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

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.