Discovery of facile amides-functionalized rhodanine-3-acetic acid derivatives as potential anticancer agents by disrupting microtubule dynamics. (1st January 2021)

• Record Type: Journal Article
• Authors: Zhou, Xiang; Liu, Jiamin; Meng, Jiao; Fu, Yihong; Wu, Zhibin; Ouyang, Guiping; Wang, Zhenchao
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 36:Number 1(2021)
• Page Start: 1996
• Page End: 2009
• Publication Date: 2021-01-01
• Subjects: Microtubule -- antiproliferative activity -- tubulin stabiliser -- taxol binding domains; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2021.1975695
• Languages: English
• ISSNs: 1475-6366

Abstract

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 β 369, 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. Graphical abstract: UF0001