Abstract

Microtubule dynamics are crucial for multiple cell functions, and cancer cells are particularly sensitive to microtubule-modulating agents. Here, we describe the design and synthesis of a series of (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives and evaluation of their microtubule-modulating and anticancer activities in vitro. Proliferation assays identified I₂₀ as the most potent of the antiproliferative compounds, with 50% inhibitory concentrations ranging from 7.0 to 20.3 µM with A549, PC-3, and HepG2 human cancer cell lines. Compound I₂₀ also disrupted cancer A549 cell migration in a concentration-dependent manner. Immunofluorescence microscopy, transmission electron microscopy, and tubulin polymerisation assays suggested that compound I₂₀ promoted protofilament assembly. In support of this possibility, computational docking studies revealed a strong interaction between compound I₂₀ and tubulin Arg β369, which is also the binding site for the anticancer drug Taxol. Our results suggest that (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives could have utility for the development of microtubule-stabilising therapeutic agents.

摘要

微管动力学对多种细胞功能至关重要，癌细胞对微管调节剂特别敏感。在这里，我们描述了一系列 ( Z )-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl) -N-苯基乙酰胺衍生物的设计和合成及其微管调节和抗癌活性的评价体外。增殖试验确定I ₂₀是最有效的抗增殖化合物，对 A549、PC-3 和 HepG2 人类癌细胞系的 50% 抑制浓度范围为 7.0 至 20.3 µM。化合物I ₂₀还以浓度依赖性方式破坏癌症 A549 细胞迁移。免疫荧光显微镜、透射电子显微镜和微管蛋白聚合测定表明化合物I ₂₀促进了原丝组装。为了支持这种可能性，计算对接研究揭示了化合物I ₂₀和微管蛋白 Arg β 369之间的强相互作用，微管蛋白 Arg β 369 也是抗癌药物紫杉醇的结合位点。我们的结果表明 ( Z )-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl) -N-苯基乙酰胺衍生物可用于开发微管稳定治疗剂。