Anti-breast cancer potential of thieno-pyrimidine derivatives as VEGFR-2 inhibitors.

Abstract

Background: Thieno-pyrimidine derivatives have emerged as promising candidates for VEGFR-2 inhibition. This study aimed to design, synthesize, and evaluate novel thieno-pyrimidine derivatives for their anti-cancer potential.

Methods: A series of thieno-pyrimidine compounds were synthesized and screened for in vitro cytotoxicity against MDA-231 and MCF-7 cell lines. The most active compound, 6b, was further analyzed for VEGFR-2 kinase inhibition, wound healing, apoptosis induction, and cell cycle arrest. Molecular docking, 200 ns molecular dynamics simulations, MM-GBSA, ProLIF PCAT, and FEL analyses were conducted to assess binding stability. DFT calculations evaluated electronic properties, while in silico ADMET profiling predicted pharmacokinetics and toxicity.

Results: Compound 6b exhibited potent cytotoxicity with IC₅₀ values of 5.91 µM (MDA-231) and 7.16 µM (MCF-7). It demonstrated VEGFR-2 inhibition is comparable to sorafenib (IC₅₀: 53.63 ± 3.14 nM). Wound healing assays showed significant inhibition of MDA-231 migration. Flow cytometry confirmed apoptosis induction (57.20% early apoptosis) and G1 phase arrest. Gene expression analysis revealed upregulation of pro-apoptotic markers and downregulation of Bcl-2. Computational studies confirmed stable VEGFR-2 binding, and ADMET predictions indicated a favorable safety profile.

Conclusion: Compound 6b exhibits strong VEGFR-2 inhibition, potent anti-cancer effects, and a favorable toxicity profile, highlighting its potential for further therapeutic development.