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Dual inhibition of VEGFR-2 and Aurora A is a promising strategy for treating complex malignancies like hepatocellular carcinoma (HCC) and breast cancer. In this study, a series of new pyrazolopyrimidine derivatives were designed and synthesized via a one-pot multicomponent reaction using both conventional and microwave-assisted techniques. Structural characterization was confirmed by spectroscopic data. The compounds were evaluated as dual inhibitors of Aurora A and VEGFR-2 kinases through molecular docking, in vitro cytotoxicity assays, and expression analysis. Docking simulations revealed compound 5b had the strongest binding affinity for both kinases. Consistently, MTT assays showed that compounds 5b, 5c, and 6b exhibited potent cytotoxicity, with compound 5b displaying the highest activity against HepG2 and MCF-7 cells (IC₅₀ = 3.0 μM and 3.5 μM, respectively). In particular, in HepG2 cells, compound 5b inhibited VEGFR-2 by 86.3 % and Aurora A by 66.7 %, demonstrating stronger dual-target inhibition compared to the reference compound, sunitinib. Furthermore, compound 5b significantly downregulated VEGFR-2 and Aurora A protein and gene expression. Toxicity evaluation in vivo indicated no lethal effects at doses up to 1000 mg/kg, with an LD₅₀ exceeding 1500 mg/kg, suggesting a favorable safety profile. These findings identify compound 5b as a promising dual-target inhibitor and potential lead candidate for the treatment of HCC and breast cancer.
Anwer et al. (Fri,) studied this question.