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

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

Keywords:

• Anticancer
• VEGFR-2
• theobromine
• semi-synthesis
• apoptosis
• immunomodulatory
• molecular docking
• MD simulations

Author contribution

Conceptualization: I. H. E., Methodology: M.A. D., H. A. M., H. E., M. S. T., A. E., M. A. E., E. G. E. E., Software: I. M. I., Investigation: A. M. M. E. B. E., Funding acquisition: A. A. A., Supervision: I. H. E, A. M. M, Project administration: I. H. E, A. M. M, Writing—original draft: H. A. M., H. E., Writing—review & editing: A. M. M., Visualization: E. B. E, A. A. A.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research was funded by Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2023R116), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. The authors extend their appreciation to the Research Center at AlMaarefa University for funding this work.