A Novel Pyrazolo[1,5-a]pyrimidine Is a Potent Inhibitor of Cyclin-Dependent Protein Kinases 1, 2, and 9, Which Demonstrates Antitumor Effects, in Human Tumor Xenografts Following Oral Administration
ABSTRACT Cyclin-dependent protein kinases (CDKs) are central to the appropriate regulation of cell proliferation, apoptosis, and gene expression. Abnormalities in CDK activity and regulation are common features of cancer, making CDK family members attractive targets for the development of anticancer drugs. Here, we report the identification of a pyrazolo[1,5-a]pyrimidine derived compound, 4k (BS-194), as a selective and potent CDK inhibitor, which inhibits CDK2, CDK1, CDK5, CDK7, and CDK9 (IC₅₀= 3, 30, 30, 250, and 90 nmol/L, respectively). Cell-based studies showed inhibition of the phosphorylation of CDK substrates, Rb and the RNA polymerase II C-terminal domain, down-regulation of cyclins A, E, and D1, and cell cycle block in the S and G₂/M phases. Consistent with these findings, 4k demonstrated potent antiproliferative activity in 60 cancer cell lines tested (mean GI₅₀= 280 nmol/L). Pharmacokinetic studies showed that 4k is orally bioavailable, with an elimination half-life of 178 min following oral dosing in mice. When administered at a concentration of 25 mg/kg orally, 4k inhibited human tumor xenografts and suppressed CDK substrate phosphorylation. These findings identify 4k as a novel, potent CDK selective inhibitor with potential for oral delivery in cancer patients.
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ABSTRACT: In Aflica, malaria kills one child each minute. It is also responsible for about one million deaths worldwide each year. Plasmodium falciparum, is the protozoan responsible for the most lethal form of the disease, with resistance developing against the available anti-malarial drugs. Among newly proposed anti-malaria targets, are the P. falciparum cyclin-dependent kinases (PfCDKs). There are involved in different stages of the protozoan growth and development but share high sequence homology with human cyclin-dependent kinases (CDKs). We previously reported the synthesis of CDKs inhibitors that are structurally-related to (R)-roscovitine, a 2,6,9-trisubstituted purine, and they showed activity against neuronal diseases and cancers. In this report, we describe the synthesis and the characterization of new CDK inhibitors, active in reducing the in vitro growth of P. falciparum (3D7 and 7G8 strains). Six compounds are more potent inhibitors than roscovitine, and three exhibited IC50 values close to 1 µM for both 3D7 and 7G8 strains. Although, such molecules do inhibit P. falciparum growth, they require further studies to improve their selectivity for PfCDKs.Molecules 09/2014; 19(9):15237-15257. DOI:10.3390/molecules190915237 · 2.10 Impact Factor
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ABSTRACT: Fused five-membered nitrogen heterocycles comprise a very important group of compounds frequently utilized in pharmaceutical applications. In this study, we report the first systematic synthesis of substituted pyrazolo[4,3-c]pyrazoles and three regio-isomers of their N-methyl derivatives. All compounds were fully characterized by using NMR spectroscopy in solution and selected compounds also by X-ray diffraction in the solid state. 1H, 13C, and 15N NMR data for all isomers were interpreted by DFT calculations of nuclear shielding constants and indirect spin-spin coupling constants. The N-methyl isomers were used in the following steps as model compounds to investigate a potential N1-H/N4-H, N2-H/N4-H, and N1-H/N5-H tautomerism of 3,6-substituted pyrazolo[4,3-c]pyrazoles by using low-temperature NMR spectroscopy. All bases were shown to occur predominantly in the N1-H/N4-H tautomeric form and the structure of minor form was governed by the substituents at positions 3 and 6. Stabilities of individual tautomeric forms are calculated by DFT methods and discussed. A relationship between the tautomeric populations and the ratios among N-methyl isomers obtained upon methylation of selected base in solution is investigated.European Journal of Organic Chemistry 10/2013; 2013(30):6811-6822. DOI:10.1002/ejoc.201300606 · 3.15 Impact Factor
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ABSTRACT: Regioselectivity was examined of reactions between nine 3(5)-aminopyrazoles and 2-acetylcyclopentanone and 2-acetylcyclohexanone under various conditions. A series of cyclopenta[e]pyrazolo-[1,5-a]pyrimidines was obtained. The highest regioselectivity of the reaction was observed in alcohol at 20°C in the presence of a catalytic quantity of trifl uoroacetic acid. The regiostructure of compounds was established by 1H and 13C NMR spectroscopy.Russian Journal of Organic Chemistry 08/2012; 48(8). DOI:10.1134/S1070428012080131 · 0.68 Impact Factor