Stereochemical Control of Splice Modulation in FD-895 Analogues

Highly functionalized skeletons of macrolide natural
products gain
access to rare spatial arrangements of atoms, where changes in stereochemistry
can have a profound impact on the structure and function. Spliceosome
modulators present a unique consensus motif, with the majority targeting
a key interface within the SF3B spliceosome complex. Our recent preparative-scale
synthetic campaign of 17S-FD-895 provided unique
access to stereochemical analogues of this complex macrolide. Here,
we report on the preparation and systematic activity evaluation of
multiple FD-895 analogues. These studies examine the effects of modifications
at specific stereocenters within the molecule and highlight future
directions for medicinal chemical optimization of spliceosome modulators.