A modular biomimetic strategy for the synthesis of macrolide P-glycoprotein inhibitors via Rh-catalyzed C-H activation

Lu Chen, Haitian Quan, Zhongliang Xu, Hao Wang, Yuanzhi Xia, Liguang Lou () and Weibo Yang ()
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Lu Chen: Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences
Haitian Quan: Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences
Zhongliang Xu: Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences
Hao Wang: Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences
Yuanzhi Xia: College of Chemistry and Materials Engineering, Wenzhou University
Liguang Lou: Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences
Weibo Yang: Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences

Nature Communications, 2020, vol. 11, issue 1, 1-8

Abstract: Abstract One of the key challenges to overcome multidrug resistance (MDR) in cancer is the development of more effective and general strategies to discover bioactive scaffolds. Inspired by natural products, we describe a strategy to achieve this goal by modular biomimetic synthesis of scaffolds of (Z)-allylic-supported macrolides. Herein, an Rh(III)-catalyzed native carboxylic acid-directed and solvent-free C−H activation allylation with high stereoselectivity and chemoselectivity is achieved. The generated poly-substituted allylic alcohol as a multifunctional and biomimetic building block is crucial for the synthesis of (Z)-allylic-supported macrolides. Moreover, the unique allylic-supported macrolides significantly potentiate the sensitivity of tumor cells to cytotoxic agents such as vinorelbine and doxetaxel by reversing p170-glycoprotein-mediated MDR. Our findings will inspire the evolution of synthetic chemistry and open avenues for expedient and diversified synthesis of bioactive macrocyclic molecules.

Date: 2020
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DOI: 10.1038/s41467-020-16084-0

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