Kinetin derivatives Dotaz Zobrazit nápovědu
The chronic exposure of skin to ultraviolet (UV) radiation causes adverse dermal reactions, such as erythema, sunburn, photoaging, and cancer, by altering several signalling pathways associated with oxidative stress, inflammation, and DNA damage. One of the possible UV light protection strategies is the use of dermal photoprotective preparations. The plant hormone kinetin (N6-furfuryladenine; KIN) exhibits antioxidant and anti-senescent effects in human cells. Topically applied KIN also reduced some of the clinical signs of photodamaged skin. To improve the biological activities of KIN, several derivatives have been recently prepared and their beneficial effects on cell viability of skin cells exposed to UVA and UVB light were screened. Two potent candidates, 6-(tetrahydrofuran-2-yl)methylamino-9-(tetrahydrofuran-2-yl)purine (HEO) and 6-(thiophen-2-yl)methylamino-9-(tetrahydrofuran-2-yl)purine (HEO6), were identified. Here the effects of KIN, its N9-substituted derivatives the tetrahydropyran-2-yl derivative of KIN (THP), tetrahydrofuran-2-yl KIN (THF), HEO and HEO6 (both THF derivatives) on oxidative stress, apoptosis and inflammation in UVA- or UVB-exposed skin cell was investigated. Human primary dermal fibroblasts and human keratinocytes HaCaT pre-treated with the tested compounds were then exposed to UVA/UVB light using a solar simulator. All compounds effectively prevented UVA-induced ROS generation and glutathione depletion in both cells. HEO6 was found to be the most potent. All compounds also reduced UVB-induced caspase-3 activity and interleukin-6 release. THP and THF exhibited the best UVB protection. In conclusion, our results demonstrated the UVA- and UVB-photoprotective potential of KIN and its derivatives. From this point of view, they seem to be useful agents for full UV spectrum protective dermatological preparations.
- MeSH
- antioxidancia farmakologie MeSH
- keratinocyty * metabolismus MeSH
- kinetin metabolismus farmakologie MeSH
- kůže * účinky záření MeSH
- lidé MeSH
- ultrafialové záření škodlivé účinky MeSH
- zánět metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The first isolated cytokinin, 6-furfurylaminopurine (kinetin or Kin), was identified almost 55years ago. Its biological effects on plant cells and tissues include influences on such processes as gene expression, cell cycle, chloroplast development, chlorophyll biosynthesis, stimulation of vascular development, delay of senescence, and mobilization of nutrients. In the present study we prepared a series of eight N9-substituted Kin derivatives, and characterized them with available physicochemical methods such as CI+ mass spectrometry and (1)H NMR spectroscopy. All compounds were tested in three classical cytokinin bioassays: a tobacco callus assay, an Amaranthus assay, and a senescence assay with excised wheat leaves. The ability of the compounds to interact with Arabidopsis cytokinin receptors CRE1/AHK4 and AHK3 was tested in a bacterial receptor assay. Prepared derivatives with certain substitutions of the N9-atom of the purine moiety enhanced the cytokinin activity of the parent compound in the bioassays to a remarkable degree but negatively affected its perception by CRE1/AHK4 and AHK3. The ability of compounds to delay the senescence of excised wheat leaves in both dark and light conditions, was highly correlated with their ability to influence membrane lipid peroxidation, which is a typical symptom of senescence. Our results were corroborated by gene expression profiling of those genes involved in cytokinin metabolism and perception, plant senescence, and the stress response, and suggest that prepared kinetin derivatives might be used as potent anti-senescence agents.
