Novel 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine derivatives: design, synthesis, and biological evaluation as potent tubulin polymerisation inhibitors with anticancer activity.

Authors

Jiake Gao, Yujing Zhang, Rui Qu, Qianqian Xu, Zhenjuan Sun, Liya Cui, Chao Wang

Published in

Journal of enzyme inhibition and medicinal chemistry. Volume 41. Issue 1. Pages 2716562. Epub Aug 13, 2026.

Abstract

Microtubules assembled from α/β-tubulin heterodimers are critical for cell division and well-established anticancer drug targets, making tubulin polymerization inhibitors a viable route for new chemotherapeutics. Guided by structural analysis of colchicine-site binders and tubulin-ligand computational simulations, we rationally designed and synthesized a series of 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidines as novel colchicine-binding site tubulin inhibitors. Derivative 9t displayed the strongest antiproliferative potency, with IC₅。 values of 0.065-0.096 μM across tested cancer lines. It exerted minimal toxicity to normal L929 fibroblasts, yielding a selectivity index over 300. Mechanistic assays confirmed 9t suppresses cell-free tubulin polymerization, destroys cellular microtubule architecture, induces persistent G_₂/M cell cycle arrest, and activates cancer cell apoptosis. Overall, 9t serves as a promising dual-function tubulin inhibitor with both cytostatic and cytotoxic anticancer effects, meriting further preclinical investigation.

PMID:
42593025
Bibliographic data and abstract were imported from PubMed on 13 Aug 2026.

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