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Design, Synthesis, and Biological Evaluation of a Novel VEGFR-2 Inhibitor Based on a 1,2,5-Oxadiazole-2-Oxide Scaffold with MAPK Signaling Pathway Inhibition. | LitMetric

Over the past few decades, the development of broad-spectrum anticancer agents with anti-angiogenic activity has witnessed considerable progress. In this study, a new series of pyrazolo[3,4-d]pyrimidines based on a phenylfuroxan scaffold were designed, synthesized, and evaluated, in terms of their anticancer activities. NCI-60 cell one-dose screening revealed that compounds - and had the best MGI%, among the tested compounds. The target fluorinated compound , as the most active one, showed better anticancer activity compared to the reference drug sorafenib, with IC values of 11.5, 11.6, and 13 µM against the HepG-2, A2780CP, and MDA-MB-231 cell lines, respectively. Furthermore, compound (IC = 0.092 µM) had VEGFR-2-inhibitory activity comparable to that of the standard inhibitor sorafenib (IC = 0.049 µM). Furthermore, the ability of compound in modulating MAPK signaling pathways was investigated. It was found to decrease the level of total ERK and its phosphorylated form, as well as leading to the down-regulation of metalloproteinase MMP-9 and the over-expression of p21 and p27, thus leading to subG1 cell-cycle arrest and, thus, the induction of apoptosis. Additionally, compound decreased the rate of wound healing in the absence of serum, in comparison to DMSO-treated cells, providing a significant impact on metastasis inhibition. The quantitative RT-PCR results for and showed lower expression of the neuronal and increased expression of epithelial , indicating the ability of to suppress metastasis. Furthermore, -treated HepG2 cells expressed a low level of anti-apoptotic and over-expressed proapoptotic genes, respectively. Using the DAF-FM DA fluorescence probe, compound produced NO intracellularly as efficiently as the reference drug JS-K. In silico molecular docking studies showed a structural similarity through an overlay of with sorafenib. Interestingly, the drug-likeness properties of compound met the expectations of Pfizer's rule for the design of new drug candidates. Therefore, this study presents a novel anticancer lead compound that is worthy of further investigation and activity improvement.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8880564PMC
http://dx.doi.org/10.3390/ph15020246DOI Listing

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