- MeSH
- Arabidopsis genetika metabolismus MeSH
- kinetin chemická syntéza chemie farmakologie MeSH
- molekulární struktura MeSH
- nukleární magnetická rezonance biomolekulární MeSH
- proteiny huseníčku metabolismus MeSH
- pšenice účinky léků metabolismus MeSH
- puriny chemická syntéza chemie MeSH
- stárnutí účinky léků MeSH
- tabák účinky léků metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Kinetin (N6-furfuryladenine), a plant growth substance of the cytokinin family, has been shown to modulate aging and various age-related conditions in animal models. Here we report the synthesis of kinetin isosteres with the purine ring replaced by other bicyclic heterocycles, and the biological evaluation of their activity in several in vitro models related to neurodegenerative diseases. Our findings indicate that kinetin isosteres protect Friedreich́s ataxia patient-derived fibroblasts against glutathione depletion, protect neuron-like SH-SY5Y cells from glutamate-induced oxidative damage, and correct aberrant splicing of the ELP1 gene in fibroblasts derived from a familial dysautonomia patient. Although the mechanism of action of kinetin derivatives remains unclear, our data suggest that the cytoprotective activity of some purine isosteres is mediated by their ability to reduce oxidative stress. Further, the studies of permeation across artificial membrane and model gut and blood-brain barriers indicate that the compounds are orally available and can reach central nervous system. Overall, our data demonstrate that isosteric replacement of the kinetin purine scaffold is a fruitful strategy for improving known biological activities of kinetin and discovering novel therapeutic opportunities.
- MeSH
- cytoprotekce MeSH
- kinetin chemická syntéza chemie farmakologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- molekulární struktura MeSH
- oxidační stres účinky léků MeSH
- puriny chemická syntéza chemie farmakologie MeSH
- viabilita buněk účinky léků 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
Kinetin (N6-furfuryladenine) belongs to a group of plant growth hormones involved in cell division, differentiation and other physiological processes. One of the possible ways to obtain biologically active compounds is to complex biologically relevant natural compounds to suitable metal atoms. In this work, two structural groups of Zn(II) complexes [Zn(L(n))2Cl2]·Solv (1-5) and [Zn(HL(n))Cl3] · xL(n) (6-7); n=1-5, Solv=CH3OH for 1 and 2H2O for 2; x =1 for 6 and 2 for 7; involving a phytohormone kinetin and its derivatives (L(n)) were evaluated for their ability to modulate secretion of tumour necrosis factor (TNF)-α, interleukin (IL)-1β and matrix metalloproteinase (MMP)-2 in a lipopolysaccharide (LPS)-activated macrophage-like THP-1 cell model. The penetration of the complexes to cells was also detected. The mechanism of interactions of the zinc(II) complexes with a fluorescent sensor N-(6-methoxy-8-quinolyl)-p-toluene sulphonamide (TSQ) and sulfur-containing biomolecules (l-cysteine and reduced glutathione) was studied by electrospray-ionization mass spectrometry and flow-injection analysis with fluorescence detection. The present study showed that the tested complexes exhibited a low cytotoxic effect on the THP-1 cell line (IC50>40 µM), apart from complex 4, with an IC50=10.9 ± 1.1 µM. Regarding the inflammation-related processes, the Zn(II) complexes significantly decreased IL-1β production by a factor of 1.47-2.22 compared with the control (DMSO), but did not affect TNF-α and MMP-2 secretions. However, application of the Zn(II) complexes noticeably changed the pro-MMP-2/MMP-2 ratio towards a higher amount of maturated MMP-2, when they induced a 4-times higher production of maturated MMP-2 in comparison with the vehicle-treated cells under LPS stimulation. These results indicated that the complexes are able to modulate an inflammatory response by influencing secretion and activity of several inflammation-related cytokines and enzymes.
