Purine inhibitors of cyclin-dependent kinases (CDK) seem to be a potential anticancer drug candidate as one of the first representatives, roscovitine, is passing Phase II clinical trials for cancer and glomerulonephritis. In this article, we describe a novel modification of the purine scaffold influencing CDK2 inhibitory activities as well as anticancer properties in cell lines of different histopathological origin. The introduced N at position 8 of the purine ring generally lowered CDK2 inhibitory activity of new 8-azapurines (1,2,3-triazolo[4,5-d]pyrimidines) in comparison to the model trisubstituted purines, whereas the antiproliferative potential of some derivatives remained very high, reflecting their ability to activate p53 tumor suppressor.

• MeSH
• cyklin-dependentní kinasa 2 MeSH
• cyklin-dependentní kinasy antagonisté a inhibitory   MeSH
• inhibitor p21 cyklin-dependentní kinasy MeSH
• kinasy CDC2-CDC28 antagonisté a inhibitory   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• proliferace buněk účinky léků   MeSH
• proteiny buněčného cyklu metabolismus   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• puriny chemická syntéza   chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CDK2 protein, human MeSH Prohlížeč
• CDKN1A protein, human MeSH Prohlížeč
• cyklin-dependentní kinasa 2 MeSH
• cyklin-dependentní kinasy MeSH
• inhibitor p21 cyklin-dependentní kinasy MeSH
• kinasy CDC2-CDC28 MeSH
• nádorový supresorový protein p53 MeSH
• proteiny buněčného cyklu MeSH
• protinádorové látky MeSH
• puriny MeSH
• triazolopyrimidinone MeSH Prohlížeč

A search among analogues of anti-CDK purines led to the identification of substituted pyrazolo[4,3-d]pyrimidines as novel inhibitors of CDK1/cyclin B. Some of these derivatives also show antiproliferative activity on cancer cell line K-562, thus may find an application as anticancer agents.

• MeSH
• buněčné dělení účinky léků   MeSH
• buňky K562 MeSH
• cyklin B antagonisté a inhibitory   MeSH
• cyklin-dependentní kinasy antagonisté a inhibitory   MeSH
• inhibiční koncentrace 50 MeSH
• inhibitory enzymů chemie   farmakologie   MeSH
• lidé MeSH
• proteinkinasa CDC2 antagonisté a inhibitory   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• pyrazoly chemie   farmakologie   MeSH
• pyrimidiny chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cyklin B MeSH
• cyklin-dependentní kinasy MeSH
• inhibitory enzymů MeSH
• proteinkinasa CDC2 MeSH
• protinádorové látky MeSH
• pyrazolo(3,4-d)pyrimidine MeSH Prohlížeč
• pyrazoly MeSH
• pyrimidiny MeSH

N2-(4-Amino-cyclohexyl)-9-cyclopentyl-N6-(6-furan-2-yl-pyridine-3-ylmethyl)-9H-purine-2,6-diamine (BP-14) and 2-(5-{[2-(4-amino-cyclohexylamino)-9-cyclopentyl-9H-purine-6-ylamino]-methyl}-pyridine-2-yl)-phenol (BP-20) are novel cyclin-dependent kinase inhibitors, structurally related to roscovitine, with significant biological activity. A simple, selective and sensitive liquid chromatography - tandem mass spectrometry method for determining them in rat plasma, using roscovitine as an internal standard, was developed and validated. Chromatographic separation was performed in reversed phase mode on Acquity BEH C18 column (100 × 2.1 mm, 1.7 μm) by gradient elution with mobile phases composed of 15 mM ammonium formate pH 4.0 and methanol at flow rate 0.25 mL/min at 40 °C. The analytes were detected based on their characteristic multiple reaction monitoring transitions in positive electrospray ionization mode m/z 473.07 > 157.93 for BP-14, m/z 499.62 > 184.2 for BP-20 and m/z 355.5 > 90.86 for internal standard. In plasma the method provided good linearity within the entire concentration range: 1-10,000 nmol/L (r2 = 0.9989) for BP-14 and 10-25,000 nmol/L (r2 = 0.9994) for BP-20; the limit of detection was 0.6 nmol/L for BP-14 and 6.1 nmol/L for BP-20. Validation was also performed in bile and urine. The results of validation fit within the acceptance limits following European Medicines Agency guidelines. The method was applied in a pharmacokinetic study of BP-14 and BP-20 in vivo in rats following intravenous and intraduodenal administration including plasma pharmacokinetics, tissue distribution and excretion (renal and biliary). Both compounds showed low bioavailability after intraduodenal administration (0.630 and 1.58% for BP-14 and BP-20, respectively). Distribution into all the analyzed tissues (brain, lungs, liver, kidney, spleen, muscle, adipose tissue) was observed 3 h after single dose administration, the highest and lowest concentrations being reached in the adipose tissue and brain, respectively. The biliary excretion of the parent BP-14 and BP-20 compounds accounted for 4.81% and 10.6% of the doses, respectively, and renal excretion for <0.5% in both cases. The obtained results represent pilot knowledge for further development of a new generation of compounds with strong anticancer activities.

• Klíčová slova
• BP-14, BP-20, Cyclin-dependent kinase inhibitor, Pharmacokinetics, Tissue distribution,
• MeSH
• 2-aminopurin analogy a deriváty   analýza   farmakokinetika   MeSH
• biologická dostupnost MeSH
• cykliny chemie   MeSH
• hepatobiliární exkrece účinky léků   MeSH
• inhibitory proteinkinas aplikace a dávkování   analýza   chemie   farmakokinetika   MeSH
• intravenózní podání metody   MeSH
• kalibrace MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• limita detekce MeSH
• molekulární struktura MeSH
• potkani Wistar MeSH
• protinádorové látky aplikace a dávkování   analýza   chemie   farmakokinetika   MeSH
• reprodukovatelnost výsledků MeSH
• tandemová hmotnostní spektrometrie metody   MeSH
• tkáňová distribuce účinky léků   MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 2-aminopurin MeSH
• cykliny MeSH
• inhibitory proteinkinas MeSH
• N2-(4-aminocyclohexyl)-9-cyclopentyl-N6-((6-(2-furyl)-3-pyridyl)methyl)purine-2,6-diamine MeSH Prohlížeč
• protinádorové látky MeSH