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.

• Klíčová slova
• Keratinocyte cell line, Kinetin, Kinetin derivatives, Normal human skin fibroblasts, UVA, UVB,
• 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
• Názvy látek
• antioxidancia MeSH
• kinetin MeSH

It has been more than 60 years since the discovery of kinetin, the first known member of a group of plant hormones called cytokinins. In this review we summarize the health-promoting activity of kinetin in animal systems, ranging from cells cultured in vitro through invertebrates to mammals. Kinetin has been shown to modulate aging, to delay age-related physiological decline and to protect against some neurodegenerative diseases. We also review studies on its mechanism of action, as well as point out gaps in our current knowledge.

• Klíčová slova
• Age-related diseases, Aging, Cytokinin, Kinetin,
• MeSH
• cytokininy MeSH
• kinetin farmakologie   terapeutické užití   MeSH
• lidé MeSH
• stárnutí * MeSH
• zdravé stárnutí * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• cytokininy MeSH
• kinetin 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.

• Klíčová slova
• Cytokinin, Kinetin, Mitoprotection – familial dysautonomia, Neuroprotection, bioisostery – Friedreich́s ataxia,
• 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
• Názvy látek
• kinetin MeSH
• purine MeSH Prohlížeč
• puriny 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
• Názvy látek
• kinetin MeSH
• proteiny huseníčku MeSH
• puriny MeSH

Motivated by the clinical success of gold(I) metallotherapeutic Auranofin in the effective treatment of both inflammatory and cancer diseases, we decided to prepare, characterize, and further study the [Au(kin)(PPh3)] complex (1), where Hkin = kinetin, 6-furfuryladenine, for its in vitro anti-cancer and anti-inflammatory activities. The results revealed that the complex (1) had significant in vitro cytotoxicity against human cancer cell lines (A2780, A2780R, PC-3, 22Rv1, and THP-1), with IC50 ≈ 1-5 μM, which was even significantly better than that for the conventional platinum-based drug Cisplatin while comparable with Auranofin. Although its ability to inhibit transcription factor NF-κB activity did not exceed the comparative drug Auranofin, it has been found that it is able to positively influence peroxisome-proliferator-activated receptor-gamma (PPARγ), and as a consequence of this to have the impact of moderating/reducing inflammation. The cellular effects of the complex (1) in A2780 cancer cells were also investigated by cell cycle analysis, induction of apoptosis, intracellular ROS production, activation of caspases 3/7 and disruption of mitochondrial membrane potential, and shotgun proteomic analysis. Proteomic analysis of R2780 cells treated with complex (1) and starting compounds revealed possible different places of the effect of the studied compounds. Moreover, the time-dependent cellular accumulation of copper was studied by means of the mass spectrometry study with the aim of exploring the possible mechanisms responsible for its biological effects.

• Klíčová slova
• PPAR, ROS, anti-inflammatory, anticancer, apoptosis, cell cycle, gold(I) complex, in vitro, kinetin,
• MeSH
• apoptóza MeSH
• auranofin farmakologie   MeSH
• kinetin farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory vaječníků * metabolismus   MeSH
• PPAR gama MeSH
• proteomika MeSH
• regulátory růstu rostlin farmakologie   MeSH
• zlato * farmakologie   chemie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• auranofin MeSH
• kinetin MeSH
• PPAR gama MeSH
• regulátory růstu rostlin MeSH
• zlato * MeSH

Studies of vitality/mortality of cortex cells, as well as of the concentrations of ethylene (ETH), gibberellins (GAs), indolic compounds/auxins (ICs/AUXs) and cytokinins (CKs), were undertaken to explain the hormonal background of kinetin (Kin)-regulated cell death (RCD), which is induced in the cortex of the apical parts of roots of faba bean (Vicia faba ssp. minor) seedlings. Quantification was carried out with fluorescence microscopy, ETH sensors, spectrophotometry and ultrahigh-performance liquid chromatography tandem mass spectrometry (UHPLC‒MS/MS). The results indicated that Kin was metabolized to the transport form, i.e., kinetin-9-glucoside (Kin9G) and kinetin riboside (KinR). KinR was then converted to cis-zeatin (cZ) in apical parts of roots with meristems, to cis-zeatin riboside (cZR) in apical parts of roots without meristems and finally to cis-zeatin riboside 5'-monophosphate (cZR5'MP), which is indicated to be a ligand of cytokinin-dependent receptors inducing CD. The process may be enhanced by an increase in the amount of dihydrozeatin riboside (DHZR) as a byproduct of the pathway of zeatin metabolism. It seems that crosstalk of ETH, ICs/AUXs, GAs and CKs with the cZR5'MP, the cis-zeatin-dependent pathway, but not the trans-zeatin-dependent pathway, is responsible for Kin-RCD, indicating that the process is very specific and offers a useful model for studies of CD hallmarks in plants.