- MeSH
- aktivace makrofágů účinky léků MeSH
- aminochinoliny MeSH
- antiflogistika chemická syntéza farmakologie MeSH
- biologický transport MeSH
- chloridy chemie MeSH
- cystein chemie MeSH
- exprese genu účinky léků MeSH
- fluorescenční barviva MeSH
- glutathion chemie MeSH
- interleukin-1beta antagonisté a inhibitory genetika sekrece MeSH
- kationty dvojmocné MeSH
- kinetin chemie MeSH
- komplexní sloučeniny chemická syntéza farmakologie MeSH
- lidé MeSH
- lipopolysacharidy farmakologie MeSH
- makrofágy cytologie účinky léků sekrece MeSH
- matrixová metaloproteinasa 2 genetika sekrece MeSH
- nádorové buněčné linie MeSH
- TNF-alfa genetika sekrece MeSH
- tosylové sloučeniny MeSH
- viabilita buněk účinky léků MeSH
- zinek chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
To study the structure-activity relationships of aromatic cytokinins, the cytokinin activity at both the receptor and cellular levels, as well as CDK inhibitory and anticancer properties of 38 6-benzylaminopurine (BAP) derivatives were compared in various in vitro assays. The compounds were prepared by the condensation of 6-chloropurine with corresponding substituted benzylamines. The majority of synthesised derivatives exhibited high activity in all three of the cytokinin bioassays employed (tobacco callus, wheat senescence and Amaranthus bioassay). The highest activities were obtained in the senescence bioassay. For some compounds tested, significant differences of activity were found in the bioassays used, indicating that diverse recognition systems may operate and suggesting that it may be possible to modulate particular cytokinin-dependent processes with specific compounds. Position-specific steric and hydrophobic effects of different phenyl ring substituents on the variation of biological activity were confirmed. In contrast to their high activity in bioassays, the BAP derivatives were recognised with much lower sensitivity than trans-zeatin in both Arabidopsis thaliana AHK3 and AHK4 receptor assays. The compounds were also investigated for their effects on cyclin-dependent kinase 2 (CDK2) and for antiproliferative properties on cancer and normal cell lines. Several of the tested compounds showed stronger inhibitory activity and cytotoxicity than BAP. There was also a significant positive correlation of the inhibitory effects on human and plant CDKs with cell proliferation of cancer and cytokinin-dependent tobacco cells, respectively. This suggests that at least a part of the antiproliferative effect of the new cytokinins was due to the inhibition of CDK activity.
- MeSH
- antitumorózní látky farmakologie chemická syntéza chemie MeSH
- benzylové sloučeniny farmakologie chemická syntéza chemie MeSH
- biotest MeSH
- buňky NIH 3T3 MeSH
- cyklin-dependentní kinasy antagonisté a inhibitory MeSH
- cytokininy farmakologie chemická syntéza chemie MeSH
- financování organizované MeSH
- kinetin farmakologie chemická syntéza chemie MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- puriny farmakokinetika chemická syntéza chemie MeSH
- rostliny metabolismus účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
The platinum(II) complexes trans-[PtCl₂(Ln)₂]∙xSolv 1-13 (Solv = H₂O or CH3OH), involving N6-benzyladenosine-based N-donor ligands, were synthesized; L(n) stands for N6-(2-methoxybenzyl)adenosine (L₁, involved in complex 1), N6-(4-methoxy-benzyl)adenosine (L₂, 2), N6-(2-chlorobenzyl)adenosine (L₃, 3), N6-(4-chlorobenzyl)-adenosine (L₄, 4), N6-(2-hydroxybenzyl)adenosine (L₅, 5), N6-(3-hydroxybenzyl)-adenosine (L₆, 6), N6-(2-hydroxy-3-methoxybenzyl)adenosine (L₇, 7), N6-(4-fluoro-benzyl)adenosine (L₈, 8), N6-(4-methylbenzyl)adenosine (L₉, 9), 2-chloro-N6-(3-hydroxy-benzyl)adenosine (L₁₀, 10), 2-chloro-N6-(4-hydroxybenzyl)adenosine (L₁₁, 11), 2-chloro-N6-(2-hydroxy-3-methoxybenzyl)adenosine (L₁₂, 12) and 2-chloro-N6-(2-hydroxy-5-methylbenzyl)adenosine (L₁₃, 13). The compounds were characterized by elemental analysis, mass spectrometry, IR and multinuclear (¹H-, ¹³C-, ¹⁹⁵Pt- and ¹⁵N-) and two-dimensional NMR spectroscopy, which proved the N7-coordination mode of the appropriate N6-benzyladenosine derivative and trans-geometry of the title complexes. The complexes 1-13 were found to be non-toxic in vitro against two selected human cancer cell lines (HOS and MCF7; with IC₅₀ > 50.0 µM). However, they were found (by ESI-MS study) to be able to interact with the physiological levels of the sulfur-containing biogenic biomolecule L-methionine by a relatively simple 1:1 exchange mechanism (one L(n) molecule was replaced by one L-methionine molecule), thus forming a mixed-nitrogen/sulfur-ligand dichlorido-platinum(II) coordination species.
