UCSF

Resorcinolic macrolides (RMs) are a structurally diverse class of natural products characterized by a conserved resorcinolic ester core linked to a highly variable macrocyclic bridge. Their ability to interact with ATP-binding sites, particularly in heat-shock protein 90 (Hsp90) paralogs, has garnered significant interest for developing selective inhibitors with therapeutic potential. Despite their structural diversity, limitations in efficient synthetic routes have hindered the comprehensive exploration of their structure-activity relationships (SAR) and the development of analogs with enhanced binding and selectivity. This dissertation presents a modular, enantioselective synthetic framework to access novel RMs, enabling a thorough investigation of their biological activity and selectivity profiles.The first chapter describes the development of a protecting group-free synthesis of (±)-de-O-methyllasiodiplodin, a structurally minimal RM derived from the fungus Lasiodiplodia theobromae. This route proceeds in 42% yield over 5 steps from commercially available 9-decenoic acid, providing a streamlined approach for generating diverse RM analogs. This synthetic route prioritizes efficiency, scalability, and functional group tolerance, facilitating access to a wide variety of analogs for biological evaluation.The second chapter details a convergent approach to synthesize a library of resorcinolic macrolide analogs targeting ATP-binding sites of Hsp90 paralogs and the KRas protein. This approach leverages modifications at the C15 position, the installation of covalent warheads, and structural rigidity to enhance binding affinity and selectivity. A total of 27 analogs were synthesized and evaluated against Hsp90α, Hsp90β, and KRas. Notably, compound 36 exhibited potent inhibitory activity with IC50 values of 14 µM and 37 µM against Hsp90α and Hsp90β, respectively. Compound 1C displayed selectivity for Hsp90α, highlighting the potential of C15 modifications for enhancing paralog specificity. Furthermore, evaluation of compounds targeting KRas, performed in collaboration with Xiakun and Xi, revealed that analogs 30 and 56 effectively inhibited the KRasG12C-CRAFRBD interaction in a dose-dependent manner.Collectively, these studies demonstrate the efficacy of a convergent synthetic approach to diversify RM analogs, enhancing their biological activity and selectivity profiles. The insights gained from this work provide a robust foundation for the design of novel RM-based inhibitors targeting Hsp90 and KRas, with potential applications in therapeutic development and biological probe design. Future efforts will focus on further optimizing these modifications and expanding the scope of RM analogs to target additional ATP-binding proteins.