d-Arabinofuranosyl-pyrimidine and -purine nucleoside analogues containing alkylthio-, acetylthio- or 1-thiosugar substituents at the C2' position were prepared from the corresponding 3',5'-O-silylene acetal-protected nucleoside 2'-exomethylenes by photoinitiated, radical-mediated hydrothiolation reactions. Although the stereochemical outcome of the hydrothiolation depended on the structure of both the thiol and the furanoside aglycone, in general, high d-arabino selectivity was obtained. The cytotoxic effect of the arabinonucleosides was studied on tumorous SCC (mouse squamous cell) and immortalized control HaCaT (human keratinocyte) cell lines by MTT assay. Three pyrimidine nucleosides containing C2'-butylsulfanylmethyl or -acetylthiomethyl groups showed promising cytotoxicity at low micromolar concentrations with good selectivity towards tumor cells. SAR analysis using a methyl β-d-arabinofuranoside reference compound showed that the silyl-protecting group, the nucleobase and the corresponding C2' substituent are crucial for the cell growth inhibitory activity. The effects of the three most active nucleoside analogues on parameters indicative of cytotoxicity, such as cell size, division time and cell generation time, were investigated by near-infrared live cell imaging, which showed that the 2'-acetylthiomethyluridine derivative induced the most significant functional and morphological changes. Some nucleoside analogues also exerted anti-SARS-CoV-2 and/or anti-HCoV-229E activity with low micromolar EC50 values; however, the antiviral activity was always accompanied by significant cytotoxicity.
- Klíčová slova
- SARS-CoV-2, anti-tumor, antiviral, coronavirus, nucleoside analogue, photocatalytic thiol-ene reaction, time-lapse imaging,
- MeSH
- acetaly MeSH
- antivirové látky farmakologie MeSH
- arabinonukleosidy chemie farmakologie MeSH
- COVID-19 * MeSH
- lidé MeSH
- myši MeSH
- nukleosidy farmakologie chemie MeSH
- puriny MeSH
- pyrimidinové nukleosidy * MeSH
- sulfhydrylové sloučeniny chemie MeSH
- thiosacharidy * MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetaly MeSH
- antivirové látky MeSH
- arabinonukleosidy MeSH
- nukleosidy MeSH
- puriny MeSH
- pyrimidinové nukleosidy * MeSH
- sulfhydrylové sloučeniny MeSH
- thiosacharidy * MeSH
Cytokinins are plant hormones with biological functions ranging from coordination of plant growth to the regulation of biotic and abiotic stress-related responses and senescence. The components of the plant immune system can learn from past elicitations by microbial pathogens and herbivores and adapt to new threats. It is known that plants can enter the primed state of enhanced defense induced by either natural or synthetic compounds. While the involvement of cytokinins in defense priming has been documented, no comprehensive model of their action has been provided to date. Here, we report the functional characterization of two aromatic cytokinin derivatives, 6-benzylaminopurine-9-arabinosides (BAPAs), 3-methoxy-BAPA and 3-hydroxy-BAPA, that proved to be effective in delaying senescence in detached leaves while having low interactions with the cytokinin pathway. An RNA-seq profiling study on Arabidopsis leaves treated with 3-methoxy-BAPA revealed that short and extended treatments with this compound shifted the transcriptional response markedly toward defense. Both treatments revealed upregulation of genes involved in processes associated with plant innate immunity such as cell wall remodeling and upregulation of specific MAP kinases, most importantly MPK11, which is a MAPK module involved in stress-related signaling during the pathogen-associated molecular patterns (PAMPs) response. In addition, elevated levels of JA and its metabolites, jasmonate/ethylene-driven upregulation of PLANT DEFENSIN 1.2 (PDF1.2) and other defensins, and also temporarily elevated levels of reactive oxygen species marked the plant response to 3-methoxy-BAPA treatment. Synergistic interactions were observed when plants were cotreated with 3-hydroxy-BAPA and the flagellin-derived bacterial PAMP peptide (flg22), leading to the enhanced expression of the PAMP-triggered immunity (PTI) marker gene FRK1. Our data collectively show that some BAPAs can sensitively prime the PTI responses in a low micromolar range of concentrations while having no observable negative effects on the overall fitness of the plant.
