Multicomponent Reaction-Enabled Semisynthesis of Taxanes Yields an Analogue with Reduced Chemotherapy-Induced Neuropathy.

Authors

Xiang Fu, Haoyi Yang, Yaxin Li, Gejun Niu, Junxin Ren, Xiangrong Liu, Xinglin Li, Yukai Li, Jirong Shu, Weijie Guo, Tao Liu, Song Cai, Taoda Shi, Wenhao Hu

Published in

JACS Au. Volume 5. Issue 9. Pages 4299-4308. Sep 22, 2025. Epub Aug 25, 2025.

Abstract

Chemotherapy-induced peripheral neuropathy (TIPN) affects up to 97% of patients receiving taxane regimens, yet no single-agent solution exists. Current practice relies on coadministration of pain-modulating agents with taxanes, which adds complexity, potential drug-drug interactions, and patient-compliance hurdles. To address TIPN at its source, we set out to create a taxane analogue that intrinsically prevents neuropathy while retaining anticancer potency. Because building even small libraries of taxane derivatives via traditional semisynthetic or total-synthesis routes is laborious and step-intensive, we developed a late-stage, multicomponent reaction (MCR)-based platform on baccatin III for rapid, modular side-chain assembly. Using this approach, we synthesized over 30 C13-diversified taxanes in two steps with excellent stereocontrol and overall yields (35-68%). Lead compound 6v displays slightly better anticancer potency and a reduced TIPN effect than paclitaxel. This one-agent strategy streamlines therapy, obviates combination regimens, and establishes a broadly applicable MCR platform for natural-product optimization.

PMID:
41001630
Bibliographic data and abstract were imported from PubMed on 26 Sep 2025.

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