A Convergent Approach to Resorcinolic Macrolides to Expand Structural Diversity.

The resorcinolic macrolide (RM) family comprises over 50 natural products with diverse biological activities, including the potent natural Hsp90 inhibitor radicicol. Here, we report a modular and enantioselective synthetic strategy featuring a biomimetic macrocyclization-aromatization cascade that enables rapid access to natural and unnatural RMs. Using this route, we generated a small panel of minimal RMs, introducing covalent warheads, double bonds for macrocycle rigidification, and modifications at the C15 position, a position that has not been modified before. We also synthesized macrocyclic peptide-RM hybrids, offering a platform for rapid diversification. We evaluated all analogs for inhibitory activity against Hsp90α and Hsp90β and for disruption of the KRasG12C-CRAF protein-protein interaction (PPI). We found that introduction of polar groups at C15 improved Hsp90 activity relative to the representative RM de-O-methyllasiodiplodin, dependent on stereochemistry, whereas introduction of larger groups at C15 or introduction of a trans double bond into the macrocycle reduced activity. Two analogs with poor Hsp90 inhibitory activity exhibited dose-dependent inhibition of the KRasG12C-CRAF PPI. This work demonstrates that strategic modifications of a minimal RM scaffold through modular chemical insight can provide foundational structure-activity relationships for the class.