FLT3 tyrosine kinase is a potential drug target in acute myeloid leukemia (AML) because patients with FLT3-ITD mutations respond poorly to standard cytotoxic agents and there is a clear link between the disease and the oncogenic properties of FLT3. We present novel 2,6,9-trisubstituted purine derivatives with potent FLT3 inhibitory activity. The lead compound 7d displays nanomolar activity in biochemical assays and selectively blocks proliferation of AML cell lines harboring FLT3-ITD mutations, whereas other transformed and normal human cells are several orders of magnitude less sensitive. The MV4-11 cells treated with 7d suppressed the phosphorylation of FLT3 and its downstream signaling pathways, with subsequent G1 cell cycle arrest and apoptosis. Additionally, a single dose of 7d in mice with subcutaneous MV4-11 xenografts caused sustained inhibition of FLT3 and STAT5 phosphorylation over 48 h, in contrast to the shorter effect observed after administration of the reference FLT3 inhibitor quizartinib.
- MeSH
- akutní myeloidní leukemie genetika patologie MeSH
- antitumorózní látky chemie metabolismus farmakologie MeSH
- diaminy chemie metabolismus farmakologie MeSH
- inhibitory proteinkinas chemie metabolismus farmakologie MeSH
- konformace proteinů MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- objevování léků * MeSH
- simulace molekulového dockingu MeSH
- tyrosinkinasa 3 podobná fms antagonisté a inhibitory chemie genetika metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- xenogenní modely - testy antitumorózní aktivity MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antitumorózní látky MeSH
- diaminy MeSH
- FLT3 protein, human MeSH Prohlížeč
- inhibitory proteinkinas MeSH
- tyrosinkinasa 3 podobná fms MeSH
Four linear diaminoalkanes (1,2-diaminoethane, 1,4-diaminobutane, 1,6-diaminohexane, and 1,8-diaminooctane) have been used to hypercrosslink poly(styrene-co-vinylbenzyl chloride-co-divinylbenzene) monolithic stationary phases by nucleophilic substitution reaction. The column efficiency of polymer monoliths improved with longer diaminoalkane with 1,8-diaminoctane providing the highest efficiency. The concentration of 1,8-diaminoctane, together with hypercrosslinking time and temperature has been optimized. To improve the permeability of prepared columns, the hypercrosslinking modification has been combined with an early termination of polymerization reaction and decrease in polymerization temperature. The optimal column has been prepared by a polymerization reaction for 2h at 65°C and hypercrosslinked in the presence of 3% 1,8-diaminooctane for 2h at 95°C. The repeatability study of the presented protocol provided relative standard deviation for nine columns prepared independently out of three individual polymerization mixtures in between 2.0-12.0% for retention factors and 1.5-6.5% for plate heights, respectively. Further, we have modified residual chloromethyl groups with 2-aminoethanesulfonic acid (taurine) to prepare monolithic columns suitable for separation of small polar molecules in hydrophilic interaction chromatography. The highest retention of polar thiourea showed the column modified at 70°C for 20 h. Taurine-modified hypercrosslinked column showed the minimum of van Deemter curve of 20 μm. The prepared column provided dual-retention mechanism, including hydrophilic interaction and reversed-phase liquid chromatography that can be controlled by the composition of the mobile phase. The prepared column has been successfully used for an isocratic separation of low-molecular phenolic acids.
- Klíčová slova
- Hypercrosslinking, Nucleophilic substitution, Phenolic acids, Polymer monoliths, Small molecules,
- MeSH
- chromatografie s reverzní fází metody MeSH
- diaminy chemie MeSH
- hydrofobní a hydrofilní interakce MeSH
- hydroxybenzoáty izolace a purifikace MeSH
- polymerizace MeSH
- polymery chemie MeSH
- putrescin chemie MeSH
- reagencia zkříženě vázaná chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 1,6-diaminohexane MeSH Prohlížeč
- diaminy MeSH
- hydroxybenzoáty MeSH
- octamethylenediamine MeSH Prohlížeč
- phenolic acid MeSH Prohlížeč
- polymery MeSH
- putrescin MeSH
- reagencia zkříženě vázaná MeSH
The ability of thorium uptake as well as responses to heavy metal stress were tested in tobacco cultivar La Burley 21. Thorium was accumulated preferentially in the root system. The presence of citric, tartaric and oxalic acids in hydroponic medium increased thorium accumulation in all plant organs. On the other hand, the addition of diamines and polyamines, the important antioxidants in plants, resulted in decrease of thorium accumulation, especially in the root system. Negative correlation was found between putrescine concentration and thorium accumulation. Nevertheless, the most important factor influencing the accumulation of thorium was the absence of phosphate ions in a hydroponic medium that caused more than 10-fold increase of thorium uptake in all plant parts. Accumulation and distribution of thorium was followed in six cultivars and 14 selected transformants. Cultivar La Barley 21 represented an average between the tested genotypes, having a very good distribution ratio between roots, stems and leaves.
