Discovery of (2-(pyrrolidin-1-yl)thieno[3,2-d]pyrimidin-4-yl)(3,4,5-trimethoxyphenyl)methanone as a novel potent tubulin depolymerizing and vascular disrupting agent

Abstract

In this study, a series of 2-substituted thieno[3,2-d]pyrimidin-4-yl(3,4,5-trimethoxyphenyl)methanones were designed, synthesized and evaluated as novel anti-tubulin polymerization and vascular disrupting agents. A pyrrolidin-1-yl derivative, compound 20, exhibited strong antiproliferative activities (average IC₅₀ = 13.4 nM) against four cancer cell lines. 20 also showed retained potency toward paclitaxel-resistant A549 cells. 20 could significantly inhibit tubulin polymerization with an IC₅₀ of 1.6 μM. 20 displayed strong induction of G2/M arrest and apoptosis through the mitochondrial pathway. Dose-dependent suppression of the migration of cancer cells and the formation of a vascular network were observed after treatment with 20. The acceptable microsomal stability implied that it is worth conducting further study on the analogues of 20 as novel drug candidates of CBSIs.

Keywords: Anti-tubulin polymerization; G2/M arrest; Induction of apoptosis; PTX-resistant A549; Vascular disrupting agent.