Journal
MOLECULES
Volume 28, Issue 21, Pages -Publisher
MDPI
DOI: 10.3390/molecules28217252
Keywords
pyrazolo[3,4-c]pyridazine; nanoparticles; cytotoxicity; EGFR and CDK-2/cyclin A2 inhibition; docking simulation; ADME analysis
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This study uses the nanoformulation method to prepare nanoparticles of a previously prepared compound, and investigates their cytotoxic activity and inhibitory effects against cancer cell lines. The nanoparticles show promising anti-cancer activity and improved effects on EGFR and CDK-2 / cyclin A2. They also regulate cancer biomarkers to exert their anti-cancer effects.
The strategic planning of this study is based upon using the nanoformulation method to prepare nanoparticles 4-SLNs and 4-LPHNPs of the previously prepared 4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-3-amine (4) after confirming its structure with single crystal X-ray analysis. These nanoparticles exhibited promising cytotoxic activity against HepG-2, HCT-116 and MCF-7 cancer cell lines in comparison with the reference doxorubicin and the original derivative 4. Moreover, their inhibitory assessment against EGFR and CDK-2/cyclin A2 displayed improved and more favorable impact than the parent 4 and the references. Detection of their influence upon cancer biomarkers revealed upregulation of Bax, p53 and caspase-3 levels and downregulation of Bcl-2 levels. The docking simulation demonstrated that the presence of the pyrazolo[3,4-c]pyridazin-3-amine scaffold is amenable to enclosure and binding well within EGFR and CDK-2 receptors through different hydrophilic interactions. The pharmacokinetic and physicochemical properties of target 4 were also assessed with ADME investigation, and the outcome indicated good drug-like characteristics.
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