The synthesis of axially chiral benzimidazoles with a peri-substituted naphthalene and a dimethylamino group at positions 1 and 2, respectively, was developed. We evaluated these compounds in the desymmetrization reaction of cis-tetrahydrophthalic anhydride with benzyl alcohol, as the nucleophilic sp2 imidazole nitrogen atom is able to catalyze the acyl-transfer reaction. The prepared benzimidazoles demonstrated catalytic activity and showed that their axial chirality impacts stereoselectivity.
- Publikační typ
- časopisecké články MeSH
Therapy of FLT3-positive acute myeloid leukemia still remains complicated, despite the availability of newly approved kinase inhibitors. Various strategies to avoid the reduced efficacy of therapy have been explored, including the development of dual targeting compounds, which inhibit FLT3 and another kinase necessary for the survival and proliferation of AML cells. We have designed new 2,7,9-trisubstituted 8-oxopurines as FLT3 inhibitors and report here the structure-activity relationship studies. We demonstrated that substituents at positions 7 and 9 modulate activity between CDK4 and FLT3 kinase, and the isopropyl group at position 7 substantially increased the selectivity toward FLT3 kinase, which led to the discovery of compound 15a (9-cyclopentyl-7-isopropyl-2-((4-(piperazin-1-yl)phenyl)amino)-7,9-dihydro-8H-purin-8-one). Cellular analyses in MV4-11 cells revealed inhibition of autophosphorylation of FLT3 kinase in nanomolar doses, including the suppression of downstream STAT5 and ERK1/2 phosphorylation. We also describe mechanistic studies in cell lines and activity in a mouse xenograft model in vivo.
- MeSH
- akutní myeloidní leukemie * farmakoterapie MeSH
- apoptóza MeSH
- fosforylace MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- lidé MeSH
- mutace MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- proliferace buněk MeSH
- tyrosinkinasa 3 podobná fms MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Cycle-regulating and transcriptional cyclin-dependent kinases (CDKs) are attractive targets in cancer drug development. Several CDK inhibitors have already been obtained or are close to regulatory approval for clinical applications. OBJECTIVE: Phenylazopyrazole CAN508 has been described as the first selective CDK9 inhibitor with an IC50 of 350 nM. Since the azo-moiety is not a suitable functionality for drugs due to pharmacological reasons, the preparation of carbo-analogues of CAN508 with similar biological activities is desirable. The present work is focused on the synthesis of carbo-analogues similar to CAN508 and their CDK inhibition activity. METHODS: Herein, the synthesis of 21 novel carbo analogues of CAN508 and their intermediates is reported. Subsequently, target compounds 8a - 8u were evaluated for protein kinase inhibition (CDK2/cyclin E, CDK4/cyclin D, CDK9/cyclin T) and antiproliferative activities in cell lines (K562, MCF-7, MV4-11). Moreover, the binding mode of derivative 8s in the active site of CDK9 was modelled. RESULTS: Compounds 8a - 8u were obtained from key intermediate 7, which was prepared by linear synthesis involving Vilsmeier-Haack, Knoevenagel, Hunsdiecker, and Suzuki-Miyaura reactions. Styrylpyrazoles 8t and 8u were the most potent CDK9 inhibitors with IC50 values of approximately 1 μM. Molecular modelling suggested binding in the active site of CDK9. The flow cytometric analysis of MV4-11 cells treated with the most active styrylpyrazoles showed a significant G1-arrest. CONCLUSION: The prepared styrylpyrazoles showed inhibition activity towards CDKs and can provide a novel chemotype of kinase inhibitors.
New screen-printed sensor with a boron-doped diamond working electrode (SP/BDDE) was fabricated using a large-area linear antenna microwave chemical deposition vapor system (LA-MWCVD) with a novel precursor composition. It combines the advantages of disposable printed sensors, such as tailored design, low cost, and easy mass production, with excellent electrochemical properties of BDDE, including a wide available potential window, low background currents, chemical resistance, and resistance to passivation. The newly prepared SP/BDDEs were characterized by scanning electron microscopy (SEM) and Raman spectroscopy. Their electrochemical properties were investigated by cyclic voltammetry and electrochemical impedance spectroscopy using inner sphere ([Fe(CN)6]4-/3-) and outer sphere ([Ru(NH3)6]2+/3+) redox probes. Moreover, the applicability of these new sensors was verified by analysis of the anti-inflammatory drug lornoxicam in model and pharmaceutical samples. Using optimized differential pulse voltammetry in Britton-Robinson buffer of pH 3, detection limits for lornoxicam were 9 × 10-8 mol L-1. The oxidation mechanism of lornoxicam was investigated using bulk electrolysis and online electrochemical cell with mass spectrometry; nine distinct reaction steps and corresponding products and intermediates were identified.
