Seventeen nucleoside derivatives (derived from arabinosylcytosine, resp. cytidine, 5-fluorouracil and uracil) were tested by agar-diffusion plaque-inhibition test for their antiviral activity with herpes simplex, vaccinia, fowl plague, Newcastle disease and western equine encephalomyelitis viruses. The highest antiviral activity against DNA viruses exhibited arabinosylcytosine, N4-acylarabinosylcytosines, arabinosylthiouracil, cyclocytidine and its 5'-chloroderivative. RNA viruses were inhibited by 5-fluorouridine only, whereas other tested compounds were ineffective or showing marginal activity only. By search for relationship between chemical structure and antiviral activity a tendency was found of higher antiviral activity at lower lipophilicity. This is probably due to better transport of the studied compounds into cell. The chemical structure, however, is the main reason of antiviral activity.

• MeSH
• antivirové látky * chemie   MeSH
• plakové testy MeSH
• pyrimidinové nukleosidy chemie   farmakologie   MeSH
• Simplexvirus účinky léků   růst a vývoj   MeSH
• virus chřipky A účinky léků   růst a vývoj   MeSH
• virus newcastleské nemoci účinky léků   růst a vývoj   MeSH
• virus vakcinie účinky léků   růst a vývoj   MeSH
• virus západoamerické encefalomyelitidy koní účinky léků   růst a vývoj   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antivirové látky * MeSH
• pyrimidinové nukleosidy MeSH

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

Several N-(S)-(3-hydroxy-2-phosphonylmethoxypropyl) (HPMP) and N-(2-phosphonylmethoxyethyl) (PME) derivatives of purine bases (adenine, guanine, 2-aminoadenine, 3-deazaadenine) and cytosine inhibit the growth of various DNA viruses. PME-derivatives (PMEA, PMEG and PMEDAP) are also active against retroviruses. Both types of nucleotide analogues undergo phosphorylation by cellular nucleotide kinases to their mono- and diphosphates. The phosphorylation with crude extracts of L-1210 cells is potentiated by an ATP-regenerating system. HPMPA is phosphorylated faster than PMEA with or without the ATP-regenerating system. The HPMP and PME analogues inhibit several virus-encoded target enzymes and their cellular counterparts: (1) HSV-1 DNA polymerase is inhibited by the diphosphates of the PME series; the virus-encoded enzyme is more sensitive than HeLa DNA pol alpha and beta. PMEApp terminates the growing DNA chain; it specifically replaces dATP. HPMPApp also acts as an alternative substrate of dATP, but, in contrast with PMEApp, it permits limited chain growth. (2) Diphosphates of both series inhibit HSV-1 ribonucleotide reductase; the greatest inhibition of CDP reduction to dCDP is exhibited by HPMPApp and PMEApp. The enzyme isolated from a PMEA-resistant HSV-1 mutant proved less sensitive to PMEApp, hydroxyurea and HPMPApp. (3) Diphosphates of PME derivatives efficiently inhibit AMV(MAV) reverse transcriptase. (4) The purine HPMP and PME analogues and, even more so, their monophosphate derivatives inhibit purine nucleoside phosphorylase from L-1210 cells.

• MeSH
• adenin analogy a deriváty   chemická syntéza   farmakologie   MeSH
• adenosin analogy a deriváty   farmakologie   MeSH
• antivirové látky * chemická syntéza   farmakologie   MeSH
• cidofovir MeSH
• cytosin analogy a deriváty   chemická syntéza   farmakologie   MeSH
• DNA viry účinky léků   enzymologie   MeSH
• guanin analogy a deriváty   chemická syntéza   farmakologie   MeSH
• inhibitory reverzní transkriptasy MeSH
• inhibitory syntézy nukleových kyselin MeSH
• nukleotidy chemická syntéza   farmakologie   MeSH
• organofosfonáty * MeSH
• organofosforové sloučeniny chemická syntéza   farmakologie   MeSH
• purinnukleosidfosforylasa metabolismus   MeSH
• ribonukleotidreduktasy metabolismus   MeSH
• techniky in vitro MeSH
• tubercidin farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 2-aminoadenosine MeSH Prohlížeč
• 3-deazaadenosine MeSH Prohlížeč
• 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine MeSH Prohlížeč
• 9-(3-hydroxy-2-phosphonomethoxypropyl)guanine MeSH Prohlížeč
• 9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine MeSH Prohlížeč
• adefovir MeSH Prohlížeč
• adenin MeSH
• adenosin MeSH
• antivirové látky * MeSH
• cidofovir MeSH
• cytosin MeSH
• guanin MeSH
• inhibitory reverzní transkriptasy MeSH
• inhibitory syntézy nukleových kyselin MeSH
• nukleotidy MeSH
• organofosfonáty * MeSH
• organofosforové sloučeniny MeSH
• purinnukleosidfosforylasa MeSH
• ribonukleotidreduktasy MeSH
• tubercidin MeSH