Identification of new theobromine-based derivatives as potent VEGFR-2 inhibitors: design, semi-synthesis, biological evaluation, and in silico studies

Ibrahim H Eissa; Reda G Yousef; Hazem Elkady; Eslam B Elkaeed; Aisha A Alsfouk; Dalal Z Husein; Ibrahim M Ibrahim; Mostafa A Elhendawy; Murrell Godfrey; Ahmed M Metwaly

doi:10.1039/d3ra04007k

Identification of new theobromine-based derivatives as potent VEGFR-2 inhibitors: design, semi-synthesis, biological evaluation, and in silico studies

RSC Adv. 2023 Aug 2;13(33):23285-23307. doi: 10.1039/d3ra04007k. eCollection 2023 Jul 26.

Authors

Affiliations

¹ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University Cairo11884 Egypt [email protected].
² Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University Riyadh 13713 Saudi Arabia.
³ Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University P.O. Box 84428 Riyadh 11671 Saudi Arabia.
⁴ Chemistry Department, Faculty of Science, New Valley University El-Kharja 72511 Egypt.
⁵ Biophysics Department, Faculty of Science, Cairo University Cairo 12613 Egypt.
⁶ Department of Chemistry and Biochemistry, University of Mississippi University MS 38677 USA.
⁷ Department of Agriculture Chemistry, Faculty of Agriculture, Damietta University Damietta Egypt.
⁸ Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University Cairo 11884 Egypt [email protected].
⁹ Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City) Alexandria Egypt.

Abstract

This study aimed to design anticancer theobromine derivatives inhibiting VEGFR-2. The new compounds were tested in vitro to evaluate their effectiveness against MCF-7 and HepG2 cancer cell lines. Among these compounds, 15a showed the highest cytotoxicity against HepG2, with an IC₅₀ value of 0.76 μM, and significant anti-proliferative effects on MCF-7, with an IC₅₀ value of 1.08 μM. Notably, the selectivity index of 15a against the two cancer cells was 98.97 and 69.64, respectively. Moreover, 15a demonstrated potent VEGFR-2 inhibitory activity (IC₅₀ = 0.239 μM). Further investigations revealed that 15a induced apoptosis in HepG2 cells, significantly increasing early-stage and late-stage apoptosis percentages from 3.06% and 0.71% to 29.49% and 9.63%, respectively. It also upregulated caspase-3 and caspase-9 levels by 3.45-fold and 2.37-fold, respectively compared to control HepG2 cells. Additionally, 15a inhibited the migration and wound healing ability of HepG2 cells. Molecular docking confirmed the binding affinities of the semi-synthesized compounds to VEGFR-2, consistent with in vitro results. Several computational analyses (DFT, MD simulations, MM-GBSA, PLIP, and essential dynamics) supported the stability of the 15a-VEGFR-2 complex. Overall, the biological and computational findings suggest that compound 15a could be a promising lead compound for the development of a novel apoptotic anticancer agent.