Design, synthesis, anti-proliferative evaluation, docking, and MD simulations studies of new thiazolidine-2,4-diones targeting VEGFR-2 and apoptosis pathway

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...

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Bibliographic Details
Published in:PloS one 2022-09, Vol.17 (9), p.e0272362-e0272362
Main Authors: Taghour, Mohammed S, Elkady, Hazem, Eldehna, Wagdy M, El-Deeb, Nehal, Kenawy, Ahmed M, Elkaeed, Eslam B, Alsfouk, Bshra A, Alesawy, Mohamed S, Husein, Dalal Z, Metwaly, Ahmed M, Eissa, Ibrahim H
Format: Article
Language:English
Subjects:
Analysis
Angiogenesis
Angiogenesis inhibitors
Anticancer properties
Antimitotic agents
Antineoplastic agents
Antitumor activity
Apoptosis
Bcl-x protein
Binding sites
Biology and Life Sciences
Cancer
Cell migration
Computer applications
Cytotoxicity
Gene expression
Health aspects
Inhibitors
Medicine and Health Sciences
Methods
Molecular docking
Potassium
Research and Analysis Methods
Selectivity
Simulation
Simulation methods
Survivin
Synthesis
Toxicity
Tumor cell lines
Vascular endothelial growth factor
Vascular endothelial growth factor receptors
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Summary: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 (IC.sub.50 = of 1.5 and 31.5 [mu]M, 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0272362