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

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.