- MeSH
- antitumorózní látky chemie farmakologie MeSH
- hmotnostní spektrometrie MeSH
- inhibiční koncentrace 50 MeSH
- kinetin chemie farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- nádorové buněčné linie MeSH
- nukleární magnetická rezonance biomolekulární MeSH
- organoplatinové sloučeniny chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of gold(III) complexes involving differently substituted derivatives of a plant hormone N6-benzyladenine (HL1-5) is reported. The complexes have the general formula [Au(HL1-5)Cl3]∙nH2O (n=0 for 1, 3-5; and n=1 for 2), where N6-(2-fluorobenzyl)adenine (HL1), N6-(2-chlorobenzyl)adenine (HL2), N6-(3-chlorobenzyl)adenine (HL3), N6-(4-chlorobenzyl)adenine (HL4) and N6-(4-methylbenzyl)adenine (HL5) represent the N9-coordinated ligands. The results of thorough characterization (elemental and thermal analyses, FT-IR, Raman and NMR spectroscopies, ESI+ mass spectrometry, conductivity measurements, DFT calculations) showed that the presented complexes 1-5 involve a central gold(III) atom coordinated in a square-planar geometry by the N9 atom of the purine moiety of HL1-5 and by three chlorido ligands. The complexes (1-5) were studied in vitro for cytotoxicity and anti-inflammatory activity on LPS-activated macrophages (THP-1 cell line), and in vivo for anti-inflammatory effects (1, 2, 5) using the carrageenan-induced hind paw oedema model on rats. Surprisingly, the results on the in vitro level revealed that the complexes show negligible cytotoxicity and anti-inflammatory activity, however, the activity on the in vivo level was found to be significant, fully comparable with the utilized drug Indomethacin, or even better as compared to a gold-containing metallodrug Auranofin.
- MeSH
- antiflogistika nesteroidní chemická syntéza farmakologie MeSH
- auranofin farmakologie MeSH
- chloridy chemie MeSH
- edém farmakoterapie patologie MeSH
- indomethacin farmakologie MeSH
- kinetin chemie MeSH
- komplexní sloučeniny chemická syntéza farmakologie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- ligandy MeSH
- monocyty cytologie účinky léků MeSH
- nádorové buněčné linie MeSH
- potkani Wistar MeSH
- viabilita buněk účinky léků MeSH
- zadní končetina MeSH
- zlato chemie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of considerably anti-inflammatory active gold(I) mixed-ligand complexes, involving the benzyl-substituted derivatives of N6-benzyladenine (HLn) and triphenylphosphine (PPh3) as ligands and having the general formula [Au(Ln)(PPh3)]·xH2O (1-4; n=1-4 and x=0-1), was evaluated for the ability to influence the expression of CYP1A1/2 and CYP3A4 and transcriptional activity of glucocorticoid (GR) and aryl hydrocarbon (AhR) receptors in primary human hepatocytes and HepG2 cells. In both tests, evaluating the ability of the complexes to modulate the expression of CYP1A1, CYP1A2 and CYP3A4 in primary human hepatocytes and influence the transcriptional activity of AhR and GR in the reporter cell lines, no negative influence on the major drug-metabolizing cytochrome P450 isoenzymes and their signaling pathway (through GR and AhR receptors) was observed. These positive findings revealed another substantial evidence that could lead to utilization of the complexes as effective and relatively safe drugs for the treatment of hard-to-treat inflammation-related diseases, such as rheumatoid arthritis, comparable or even better than clinically used gold-containing drug Auranofin.
