New thiazolidine-2,4-diones as potential anticancer agents and apoptotic inducers targeting VEGFR-2 kinase: Design, synthesis, in silico and in vitro studies

VEGFR-2 has emerged as a prominent positive regulator of cancer progression. Discovery of new anticancer agents and apoptotic inducers targeting VEGFR-2. Design and synthesis of new thiazolidine-2,4-diones followed by extensive in vitro studies, including VEGFR-2 inhibition assay, MTT assay, apoptos...

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Veröffentlicht in:Biochimica et biophysica acta. General subjects Jg. 1868; H. 6; S. 130599
Hauptverfasser: Elkady, Hazem, Mahdy, Hazem A., Taghour, Mohammed S., Dahab, Mohammed A., Elwan, Alaa, Hagras, Mohamed, Hussein, Mona H., Ibrahim, Ibrahim M., Husein, Dalal Z., Elkaeed, Eslam B., Alsfouk, Aisha A., Metwaly, Ahmed M., Eissa, Ibrahim H.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Netherlands Elsevier B.V 01.06.2024
Schlagworte:
Anti-proliferative
antineoplastic activity
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
cell movement
Cell Movement - drug effects
Cell Proliferation - drug effects
computer simulation
DFT
Docking
Drug Design
Drug Screening Assays, Antitumor
Hep G2 Cells
Humans
interphase
MCF-7 Cells
MD simulations
Molecular Docking Simulation
Molecular Dynamics Simulation
neoplasm cells
neoplasm progression
pharmacokinetics
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Sorafenib - chemistry
Sorafenib - pharmacology
Thiazolidine-2,4-dione
Thiazolidinediones - chemical synthesis
Thiazolidinediones - chemistry
Thiazolidinediones - pharmacology
toxicity
toxicity testing
vascular endothelial growth factor receptor-2
Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 - metabolism
VEGFR-2
Anti-proliferative
DFT
VEGFR-2
MD simulations
Docking
Thiazolidine-2,4-dione
Apoptosis
ISSN:0304-4165, 1872-8006, 1872-8006
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Zusammenfassung:VEGFR-2 has emerged as a prominent positive regulator of cancer progression. Discovery of new anticancer agents and apoptotic inducers targeting VEGFR-2. Design and synthesis of new thiazolidine-2,4-diones followed by extensive in vitro studies, including VEGFR-2 inhibition assay, MTT assay, apoptosis analysis, and cell migration assay. In silico investigations including docking, MD simulations, ADMET, toxicity, and DFT studies were performed. Compound 15 showed the strongest VEGFR-2 inhibitory activity with an IC50 value of 0.066 μM. Additionally, most of the synthesized compounds showed anti-proliferative activity against HepG2 and MCF-7 cancer cell lines at the micromolar range with IC50 values ranging from 0.04 to 4.71 μM, relative to sorafenib (IC50 = 2.24 ± 0.06 and 3.17 ± 0.01 μM against HepG2 and MCF-7, respectively). Also, compound 15 showed selectivity indices of 1.36 and 2.08 against HepG2 and MCF-7, respectively. Furthermore, compound 15 showed a significant apoptotic effect and arrested the cell cycle of MCF-7 cells at the S phase. Moreover, compound 15 had a significant inhibitory effect on the ability of MCF-7 cells to heal from. Docking studies revealed that the synthesized thiazolidine-2,4-diones have a binding pattern approaching sorafenib. MD simulations indicated the stability of compound 15 in the active pocket of VEGFR-2 for 200 ns. ADMET and toxicity studies indicated an acceptable pharmacokinetic profile. DFT studies confirmed the ability of compound 15 to interact with VEGFR-2. Compound 15 has promising anticancer activity targeting VEGFR-2 with significant activity as an apoptosis inducer. •New VEGFR-2 inhibitors based on thiazolidine-2,4-diones have been designed and synthesized.•Anti-proliferative and VEGFR-2 inhibitory activity were tested.•Cell cycle and apoptosis analyses were assessed.•In silico docking, MD simulation, DFT, ADMET, and toxicity studies were performed.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0304-4165
1872-8006
1872-8006
DOI:10.1016/j.bbagen.2024.130599