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

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.