Design, synthesis, anti-proliferative evaluation, docking, and MD simulation studies of new thieno[2,3-d]pyrimidines targeting VEGFR-2

Souad A. El-Metwally; Hazem Elkady; Mohamed Hagras; Dalal Z. Husein; Ibrahim M. Ibrahim; Mohammed S. Taghour; Hesham A. El-Mahdy; Ahmed Ismail; Bshra A. Alsfouk; Eslam B. Elkaeed; Ahmed M. Metwaly; Ibrahim H. Eissa

doi:10.1039/D3RA03128D

Design, synthesis, anti-proliferative evaluation, docking, and MD simulation studies of new thieno[2,3-d]pyrimidines targeting VEGFR-2†

Souad A. El-Metwally,^a Hazem Elkady,

*^b Mohamed Hagras,

^c Dalal Z. Husein,^d Ibrahim M. Ibrahim,^e Mohammed S. Taghour,^b Hesham A. El-Mahdy,^f Ahmed Ismail,^f Bshra A. Alsfouk,^g Eslam B. Elkaeed,

^h Ahmed M. Metwaly

*^ij and Ibrahim H. Eissa

*^b

Author affiliations

* Corresponding authors

^a Department of Basic Science, Higher Technological Institute, 10th of Ramadan City, Egypt

^b Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
E-mail: Ibrahimeissa@azhar.edu.eg, Hazemelkady@azhar.edu.eg

^c Department of Pharmaceutical Organic Chemistry, College of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt

^d Chemistry Department, Faculty of Science, New Valley University, El-Kharja 72511, Egypt

^e Biophysics Department, Faculty of Science, Cairo University, Cairo 12613, Egypt

^f Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11231, Egypt

^g Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia

^h Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh 13713, Saudi Arabia

ⁱ Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt
E-mail: ametwaly@azhar.edu.eg

^j Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt

Abstract

In this work, new thieno[2,3-d]pyrimidine-derived compounds possessing potential anticancer activities were designed and synthesized to target VEGFR-2. The thieno[2,3-d]pyrimidine derivatives were tested in vitro for their abilities to inhibit VEGFR-2 and to prevent cancer cell growth in two types of cancer cells, MCF-7 and HepG2. Compound 18 exhibited the strongest anti-VEGFR-2 potential with an IC₅₀ value of 0.084 μM. Additionally, it displayed excellent proliferative effects against MCF-7 and HepG2 cancer cell lines, with IC₅₀ values of 10.17 μM and 24.47 μM, respectively. Further studies revealed that compound 18 induced cell cycle arrest in G2/M phase and promoted apoptosis in MCF-7 cancer cells. Apoptosis was stimulated by compound 18 by increasing BAX (3.6-fold) and decreasing Bcl-2 (3.1-fold). Additionally, compound 18 significantly raised the levels of caspase-8 (2.6-fold) and caspase-9 (5.4-fold). Computational techniques were also used to investigate the VEGFR-2-18 complex at a molecular level. Molecular docking and molecular dynamics simulations were performed to assess the structural and energetic features of the complex. The protein-ligand interaction profiler analysis identified the 3D interactions and binding conformation of the VEGFR-2-18 complex. Essential dynamics (ED) study utilizing principal component analysis (PCA) described the protein dynamics of the VEGFR-2-18 complex at various spatial scales. Bi-dimensional projection analysis confirmed the proper binding of the VEGFR-2-18 complex. In addition, the DFT studies provided insights into the structural and electronic properties of compound 18. Finally, computational ADMET and toxicity studies were conducted to evaluate the potential of the thieno[2,3-d]pyrimidine derivatives for drug development. The results of the study suggested that compound 18 could be a promising anticancer agent that may provide effective treatment options for cancer patients. Furthermore, the computational techniques used in this research provided valuable insights into the molecular interactions of the VEGFR-2-18 complex, which may guide future drug design efforts. Overall, this study highlights the potential of thieno[2,3-d]pyrimidine derivatives as a new class of anticancer agents and provides a foundation for further research in this area.

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Design, synthesis, anti-proliferative evaluation, docking, and MD simulation studies of new thieno[2,3-d]pyrimidines targeting VEGFR-2†

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Design, synthesis, anti-proliferative evaluation, docking, and MD simulation studies of new thieno[2,3-d]pyrimidines targeting VEGFR-2

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