Related Experiment Video
Updated: May 16, 2025
07:51
High-throughput Identification of Synergistic Drug Combinations by the Overlap2 Method
Published on: May 21, 2018
11.6K
A Convergent Approach to Resorcinolic Macrolides to Expand Structural Diversity
Jesus M Madrigal Lombera1, Xi Feng1, Xiaokun Shu1
1Department of Pharmaceutical Chemistry and Cardiovascular Research Institute, University of California, San Francisco, CA 94158-9001, USA.
Chemistry (Weinheim an Der Bergstrasse, Germany)
|May 7, 2025
Summary
Researchers developed a new synthetic method for resorcinolic macrolides (RMs), enabling the creation of novel analogs. Modifications at the C15 position and peptide hybrids were explored, revealing structure-activity relationships for Hsp90 inhibition and KRas-CRAF interaction.
Area of Science:
- Medicinal Chemistry
- Natural Product Synthesis
- Chemical Biology
Background:
- The resorcinolic macrolide (RM) family includes over 50 natural products with significant biological activities.
- Radicicol, a potent Hsp90 inhibitor, belongs to the RM family, highlighting their therapeutic potential.
- Understanding RM structure-activity relationships is crucial for developing new therapeutic agents.
Purpose of the Study:
- To develop a modular and enantioselective synthetic strategy for accessing natural and unnatural resorcinolic macrolides.
- To explore novel modifications on the RM scaffold, including at the previously unexplored C15 position and through peptide-RM hybrids.
- To evaluate the synthesized analogs for inhibitory activity against Hsp90α/β and their ability to disrupt the KRas-CRAF protein-protein interaction.
Main Methods:
- A biomimetic macrocyclization-aromatization cascade was employed for efficient RM synthesis.
- Minimal RMs were generated with covalent warheads, rigidifying double bonds, and C15 modifications.
- Macrocyclic peptide-RM hybrids were synthesized to facilitate rapid diversification.
- Biological evaluation included Hsp90α/β inhibition assays and KRasG12C-CRAF protein-protein interaction disruption assays.
Main Results:
- The synthetic strategy provided rapid access to a diverse panel of natural and unnatural RMs.
- Introduction of polar groups at C15 enhanced Hsp90 activity, with stereochemistry being a critical factor.
- Modifications such as larger C15 groups or a trans double bond in the macrocycle decreased Hsp90 activity.
- Two analogs with low Hsp90 inhibition showed potent, dose-dependent disruption of the KRasG12C-CRAF PPI.
Conclusions:
- Strategic modifications of the minimal RM scaffold yield foundational structure-activity relationships.
- The developed synthetic platform allows for rapid diversification and exploration of RM analogs.
- The findings offer insights into targeting Hsp90 and KRas-CRAF PPIs through novel RM derivatives.
