Anti-breast cancer potential of a new xanthine derivative: In silico, antiproliferative, selectivity, VEGFR-2 inhibition, apoptosis induction and migration inhibition studies

Pathol Res Pract. 2023 Nov:251:154894. doi: 10.1016/j.prp.2023.154894.

Ibrahim H Eissa ¹, Reda G Yousef ², Hazem Elkady ³, Eslam B Elkaeed ⁴, Bshra A Alsfouk ⁵, Dalal Z Husein ⁶, Mostafa A Asmaey ⁷, Ibrahim M Ibrahim ⁸, Ahmed M Metwaly ⁹

Affiliations

1 Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: [email protected].
2 Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: [email protected].
3 Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: [email protected].
4 Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh 13713, Saudi Arabia. Electronic address: [email protected].
5 Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia. Electronic address: [email protected].
6 Chemistry Department, Faculty of Science, New Valley University, El-Kharja 72511, Egypt. Electronic address: [email protected].
7 Department of Chemistry, Faculty of Science, Al-Azhar University, Assiut Branch, 71524 Assiut, Egypt. Electronic address: [email protected].
8 Biophysics Department, Faculty of Science, Cairo University. Cairo 12613, Egypt. Electronic address: [email protected].
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: [email protected].

PMID: 37857034 DOI: 10.1016/j.prp.2023.154894

Abstract

Background: The overexpression of VEGFR-2 receptors in breast Cancer provides a valuable approach to Anticancer strategies. Targeting VEGFR-2, a new semisynthetic compound (T-1-MCPAB) has been designed.

Methods: Computational methods (ADMET, toxicity, DFT, Molecular Docking, Molecular Dynamics Simulations, MM-GBSA, PLIP, and PCAT) were conducted. In addition to the semi-synthesis, in vitro studies (anti-VEGFR-2, anti-proliferative, flow cytometry, and wound scratch assay) were employed.

Results: ADME and toxicity profiles of T-1-MCPAB studies indicated its overall drug-likeness showing results much better than Sorafenib. Then, T-1-MCPAB's exact 3D structure, stability, and reactivity were evoked by the DFT calculations. Molecular docking, molecular dynamics simulations, MM-GPSA, PLIP, and PCAT studies denoted the correct binding and inhibiting potential of T-1-MCPAB, towards VEGFR-2 protein. After the semisynthesis, T-1-MCPAB inhibited VEGFR-2 with an IC₅₀ of 0.135 µM, which was comparable to sorafenib's IC₅₀ of 0.0591 µM. T-1-MCPAB also showed a notable performance against MCF7 and T47D breast Cancer cell lines with IC₅₀ values of 30.95 µM and 63.64 µM, respectively, and had high selectivity index values of 3.7 and 1.8, respectively. Furthermore, T-1-MCPAB influenced early and late Apoptosis and significantly decreased the potential of MCF7 cells to heal and migrate.

Conclusion: T-1-MCPAB is a promising VEGFR-2 inhibitor with potential for breast Cancer treatment. Further chemical and biological studies are needed to explore its potential as a therapeutic agent.

Keywords

ADMET; Breast cancer; DFT; MD simulations; PCAT; Semi synthesis; Theobromine derivatives; VEGFR-2 inhibitors.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-156452

T-1-MCPAB

VEGFR-2 Inhibitor

VEGFR

Cancer

Name
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