Semi-synthesized anticancer theobromine derivatives targeting VEGFR-2: <i>in silico</i> and <i>in vitro</i> evaluations
Mohammed A. Dahab, Hazem A. Mahdy, Hazem Elkady, Mohammed S. Taghour, Alaa Elwan, Mohamed A. Elkady, Elsayed G.E. Elsakka, Eslam B. Elkaeed, Aisha A. Alsfouk, Ibrahim M. Ibrahim, Ahmed M. Metwaly, Ibrahim H. Eissa
Abstract
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 IC50 value of 0.072 µM, and demonstrated excellent dose-dependent inhibitory activity against both MCF-7 and HepG2 cancer cells with IC50 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