article · PLoS ONE
New chemical compounds based on thiazolidine-2,4-diones have been designed and synthesised to target vascular endothelial growth factor receptor 2, an enzyme linked to cancer progression. Laboratory testing against several human cancer cell lines identified a primary candidate, designated compound 14a, which demonstrated strong anti-proliferative activity against colon and liver cancer cells. Safety evaluations against normal cells indicated high selectivity. In colon cancer models, compound 14a successfully suppressed cell migration and tissue healing while inducing programmed cell death through the reduced expression of the Bcl2, Survivin, and TGF genes. Detailed computational analyses, including molecular docking, toxicity assessments, and molecular dynamics simulations, confirmed the strong binding reactivity of the compound against its target enzyme. These results present the molecule as a viable lead structure for creating more potent anticancer treatments.
Inhibiting specific enzymatic pathways is essential for stopping tumour growth and preventing cancer cells from spreading. By identifying molecules that selectively target cancer cells while sparing healthy tissue, researchers can establish safer approaches to therapy. Demonstrating that a single compound can halt cell migration and trigger natural cell death mechanisms provides valuable biological targets for addressing hard-to-treat malignancies such as colon and liver cancers.
This work represents early-stage drug discovery that could assist biotechnology and pharmaceutical companies focused on oncology therapeutics. Compound 14a acts as a validated chemical lead for developing targeted VEGFR-2 inhibitors. Because the data relies entirely on computational predictions and laboratory cell culture assays, the compound is at a discovery-phase distance from practical use, requiring extensive in vivo evaluation, pharmacokinetic profiling, and preclinical safety testing before any commercial development.
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We report herein, the design and synthesis of thiazolidine-2,4-diones derivatives as new inhibitors for VEGFR-2. The designed members were assessed for their in vitro anticancer activity against four cancer cell lines; A549, Caco-2, HepG-2 and MDA-MB-231. Compound 14a showed the most potent effects against Caco-2, and HepG-2 cell lines (IC50 = of 1.5 and 31.5 μM, respectively). Next, the in vitro VEGFR-2 inhibitory activity, safety profiles and selectivity indices were examined for all the synthesized members against the normal Vero cell line. Compound 14a (the safest member against Caco-2 cell line) was further investigated for its ability to inhibit Caco-2 cells migration and healing. Moreover, the apoptotic induction of compound 14a against Caco-2 cell line was investigated by assessing against four apoptotic genes (Bcl2, Bcl-xl, TGF, and Survivin). The results revealed that compound 14a can exert apoptosis through significant reduction of Bcl2, Survivin, and TGF gene expression levels. Finally, deep computational studies including molecular docking, ADMET, toxicity studies, and MD simulation were carried out. Also, the DFT calculations were performed and discussed, and the results confirmed the inhibitory reactivity of 14a against VEGFR-2. Compound 14a is expected to be used as a potential lead in the development of new VEGFR-2 inhibitors with increased potency.
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DOI: 10.1371/journal.pone.0272362
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