Design, semi-synthesis, anti-cancer assessment, docking, MD simulation, and DFT studies of novel theobromine-based derivatives as VEGFR-2 inhibitors and apoptosis inducers

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:10.1016/j.compbiolchem.2023.107953

Design, semi-synthesis, anti-cancer assessment, docking, MD simulation, and DFT studies of novel theobromine-based derivatives as VEGFR-2 inhibitors and apoptosis inducers

Comput Biol Chem. 2023 Dec:107:107953. doi: 10.1016/j.compbiolchem.2023.107953. Epub 2023 Aug 30.

Authors

Affiliations

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

PMID: 37673011
DOI: 10.1016/j.compbiolchem.2023.107953

Abstract

A group of theobromine derivatives was designed based on the key pharmacophoric characteristics of VEGFR-2 inhibitors. HepG2 and MCF-7 cancer cell lines were used to test the obtained compounds for their in vitro anti-proliferative activities. Compound 15 (2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-(4-(1-(2-(4-hydroxybenzoyl)hydrazono)ethyl) phenyl)acetamide) was the most potent cytotoxic member against MCF-7 (IC₅₀ = 0.42 µM) and HepG2 (IC₅₀ = 0.22 µM). The effectiveness of VEGFR-2 inhibition was assessed for compound 15, and its IC₅₀ value was calculated to be 0.067 µM. Additional cellular mechanistic investigations showed that compound 15 dramatically increased the population of apoptotic HepG2 cells in both early and late apoptosis. The investigation of apoptotic markers confirmed that compound 15 upregulated the levels of BAX (2.26-fold) and downregulated the levels of Bcl-2 (4.4-fold). The molecular docking investigations, MM-GPSA, PLIP studies, and MD simulations validated the potential of compound 15 to be a VEGFR-2 inhibitor. DFT calculations have been completed to comprehend how the electrical charge is distributed within compound 15 and to predict how it would bond to VEGFR-2. Lastly, ADMET prediction showed that the designed members have drug-like characteristics and minimal levels of toxicity. In conclusion, our in vitro and in silico investigations showed that compound 15 exhibited promising apoptotic anticancer potential through the suppression of VEGFR-2.

Keywords: Anticancer; Apoptosis; DFT, MD simulation; Theobromine; VEGFR-2.

MeSH terms

Antineoplastic Agents* / pharmacology
Apoptosis / drug effects
Cell Proliferation
Computer Simulation
Drug Screening Assays, Antitumor
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors
Structure-Activity Relationship
Theobromine* / chemistry
Theobromine* / pharmacology
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Theobromine
Vascular Endothelial Growth Factor Receptor-2