Semi-synthesized anticancer theobromine derivatives targeting VEGFR-2: and 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 cancer treatment. In this study, novel semisynthetic theobromine derivatives were rationally designed as VEGFR-2 inhibitors and subjected to testing for their ability to block VEGFR-2 activation. Furthermore, the antiproliferative effects of these derivatives were evaluated. Compound exhibited the most potent anti-VEGFR-2 activity, with an IC value of 0.072 µM, and demonstrated excellent dose-dependent inhibitory activity against both MCF-7 and HepG2 cancer cells with IC values of 19.35 and 27.89 µM, respectively. Notably, compound exhibited high selectivity indices of 2.6 and 1.8 against MCF-7 and HepG2 cells, respectively. Compound induced G2/M phase cell cycle arrest, promoted apoptosis, and boosted immunomodulation by downregulating TNF- expression and upregulating IL-2 levels in MCF-7 cells. The molecular docking analysis revealed that compound could bind effectively to the active site of VEGFR-2, and molecular dynamic simulations confirmed the stability of the VEGFR-2/compound complex. Furthermore, ADME and toxicity profiling indicated the potential suitability of these compounds as drug candidates. In summary, compound hold promise as a VEGFR-2 inhibitor.Communicated by Ramaswamy H. Sarma.