatuni, Alexander
Shuster, Anton
Abegg, Daniel
Adibekian, Alexander
Renata, Hans
Comprehensive Structure–Activity Relationship Studies of Cepafungin Enabled by Biocatalytic C–H Oxidations
title Comprehensive Structure–Activity Relationship Studies of Cepafungin Enabled by Biocatalytic C–H Oxidations
title_full Comprehensive Structure–Activity Relationship Studies of Cepafungin Enabled by Biocatalytic C–H Oxidations
title_fullStr Comprehensive Structure–Activity Relationship Studies of Cepafungin Enabled by Biocatalytic C–H Oxidations
title_full_unstemmed Comprehensive Structure–Activity Relationship Studies of Cepafungin Enabled by Biocatalytic C–H Oxidations
title_short Comprehensive Structure–Activity Relationship Studies of Cepafungin Enabled by Biocatalytic C–H Oxidations
title_sort comprehensive structure–activity relationship studies of cepafungin enabled by biocatalytic c–h oxidations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9951290/
https://www.ncbi.nlm.nih.gov/pubmed/36844499
http://dx.doi.org/10.1021/acscentsci.2c01219
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