Synthesis and Evaluation of 9- epi -Koshidacin B as Selective Inhibitor of Histone Deacetylase 1

A concise synthetic route to an epimer of the recently isolated biologically active cyclic tetrapeptide koshidacin B has been developed, which featured a late-stage functionalization of a macrocyclic scaffold through a cross metathesis reaction. The synthetic 9- -koshidacin B showed marginal differe...

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Bibliographic Details
Published in:Journal of natural products (Washington, D.C.) D.C.), 2024-12
Main Authors: Ghosh, Rajat, Biswas, Sima, Bagchi, Angshuman, Chattopadhyay, Shital K
Format: Article
Language:English
Online Access:Get full text
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Summary:A concise synthetic route to an epimer of the recently isolated biologically active cyclic tetrapeptide koshidacin B has been developed, which featured a late-stage functionalization of a macrocyclic scaffold through a cross metathesis reaction. The synthetic 9- -koshidacin B showed marginal differences in spectroscopic behavior with that of the natural product but exhibited conformational preferences similar to those reported for analogous substrate chlamydocin. Moreover, it exhibited a useful level of selective inhibition of biologically relevant enzyme histone deacetylase 1 with an IC value of 0.145 μM over two other isoforms. Docking studies indicate that the natural product as well as its 9-epimer binds very similarly to the active site of HDAC1 indicating little influence of the configuration of the C9-stereocenter.
ISSN:1520-6025
1520-6025
DOI:10.1021/acs.jnatprod.4c00913