Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity

Abstract

Cyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivatives ( 4–15 ) was designed and synthesised as novel CDK2 inhibitors. The anti-proliferative activities against MCF-7, HCT-116, and HepG-2 were used to evaluate their anticancer activity as novel CDK2 inhibitors. Most of the compounds showed superior cytotoxic activity against MCF-7 and HCT-116 compared to Sorafenib. Only compounds 8 , 14 , and 15 showed potent activity against HepG-2. The CDK2/cyclin A2 enzyme inhibitory activity was tested for all synthesised compounds. Compound 15 showed the most significant inhibitory activity with IC 50 0.061 ± 0.003 µM. It exerted remarkable alteration in Pre G1 and S phase cell cycle progression and caused apoptosis in HCT cells. In addition, the normal cell line cytotoxicity for compound 15 was assigned revealing low cytotoxic results in normal cells rather than cancer cells. Molecular docking was achieved on the designed compounds and confirmed the two essential hydrogen binding with Leu83 in CDK2 active site. In silico ADMET studies and drug-likeness showed proper pharmacokinetic properties which helped in structure requirements prediction for the observed antitumor activity.

Synthesis, Characterization, in silico DFT, Molecular docking, ADMET Profiling Studies and Toxicity Predictions of Ag(I) Complex Derived from 4‐Aminoacetophenone

“…A few programs such as Molsoft and SwissADME were used to calculate the absorption, distribution, metabolism, excretion, and toxicity (ADMET) for ligand DMPDE and Ag(I) complex. This study examined several parameters, including the number of hydrogen bond donors and acceptors, blood‐brain barrier levels, absorption levels, two‐dimensional polar surface areas, Cytochrome P450 2D6, hepatotoxicity probability, aqueous solubility levels, and plasma protein binding logarithmic levels, all of which were calculated using SwissADME [81] . This study considers small molecules that are ideal drug‐like candidates, have high bioavailability, and follow the Lipinski rule and the “Veber's rule”, which requires the following features, i. e., mw≤500, log P≤5, TPSA≤140 Å 2 , number of hydrogen bond acceptors≤10 (i. e., N or O atoms), and hydrogen bond donors ≤ 5 [82] .…”

Interaction Patterns of Pyrazolopyrimidines with Receptor Proteins

“…Their structural similarity to ATP makes them a potential candidate for designing ATP-competitive inhibitors of protein kinases. , The most accepted mechanism of anticancer activity for this class of molecules is the inhibition of various protein kinases such as Abl, tyrosine kinases, Aurora kinases, and CDKs. Over the years, innumerable publications have reported Pyp-based kinase inhibitors. ,,− ,− In addition, CNS activity has been evaluated for all four isomers. ,, Pyrazolo­[1,5- a ]­pyrimidines are TRPC6 agonists and also inhibit enoyl-ACP reductase (InhA) with potential applications in anti-tubercular drug development . Pyrazolo­[1,5- c ]­pyrimidines are reported as selective negative modulators of α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors .…”

Novel pyrazolo[3,4-d]pyrimidine derivatives: design, synthesis, anticancer evaluation, VEGFR-2 inhibition, and antiangiogenic activity

“…Extensive investigations have revealed diverse pharmacological properties associated with this scaffold, 26,27 with notable attributes of potent anticancer activity. 28–30 Previous reports suggest that this scaffold exerts its anticancer effects through various distinct mechanisms, such as inhibition of cyclin-dependent kinases (CDK) 31–33 and the epidermal growth factor receptor (EGFR). 34…”