Discovery of facile amides-functionalized rhodanine-3-acetic acid derivatives as potential anticancer agents by disrupting microtubule dynamics |
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Authors: | Xiang Zhou Jiamin Liu Jiao Meng Yihong Fu Zhibin Wu Guiping Ouyang Zhenchao Wang |
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Institution: | aState Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guiyang, People’s Republic of China;bCollege of Pharmacy, Guizhou University, Guiyang, People’s Republic of China |
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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. |
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Keywords: | Microtubule antiproliferative activity tubulin stabiliser taxol binding domains |
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