• MeSH
• buněčná smrt MeSH
• cytokininy metabolismus   MeSH
• kinetin farmakologie   MeSH
• kyseliny indoloctové MeSH
• semenáček metabolismus   MeSH
• tandemová hmotnostní spektrometrie MeSH
• Vicia faba * metabolismus   MeSH
• zeatin metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokininy MeSH
• kinetin MeSH
• kyseliny indoloctové MeSH
• zeatin 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   metabolismus   MeSH
• kationty dvojmocné MeSH
• kinetin chemie   MeSH
• komplexní sloučeniny chemická syntéza   farmakologie   MeSH
• lidé MeSH
• lipopolysacharidy farmakologie   MeSH
• makrofágy cytologie   účinky léků   metabolismus   MeSH
• matrixová metaloproteinasa 2 genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• TNF-alfa genetika   metabolismus   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
• Názvy látek
• aminochinoliny MeSH
• antiflogistika MeSH
• chloridy MeSH
• cystein MeSH
• fluorescenční barviva MeSH
• glutathion MeSH
• interleukin-1beta MeSH
• kationty dvojmocné MeSH
• kinetin MeSH
• komplexní sloučeniny MeSH
• lipopolysacharidy MeSH
• matrixová metaloproteinasa 2 MeSH
• N-(6-methoxy-8-quinolyl)-4-toluenesulfonamide MeSH Prohlížeč
• TNF-alfa MeSH
• tosylové sloučeniny MeSH
• zinek MeSH

Embryos of flax (Linum usitatissimum L. cv. Viera) may be cultured in vitro from the globular stage of their development to germination. Kinetin added to the culture medium at the concentration of 5×10-8 mol/l accelerates embryo development, including the transition from greater expansion in width to greater expansion in length during the heart stage.

• Publikační typ
• časopisecké články MeSH

Cytokinins are phytohormones that are involved in many processes in plants, including growth, differentiation and leaf senescence. However, they also have various activities in animals. For example, kinetin and trans-zeatin can reduce levels of several aging markers in human fibroblasts. Kinetin can also protect mice against oxidative and glyoxidative stress, and prolong fruit flies' lifespan. Additionally, several cytokinins are currently used in cosmetics. To extend knowledge of the breadth of cytokinins' activities, we examined effects of natural cytokinin bases on the model nematode Caenorhabditis elegans. We found that kinetin, para-topolin and meta-topolin prolonged the lifespan of C. elegans. Kinetin also protected the organism against oxidative and heat stress. Furthermore, our results suggest that presence of reactive oxygen species, but not DAF-16 (the main effector of the insulin/insulin-like growth factor signaling pathway), is required for the beneficial effects of kinetin. Ultra-high performance liquid chromatography-tandem mass spectrometric analysis showed that kinetin is unlikely to occur naturally in C. elegans, but the worm efficiently absorbs and metabolizes it into kinetin riboside and kinetin riboside-5'-monophosphate.

• Klíčová slova
• Aging, Caenorhabditis elegans, Cytokinin, Kinetin, Phytohormones, Topolin, Zeatin,
• MeSH
• Caenorhabditis elegans účinky léků   genetika   fyziologie   MeSH
• cytokininy farmakokinetika   farmakologie   MeSH
• dlouhověkost účinky léků   fyziologie   MeSH
• forkhead transkripční faktory genetika   metabolismus   MeSH
• inzulin metabolismus   MeSH
• kinetin farmakokinetika   farmakologie   MeSH
• mutace MeSH
• oxidační stres účinky léků   MeSH
• proteiny Caenorhabditis elegans genetika   metabolismus   MeSH
• reakce na tepelný šok účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• regulátory růstu rostlin farmakokinetika   farmakologie   MeSH
• signální transdukce účinky léků   MeSH
• termotolerance účinky léků   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• cytokininy MeSH
• daf-16 protein, C elegans MeSH Prohlížeč
• forkhead transkripční faktory MeSH
• inzulin MeSH
• kinetin MeSH
• proteiny Caenorhabditis elegans MeSH
• reaktivní formy kyslíku MeSH
• regulátory růstu rostlin MeSH

Cytokinin ribosides (N6-substituted adenosines) have demonstrated anticancer activity in various cultured cell lines, several xenografts and even a small clinical trial. Effects of kinetin riboside, N6-benzyladenosine (BAR) and N6-isopentenyladenosine on various parameters related to apoptosis have also been reported, but not directly compared with those of the highly active naturally occurring aromatic cytokinins oTR (ortho-topolin riboside) and 2OH3MeOBAR (N6-(2-hydroxy-3-methoxybenzyl)adenosine). Here we show that 2OH3MeOBAR is the most active cytokinin riboside studied to date (median, 1st quartile, 3rd quartile and range of GI50 in tests with the NCI60 cell panel: 0.19, 0.10, 0.43 and 0.02 to 15.7 μM, respectively) and it differs from other cytokinins by inducing cell death without causing pronounced ATP depletion. Analysis of NCI60 test data suggests that its activity is independent of p53 status. Further we demonstrate that its 5'-monophosphate, the dominant cancer cell metabolite, inhibits the candidate oncogene DNPH1. Synthesis, purification, HPLC-MS identification and HPLC-UV quantification of 2OH3MeOBAR metabolites are also reported.

• Klíčová slova
• Apoptosis, Cancer, Cytokinin, Leukemia, NCI60 panel, Phytohormone,
• MeSH
• adenosin analogy a deriváty   chemie   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• buněčná smrt účinky léků   MeSH
• cytokininy chemie   farmakologie   MeSH
• glykosidy farmakologie   MeSH
• isopentenyladenosin farmakologie   MeSH
• kinetin farmakologie   MeSH
• molekulární struktura MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adenosin MeSH
• cytokininy MeSH
• glykosidy MeSH
• isopentenyladenosin MeSH
• kinetin riboside MeSH Prohlížeč
• kinetin MeSH
• N6-(2-hydroxy-3-methoxybenzyl)adenosine MeSH Prohlížeč
• ortho-topolin riboside MeSH Prohlížeč