A convergent approach to resorcinolic macrolides to expand structural diversity

The resorcinolic macrolide (RM) class of natural products is characterized by a resorcinolic ester core linked to a 10-14-membered macrocyclic lactone, encompassing over 50 members with diverse biological activities. Among the most notable is radicicol, a potent natural inhibitor of the 90-kDa heat-shock protein (Hsp90). Here we present an enantioselective, modular synthetic strategy to access diverse RMs, focusing on the modification of the C15 position, covalent warheads, and rigidity of the macrocycle to explore their effects on Hsp90 inhibitory activity and isoform selectivity. We synthesized 27 RM derivatives and evaluated their inhibitory activity against Hsp90𝛼 and Hsp90β isoforms and KRas. Compound 12A exhibited the highest potency with IC50 values of 14 µM and 37 µM against Hsp90𝛼 and Hsp90β, respectively. Additionally, compound 1C displayed high selectivity for Hsp90𝛼. These findings indicate that targeted modifications at C15 can yield novel RMs with potential as biological probes and therapeutic leads, offering a new avenue for the development of Hsp90 or KRas inhibitors with reduced resistance and improved specificity.