Semi-synthesized anticancer theobromine derivatives targeting VEGFR-2: in silico and in vitro evaluations

Vascular endothelial cell proliferation and angiogenesis are all crucially impacted by Endothelial Growth Factor Receptor-2 (VEGFR-2). Its expression is significantly boosted throughout pathologic angiogenesis causing the development of tumors. Sothat, inhibition of VEGFR-2 has crucial role in cance...

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Bibliographic Details
Published in:Journal of biomolecular structure & dynamics 2024-05, Vol.42 (8), p.4214-4233
Main Authors: Dahab, Mohammed A., Mahdy, Hazem A., Elkady, Hazem, Taghour, Mohammed S., Elwan, Alaa, Elkady, Mohamed A., Elsakka, Elsayed G. E., Elkaeed, Eslam B., Alsfouk, Aisha A., Ibrahim, Ibrahim M., Metwaly, Ahmed M., Eissa, Ibrahim H.
Format: Article
Language:English
Subjects:
Anticancer
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
apoptosis
Apoptosis - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Computer Simulation
Hep G2 Cells
Humans
immunomodulatory
MCF-7 Cells
MD simulations
molecular docking
Molecular Docking Simulation
Molecular Dynamics Simulation
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
semi-synthesis
Structure-Activity Relationship
theobromine
Theobromine - chemistry
Theobromine - pharmacology
Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 - metabolism
VEGFR-2
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Summary:Vascular endothelial cell proliferation and angiogenesis are all crucially impacted by Endothelial Growth Factor Receptor-2 (VEGFR-2). Its expression is significantly boosted throughout pathologic angiogenesis causing the development of tumors. Sothat, inhibition of VEGFR-2 has crucial role in cancer treatment. In this study, novel semisynthetic theobromine derivatives were rationally designed as VEGFR-2 inhibitors and subjected to in vitro testing for their ability to block VEGFR-2 activation. Furthermore, the antiproliferative effects of these derivatives were evaluated. Compound 7 g exhibited the most potent anti-VEGFR-2 activity, with an IC 50 value of 0.072 µM, and demonstrated excellent dose-dependent inhibitory activity against both MCF-7 and HepG2 cancer cells with IC 50 values of 19.35 and 27.89 µM, respectively. Notably, compound 7 g exhibited high selectivity indices of 2.6 and 1.8 against MCF-7 and HepG2 cells, respectively. Compound 7 g induced G2/M phase cell cycle arrest, promoted apoptosis, and boosted immunomodulation by downregulating TNF-α expression and upregulating IL-2 levels in MCF-7 cells. The molecular docking analysis revealed that compound 7 g could bind effectively to the active site of VEGFR-2, and molecular dynamic simulations confirmed the stability of the VEGFR-2/compound 7 g complex. Furthermore, ADME and toxicity profiling indicated the potential suitability of these compounds as drug candidates. In summary, compound 7 g hold promise as a VEGFR-2 inhibitor. Communicated by Ramaswamy H. Sarma
ISSN:0739-1102
1538-0254
DOI:10.1080/07391102.2023.2219333