- Klíčová slova
- Citric acid, Phosphate, Plant uptake, Polyamines, Thorium, Tobacco,
- MeSH
- diaminy chemie farmakologie MeSH
- fosfáty chemie nedostatek MeSH
- genotyp MeSH
- hydroponie MeSH
- ionty chemie MeSH
- kořeny rostlin účinky léků metabolismus MeSH
- listy rostlin účinky léků metabolismus MeSH
- polyaminy chemie farmakologie MeSH
- putrescin chemie farmakologie MeSH
- stonky rostlin účinky léků metabolismus MeSH
- tabák metabolismus MeSH
- thorium chemie metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- diaminy MeSH
- fosfáty MeSH
- ionty MeSH
- polyaminy MeSH
- putrescin MeSH
- thorium MeSH
Another new substance from the family of Pt-based coordination complexes with potential use in cancer chemotherapy has been synthesized, crystallized and structurally characterized. In this compound {systematic name cis-dibromido[(1R,2R)-cyclohexane-1,2-diamine-κ(2)N,N']platinum(II)}, cis-[PtBr(2)(C(6)H(14)N(2))], there are two molecules with very similar conformations in the asymmetric unit. The component species interact by way of N-H...Br and C-H...Br hydrogen bonds to give two-dimensional networks which lie parallel to the (100) plane.
- MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- cyklohexany chemie MeSH
- cytostatické látky chemická syntéza chemie farmakologie MeSH
- diaminy chemie MeSH
- krystalografie rentgenová MeSH
- molekulární konformace MeSH
- myši MeSH
- nádory chemie farmakoterapie MeSH
- organoplatinové sloučeniny chemická syntéza chemie farmakologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antitumorózní látky MeSH
- cis-dibromido((1R,2R)-cyclohexane-1,2-diamine-kappa(2)N,N')platinum(II) MeSH Prohlížeč
- Cyclohexane MeSH Prohlížeč
- cyklohexany MeSH
- cytostatické látky MeSH
- diaminy MeSH
- organoplatinové sloučeniny MeSH
This review reports on inhibitors of copper-containing amine oxidases and flavoprotein polyamine oxidases, which are structurally based on diamines. In the introduction, basic characteristics and classification of amine oxidases are described together with the significance of their synthetic inhibitors. The following text is divided into several chapters, which deal with diaminoketones, aza-diamines, unsaturated diamine analogs and diamines with heterocyclic substituents. Then it continues with diamine- and agmatine-based inhibitors of polyamine oxidases. Each chapter gives detailed information on the inhibition mode, potency and structural relationships. The conclusion points out possible roles of mechanism-based inhibitors of amine oxidases in physiological and medicinal research.
- MeSH
- agmatin chemie farmakologie MeSH
- aktivace enzymů účinky léků fyziologie MeSH
- diaminy chemie farmakologie MeSH
- histaminasa antagonisté a inhibitory metabolismus MeSH
- inhibitory enzymů chemie farmakologie MeSH
- ketony chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- oxidoreduktasy působící na CH-NH vazby antagonisté a inhibitory metabolismus MeSH
- polyaminoxidasa MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- agmatin MeSH
- diaminy MeSH
- histaminasa MeSH
- inhibitory enzymů MeSH
- ketony MeSH
- oxidoreduktasy působící na CH-NH vazby MeSH
A series of N,N'-bis(2-pyridinylmethyl)diamines was synthesized and characterized for their inhibition effects towards plant copper-containing amine oxidase (EC 1.4.3.6) and polyamine oxidase (EC 1.5.3.11), which mediate the catabolic regulation of cellular polyamines. Even though these enzymes catalyze related reactions and, among others, act upon two common substrates (spermidine and spermine), their molecular and kinetic properties are different. They also show a different spectrum of inhibitors. It is therefore of interest to look for compounds providing a dual inhibition (i.e. inhibiting both enzymes with the same inhibition potency), which would be useful in physiological studies involving modulations of polyamine catabolism. The synthesized diamine derivatives comprised from two to eight carbon atoms in the alkyl spacer chain. Kinetic measurements with pea (Pisum sativum) diamine oxidase and oat (Avena sativa) polyamine oxidase demonstrated reversible binding of the compounds at the active sites of the enzymes as they were almost exclusively competitive inhibitors with K(i) values ranging from 10(-5) to 10(-3)M. In case of oat polyamine oxidase, the K(i) values were significantly influenced by the number of methylene groups in the inhibitor molecule. The measured inhibition data are discussed with respect to enzyme structure. For that reason, the oat enzyme was analyzed by de novo peptide sequencing using mass spectrometry and shown to be homologous to polyamine oxidases from barley (isoform 1) and maize. We conclude that some of the studied N,N'-bis(2-pyridinylmethyl)diamines might have a potential to be starting structures in design of metabolic modulators targeted to both types of amine oxidases.
- MeSH
- diaminy chemická syntéza chemie metabolismus MeSH
- elektroforéza v polyakrylamidovém gelu MeSH
- histaminasa antagonisté a inhibitory genetika MeSH
- inhibitory enzymů chemická syntéza chemie metabolismus MeSH
- molekulární sekvence - údaje MeSH
- oxidoreduktasy působící na CH-NH vazby antagonisté a inhibitory MeSH
- polyaminoxidasa MeSH
- rostlinné proteiny genetika metabolismus MeSH
- sekvence aminokyselin MeSH
- sekvenční homologie aminokyselin MeSH
- spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- diaminy MeSH
- histaminasa MeSH
- inhibitory enzymů MeSH
- oxidoreduktasy působící na CH-NH vazby MeSH
- rostlinné proteiny MeSH