- MeSH
- Arabidopsis chemie metabolismus MeSH
- arabinonukleosidy chemie farmakologie MeSH
- cytokininy chemie farmakologie MeSH
- imunita rostlin účinky léků MeSH
- listy rostlin účinky léků MeSH
- MAP kinasový signální systém účinky léků MeSH
- mitogenem aktivované proteinkinasy genetika metabolismus MeSH
- molekulární struktura MeSH
- PAMP struktury farmakologie MeSH
- proteiny huseníčku genetika metabolismus MeSH
- regulace genové exprese u rostlin účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- arabinonukleosidy MeSH
- cytokininy MeSH
- mitogenem aktivované proteinkinasy MeSH
- PAMP struktury MeSH
- proteiny huseníčku MeSH
A series of novel sugar-modified derivatives of cytostatic 7-hetaryl-7-deazaadenosines (2'-C-methylribonucleosides, 2'-deoxy-2'-fluoroarabinonucleosides, arabinonucleosides and 2'-deoxyribonucleosides) was prepared and screened for biological activity. The synthesis consisted of preparation of the corresponding sugar-modified 7-iodo-7-deazaadenine nucleosides and their aqueous-phase Suzuki-Miyaura cross-coupling reactions with (het)arylboronic acids or Stille couplings with hetarylstannanes in DMF. The synthesis of 7-iodo-7-deazaadenine nucleosides was based on a glycosidation of 6-chloro-7-iodo-7-deazapurine with a suitable sugar synthon or on an interconversion of 2'-OH stereocenter (for arabinonucleosides). Several examples of 2'-C-Me-ribonucleosides showed moderate anti-HCV activities in a replicon assay accompanied by cytotoxicity. Several 7-hetaryl-7-deazaadenine fluoroarabino- and arabinonucleosides exerted moderate micromolar cytostatic effects. The most active was 7-ethynyl-7-deazaadenine fluoroarabinonucleoside which showed submicromolar antiproliferative activity. However, all the sugar-modified derivatives were less active than the parent ribonucleosides.
- MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- antivirové látky chemická syntéza chemie farmakologie MeSH
- arabinonukleosidy chemická syntéza chemie farmakologie MeSH
- deoxyribonukleosidy chemická syntéza chemie farmakologie MeSH
- HeLa buňky MeSH
- Hepacivirus účinky léků MeSH
- HL-60 buňky MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- replikace viru účinky léků MeSH
- sacharidy chemie 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
- antitumorózní látky MeSH
- antivirové látky MeSH
- arabinonukleosidy MeSH
- deoxyribonukleosidy MeSH
- sacharidy MeSH
Few studies have examined the treatment of molecular relapse in patients with acute myeloid leukemia (AML) using different treatment regimens. We describe for the first time in the literature experiences with administration of clofarabine monotherapy in the treatment of eight patients with AML with molecular relapse of the disease.
- MeSH
- adeninnukleotidy farmakologie terapeutické užití MeSH
- akutní myeloidní leukemie farmakoterapie genetika mortalita patologie MeSH
- analýza přežití MeSH
- antitumorózní látky farmakologie terapeutické užití MeSH
- arabinonukleosidy farmakologie terapeutické užití MeSH
- dospělí MeSH
- fúzní onkogenní proteiny genetika MeSH
- indukce remise MeSH
- jaderné proteiny genetika MeSH
- klofarabin MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace MeSH
- nukleofosmin MeSH
- recidiva MeSH
- rozvrh dávkování léků MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adeninnukleotidy MeSH
- antitumorózní látky MeSH
- arabinonukleosidy MeSH
- fúzní onkogenní proteiny MeSH
- jaderné proteiny MeSH
- klofarabin MeSH
- nukleofosmin MeSH
