Synthesis, biological evaluation and computer-aided discovery of new thiazolidine-2,4-dione derivatives as potential antitumor VEGFR-2 inhibitors
Hazem Elkady, Osama A. El-Dardir, Alaa Elwan, Mohammed S. Taghour, Hazem A. Mahdy, Mohammed A. Dahab, Eslam B. Elkaeed, Bshra A. Alsfouk, Ibrahim M. Ibrahim, Dalal Z. Husein, E. S. E. Hafez, Amira M.G. Darwish, Ahmed M. Metwaly, Ibrahim H. Eissa
Abstract
values ranging from 13.56 to 17.8 μM. Additional flow cytometric investigations showed that compound 15 increased apoptosis in HT-29 cancer cells (from 3.1% to 31.4%) arresting their growth in the S phase. Furthermore, compound 15's apoptosis induction in the same cell line was confirmed by increasing the levels of BAX (4.8-fold) and decreasing Bcl-2 (2.8-fold). Also, compound 15 noticeably increased caspase-8 and caspase-9 levels by 1.7 and 3.2-fold, respectively. Computational methods were used to perform molecular analysis of the VEGFR-2-15 complex. Molecular dynamics simulations and molecular docking were utilized to analyze the complex's kinetic and structural characteristics. Protein-ligand interaction profiler analysis (PLIP) determined the 3D interactions and binding conformation of the VEGFR-2-15 complex. DFT analyses also provided insights into the 3D geometry, reactivity, and electronic characteristics of compound 15. Computational ADMET and toxicity experiments were conducted to determine the potential of the synthesized compounds for therapeutic development. The study's findings suggest that compound 15 might be an effective anticancer lead compound and could guide future attempts to develop new drugs.