Discovery of facile amides-functionalized rhodanine-3-acetic acid derivatives as potential anticancer agents by disrupting microtubule dynamics

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 36; no. 1; pp. 1996 - 2009
• Main Authors: Zhou, Xiang, Liu, Jiamin, Meng, Jiao, Fu, Yihong, Wu, Zhibin, Ouyang, Guiping, Wang, Zhenchao
• Format: Journal Article
• Language: English
• Published: ABINGDON Taylor & Francis 01.01.2021; Taylor & Francis Group
• Subjects: antiproliferative activity; Biochemistry & Molecular Biology; Chemistry, Medicinal; Life Sciences & Biomedicine; Microtubule; Pharmacology & Pharmacy; Research Paper; Science & Technology; taxol binding domains; tubulin stabiliser; TARGET; MIGRATION; APOPTOSIS; taxol binding domains; DESIGN; tubulin stabiliser; TUBULIN POLYMERIZATION; ANTITUMOR-ACTIVITY; CANCER; antiproliferative activity; BIOLOGICAL EVALUATION; Microtubule; INHIBITORS; BINDING
• ISSN: 1475-6366; 1475-6374; 1475-6374
• DOI: 10.1080/14756366.2021.1975695

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 I 20 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 I 20 also disrupted cancer A549 cell migration in a concentration-dependent manner. Immunofluorescence microscopy, transmission electron microscopy, and tubulin polymerisation assays suggested that compound I 20 promoted protofilament assembly. In support of this possibility, computational docking studies revealed a strong interaction between compound I 20 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.