New Thieno[2,3-d]pyrimidines as Anticancer VEGFR-2 Inhibitors with Apoptosis Induction: Design, Synthesis, and Biological and In Silico Studies

Title:New Thieno[2,3-d]pyrimidines as Anticancer VEGFR-2 Inhibitors with Apoptosis Induction: Design, Synthesis, and Biological and In Silico Studies

Volume: 20 Issue: 9

Author(s): Eman A. Sobh*, Mohammed A. Dahab*, Eslam B. Elkaeed, Bshra A. Alsfouk, Ibrahim M. Ibrahim, Ahmed M. Metwaly and Ibrahim H. Eissa*

Affiliation:

• Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Menoufia University, Menoufia, Shibin-Elkom, Gamal Abd Al-Nasir Street, Egypt

• Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt

• Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt

Abstract:

Background: Vascular endothelial growth factor receptor-2 (VEGFR-2) is a critical protein involved in tumor progression, making it an attractive target for cancer therapy.

Objective: This study aimed to synthesize and evaluate novel thieno[2,3-d]pyrimidine analogues as potential anticancer VEGFR-2 inhibitors.

Methods: The thieno[2,3-d]pyrimidine analogues were synthesized following the pharmacophoric features of VEGFR-2 inhibitors. The anticancer potential was assessed against PC3 and HepG2 cell lines. The VEGFR-2 inhibition was evaluated through IC₅₀ determination. Cell cycle analysis and apoptosis assays were performed to elucidate the mechanisms of action. Molecular docking, molecular dynamics simulations, MM-GBSA, and PLIP studies were conducted to investigate the binding affinities and interactions with VEGFR-2. Additionally, in silico ADMET studies were performed.

Results: Compound 8b demonstrated significant anti-proliferative activities with IC₅₀ values of 16.35 μM and 8.24 μM against PC3 and HepG2 cell lines, respectively, surpassing sorafenib and exhibiting enhanced selectivity indices. Furthermore, compound 8b showed an IC₅₀ value of 73 nM for VEGFR-2 inhibition. Cell cycle analysis revealed G2-M phase arrest, while apoptosis assays demonstrated increased apoptosis in HepG2 cells. Molecular docking and dynamic simulations confirmed the binding affinity and interaction of compound 8b with VEGFR-2, supported by MMGBSA and PLIP studies. In silico ADMET studies indicated the drug development potential of the synthesized thieno[2,3-d]pyrimidines.

Conclusion: The study highlights compound 8b as a promising VEGFR-2 inhibitor with potent anti-proliferative activities. Its mechanism of action involves cell cycle arrest and induction of apoptosis. Further, molecular docking and dynamic simulations support the strong binding affinity of compound 8b to VEGFR-2.

Cite this article as:

Sobh A. Eman*, Dahab A. Mohammed*, Elkaeed B. Eslam, Alsfouk A. Bshra, Ibrahim M. Ibrahim, Metwaly M. Ahmed and Eissa H. Ibrahim*, New Thieno[2,3-d]pyrimidines as Anticancer VEGFR-2 Inhibitors with Apoptosis Induction: Design, Synthesis, and Biological and In Silico Studies, Medicinal Chemistry 2024; 20 (9) . https://dx.doi.org/10.2174/0115734064285433240513092047