- MeSH
- antiflogistika farmakologie MeSH
- buňky Hep G2 MeSH
- cytochrom P-450 CYP1A1 genetika metabolismus MeSH
- cytochrom P-450 CYP1A2 genetika metabolismus MeSH
- cytochrom P-450 CYP3A genetika metabolismus MeSH
- hepatocyty účinky léků metabolismus MeSH
- kinetin chemie MeSH
- komplexní sloučeniny farmakologie MeSH
- kultivované buňky MeSH
- lékové interakce MeSH
- lidé MeSH
- organofosforové sloučeniny chemie MeSH
- receptory aromatických uhlovodíků genetika MeSH
- receptory glukokortikoidů genetika MeSH
- reportérové geny MeSH
- zlato chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of seven platinum(II) cyclobutane-1,1-dicarboxylato (cbdc) complexes {[Pt(cbdc)(L(n))(2)], 1-7}, derived from carboplatin by a substitution of two NH(3) molecules for two 2,6,9-trisubstituted 6-benzylaminopurine-based N-donor ligands (L(n)), was studied by the MTT assay for their in vitro cytotoxic activity against seven human cancer cell lines, i.e. lung carcinoma (A549), cervix epithelioid carcinoma (HeLa), osteosarcoma (HOS), malignant melanoma (G361), breast adenocarcinoma (MCF7), ovarian carcinoma (A2780) and its cisplatin-resistant analogue (A2780cis), and against two primary cultures of human hepatocytes (LH31 and LH32). The prepared complexes were cytotoxic against several cancer cells, in some cases even more than cisplatin. The best results were achieved for complexes 1 (IC(50)=17.4 ± 2.0 μM) and 2 (IC(50)=14.8 ± 2.1 μΜ) against HOS cells, 1 (IC(50)=15.1 ± 6.8 μM), 2 (IC(50)=13.6 ± 5.2 μM) and 6 (IC(50)=19.0 ± 6.6 μM) against MCF7, 6 (IC(50)=6.4 ± 0.1 μM) against A2780, and 1-6 (IC(50)=15.6 ± 4.0, 12.9 ± 3.7, 15.8 ± 3.8, 16.6 ± 5.5, 22.1 ± 2.5, and 5.6 ± 1.7 μM, respectively) against A2780cis. Viability of human hepatocytes was not declined by the tested complexes up to the concentration of 50 μM (for 1, 3-7) and 20 μM (for 2; caused by lower solubility of this complex).
- MeSH
- antitumorózní látky farmakologie MeSH
- cisplatina farmakologie MeSH
- dospělí MeSH
- hepatocyty účinky léků metabolismus patologie MeSH
- karboplatina analogy a deriváty chemie farmakologie MeSH
- kinetin chemie farmakologie MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory farmakoterapie metabolismus patologie MeSH
- organoplatinové sloučeniny chemická syntéza farmakologie MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Recently we reported 6-(2-hydroxy-3-methylbenzylamino)purine (PI-55) as the first molecule to antagonize cytokinin activity at the receptor level. Here we report the synthesis and in vitro biological testing of eleven BAP derivatives substituted in the benzyl ring and in the C2, N7 and N9 positions of the purine moiety. The ability of the compounds to interact with Arabidopsis cytokinin receptors AHK3 and CRE1/AHK4 was tested in bacterial receptor and in live-cell binding assays, and in an Arabidopsis ARR5:GUS (Arabidopsis response regulator 5) reporter gene assay. Cytokinin activity of the compounds was determined in classical cytokinin biotests (tobacco callus, wheat leaf senescence and Amaranthus bioassays). 6-(2,5-Dihydroxybenzylamino)purine (LGR-991) was identified as a cytokinin receptor antagonist. At the molecular level LGR-991 blocks the cytokinin receptor CRE1/AHK4 with the same potency as PI-55. Moreover, LGR-991 acts as a competitive inhibitor of AHK3, and importantly shows reduced agonistic effects in comparison to PI-55 in the ARR5:GUS reporter gene assay and in cytokinin bioassays. LGR-991 causes more rapid germination of Arabidopsis seeds and increases hypocotyl length of dark-grown seedlings, which are characteristics of plants with a reduced cytokinin status. LGR-991 exhibits a structural motive that might lead to preparation of cytokinin antagonists with a broader specificity and reduced agonistic properties.
