Diene Substitution Patterns in the Conformation-Activity Relationships of GEX1A

GEX1A (herboxidiene) is a polyketide natural product that possesses potent biological activities for a number of indications. GEX1A binds the splicing factor 3B subunit 1 (SF3B1), inhibiting the splicing of pre-mRNA. Moreover, we have reported that GEX1A reverses cholesterol accumulation in Niemann-Pick Type C mutant fibroblasts. Several groups have investigated the structure-activity relationships of this polyketide, mostly focusing on the tetrahydropyran core and the distal, oxygenated section of the side chain. Herein, we present the design, synthesis, and conformational studies of a series of analogues to explore substitution on the diene section of GEX1A. We employed computational and high-field NMR studies to describe the analogues' conformational landscape and their relative biological activities to describe their conformational-activity profile. We found that modifications on the diene section brought significant changes to both the molecule's conformation and biological activity.