- MeSH
- bor * chemie MeSH
- elektrody MeSH
- elektrolýza * MeSH
- oxidace-redukce MeSH
- Ramanova spektroskopie MeSH
- Publikační typ
- časopisecké články MeSH
Synthesis of [15 N4 ] purine labeled cytokinine glycosides derived from zeatins and topolins containing a 9-β-d, 7-β-d-glucopyranosyl, or 9-β-d-ribofuranosyl group is described. These N6 -substituted adenine derivatives are intended as internal analytic standards for phytohormone analysis. All labeled compounds were prepared from 6-chloro[15 N4 ]purine (1). The equilibrium reaction of 1 with acetobromo-α-d-glucose gave isomeric 7-β-d (3) and 9-β-d (4) chloro glucosyl precursors, which were treated with the corresponding amines to get desired labeled cytokinin 7-β-d (6) and 9-β-d (5) glucopyranosides. Cytokinins containing 9-β-d-ribofuranosyl group (8) were obtained by direct enzymatic transglycosylation reaction of cytokinins (7) prepared from 6-chloro[15 N4 ] purine (1).
The cyclin-dependent kinase inhibitor, CAN508, was protected with di-tert-butyl dicarbonate to access the amino-benzoylated pyrazoles. The bromo derivatives were further arylated by Suzuki-Miyaura coupling using the XPhos Pd G2 pre-catalyst. The coupling reaction provided generally the para-substituted benzoylpyrazoles in the higher yields than the meta-substituted ones. The Boc groups were only utilized as directing functionalities for the benzoylation step and were hydrolyzed under conditions of Suzuki-Miyaura coupling, which allowed for elimination of the additional deprotection step.
Here, we describe new 4-arylazo-3,5-diamino-1H-pyrazole derivatives developed from CAN508, one of the first inhibitors to show preference for transcriptional regulator cyclin-dependent kinase 9. By substituting nitrogen in the pyrazole ring and employing a heteroatom in the 4-aryl ring, we obtained more potent derivatives differing in their CDK-selectivity profiles. The antiproliferative and anti-CDK kinase activities of the novel arylazopyrazoles were examined. The cellular effect of compound IVc was studied on MCF-7 cells synchronized by various methods and compared with other selective CDK inhibitors. The results demonstrated that IVc shows a preference for CDK4 and CDK1. In contrast to cytostatic effects induced by IVc in MCF-7 and K562 cells, we observed apoptotic activities in the RPMI-8226 cell line, which were confirmed by detecting active caspases by different biochemical assays.
- MeSH
- apoptóza účinky léků MeSH
- buňky K562 MeSH
- cyklin-dependentní kinasy antagonisté a inhibitory metabolismus MeSH
- inhibitory proteinkinas chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- molekulární struktura MeSH
- proliferace buněk účinky léků MeSH
- pyrazoly chemická syntéza chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Inhibitors of cyclin-dependent kinases 9 have been developed as potential anticancer drugs for the treatment of multiple myeloma. We have previously prepared a library of arylazo-3,5-diaminopyrazole inhibitors of CDKs. Here, we describe a novel member, AAP1742 (CDK9 inhibition with IC(50) = 0.28 μm), that reduces the viability of multiple myeloma cell lines in low micromolar concentrations. Consistent with inhibition of CDK9, AAP1742 decreases the phosphorylation of RNA polymerase II and inhibits mRNA synthesis of anti-apoptotic proteins Mcl-1, Bcl-2, and XIAP, followed by apoptosis in the RPMI-8226 cell line in a dose- and a time-dependent manner. These results are consistent with the biochemical profile of AAP1742 and further suggest cellular inhibition of CDK9 as a possible target for anticancer drugs.
- MeSH
- aktivace enzymů účinky léků MeSH
- apoptóza účinky léků MeSH
- azosloučeniny chemie farmakologie MeSH
- cyklin-dependentní kinasa 9 antagonisté a inhibitory metabolismus MeSH
- down regulace účinky léků MeSH
- fosforylace účinky léků MeSH
- lidé MeSH
- messenger RNA metabolismus MeSH
- mitochondrie metabolismus MeSH
- mnohočetný myelom metabolismus patologie MeSH
- nádorové buněčné linie MeSH
- protein MCL-1 genetika metabolismus MeSH
- protinádorové látky chemie farmakologie MeSH
- protoonkogenní proteiny c-bcl-2 genetika metabolismus MeSH
- pyrazoly chemie farmakologie MeSH
- RNA-polymerasa II metabolismus MeSH
- X-vázaný inhibitor apoptózy genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The fluorescence properties of selected benzo[c]phenanthridines (BPs) were examined. The effect of structure, pH and solvent on the fluorescence properties has been investigated. It was found out that the presence of charged iminium nitrogen significantly decreased the fluorescence of the compounds. The fluorescence (intensity as well as emission spectra shape) of the investigated compounds was significantly dependent on pH as well as used solvent. The utilization in epigenetic modification mechanisms studies as demethylase probe and as possible pH indicator was suggested.
- MeSH
- benzofenantridiny chemická syntéza chemie MeSH
- fluorescence * MeSH
- fluorescenční barviva chemická syntéza chemie MeSH
- fluorescenční spektrometrie MeSH
- koncentrace vodíkových iontů MeSH
- molekulární struktura MeSH
- průtoková cytometrie MeSH
- rozpouštědla chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
