Anti-breast cancer potential of thieno-pyrimidine derivatives as VEGFR-2 inhibitors
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.
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.
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.
Compound 6b exhibits strong VEGFR-2 inhibition, potent anti-cancer effects, and a favorable toxicity profile, highlighting its potential for further therapeutic development.
