The fluorine atom plays an important role in medicinal chemistry because fluorine substitution has a strong impact on the physical, chemical, and biological properties of bioactive compounds. Such fluorine modifications have also been extensively studied among the pharmaceutically important class of nucleoside phosphonates, nucleotide analogues in which the phosphate group is replaced by the enzymatically and chemically stable phosphonate moiety. The fluorinated nucleoside phosphonates abound with antiviral, antiparasitic, and anticancer properties because they are able to act as inhibitors of important enzymes of nucleoside/nucleotide metabolism. In this paper, we review the biological properties of cyclic and acyclic nucleoside phosphonates modified by the attachment of one or more fluorine atoms to various parts of the molecule, namely to nucleobases, alkylphosphonate groups, cyclic or acyclic linkers, or to prodrug moieties.

• Keywords
• anticancer, antiparasitic, antiviral, fluorine, nucleoside phosphosphonates,
• MeSH
• Chemistry, Pharmaceutical * MeSH
• Cyclization MeSH
• Halogenation * MeSH
• Humans MeSH
• Nucleosides chemistry   pharmacology   MeSH
• Organophosphonates chemistry   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Nucleosides MeSH
• Organophosphonates MeSH

Acyclic nucleoside phosphonates (ANPs) are important biologically active nucleotide analogs. They contain an isopolar phosphonomethyl function linked to the hydroxyl group of an acyclic side-chain via an undegradable ether group. Though their most important activity is antiviral, some exhibit cytostatic or antiprotozoic effects. The three most important groups of ANP are presented here as synthetic procedures for a large laboratory scale. Synthesis follows three principles: (1) introduction of a protected phosphonomethyl group to the hydroxyl on an appropriate alkyl side-chain of an acyclic nucleoside, (2) alkylation of the heterocyclic base by a synthon with all characteristic features of the future phoshonate-bearing side-chain, or (3) transformation of a reactive group at the heterocyclic base. The last step in all these cases is removal of the phosphonate esters. Preparation methods are described in detail for PMEA, PMEG, PMEDAP and its N(6)-cyclopropyl derivative, (R)-PMPA, and (S)-HPMPA, as well as all intermediates and synthons.

• MeSH
• Nucleosides chemical synthesis   chemistry   MeSH
• Organophosphonates chemical synthesis   chemistry   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Nucleosides MeSH
• Organophosphonates MeSH

INTRODUCTION: Zidovudine (AZT) and emtricitabine (FTC) are effective and well tolerated antiretroviral drugs, routinely used in the prevention of perinatal HIV transmission. However, precise mechanism(s) involved in their transfer from mother to fetus are not fully elucidated. Since both drugs are nucleoside analogues, we hypothesized that the mechanisms of their transplacental passage might include equilibrative nucleoside transporters, ENT1 and/or ENT2. METHODS: To address this issue, we performed in vitro accumulation assays in the BeWo placental trophoblast cell line, ex vivo uptake studies in fresh villous fragments isolated from human placenta and in situ dually perfused rat term placenta experiments. RESULTS: Applying this complex array of methods, we did not prove that ENTs play a significant role in transfer of AZT or FTC across the placenta. DISCUSSION: We conclude that the transplacental passage of AZT and FTC is independent of ENTs. Disposition of either compound into the fetal circulation should thus not be affected by ENT-mediated drug-drug interactions or placental expression of the transporters.

• Keywords
• ENTs, Emtricitabine, Nucleoside transporters, Placenta, Pregnancy, Zidovudine,
• MeSH
• Equilibrative Nucleoside Transport Proteins metabolism   MeSH
• Emtricitabine pharmacokinetics   MeSH
• Reverse Transcriptase Inhibitors pharmacokinetics   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Placenta metabolism   MeSH
• Rats, Wistar MeSH
• Pregnancy MeSH
• Zidovudine pharmacokinetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Equilibrative Nucleoside Transport Proteins MeSH
• Emtricitabine MeSH
• Reverse Transcriptase Inhibitors MeSH
• Zidovudine MeSH

There is growing evidence that Zika virus (ZIKV) can cause devastating infant brain defects and other neurological disorders in humans. However, no specific antiviral therapy is available at present. We tested a series of 2'-C- or 2'-O-methyl-substituted nucleosides, 2'-C-fluoro-2'-C-methyl-substituted nucleosides, 3'-O-methyl-substituted nucleosides, 3'-deoxynucleosides, derivatives with 4'-C-azido substitution, heterobase-modified nucleosides, and neplanocins for their ability to inhibit ZIKV replication in cell culture. Antiviral activity was identified when 2'-C-methylated nucleosides were tested, suggesting that these compounds might represent promising lead candidates for further development of specific antivirals against ZIKV.

• Keywords
• Zika virus, antiviral, flavivirus, nucleoside analogue, therapy,
• MeSH
• Antiviral Agents chemistry   isolation & purification   pharmacology   MeSH
• Chlorocebus aethiops MeSH
• Microbial Sensitivity Tests MeSH
• Nucleosides chemistry   isolation & purification   pharmacology   MeSH
• Virus Replication drug effects   MeSH
• Vero Cells MeSH
• Zika Virus drug effects   physiology   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antiviral Agents MeSH
• Nucleosides MeSH

Cells save their energy during nitrogen starvation by selective autophagy of ribosomes and degradation of RNA to ribonucleotides and nucleosides. Nucleosides are hydrolyzed by nucleoside N-ribohydrolases (nucleosidases, NRHs). Subclass I of NRHs preferentially hydrolyzes the purine ribosides while subclass II is more active towards uridine and xanthosine. Here, we performed a crystallographic and kinetic study to shed light on nucleoside preferences among plant NRHs followed by in vivo metabolomic and phenotyping analyses to reveal the consequences of enhanced nucleoside breakdown. We report the crystal structure of Zea mays NRH2b (subclass II) and NRH3 (subclass I) in complexes with the substrate analog forodesine. Purine and pyrimidine catabolism are inseparable because nucleobase binding in the active site of ZmNRH is mediated via a water network and is thus unspecific. Dexamethasone-inducible ZmNRH overexpressor lines of Arabidopsis thaliana, as well as double nrh knockout lines of moss Physcomitrium patents, reveal a fine control of adenosine in contrast to other ribosides. ZmNRH overexpressor lines display an accelerated early vegetative phase including faster root and rosette growth upon nitrogen starvation or osmotic stress. Moreover, the lines enter the bolting and flowering phase much earlier. We observe changes in the pathways related to nitrogen-containing compounds such as β-alanine and several polyamines, which allow plants to reprogram their metabolism to escape stress. Taken together, crop plant breeding targeting enhanced NRH-mediated nitrogen recycling could therefore be a strategy to enhance plant growth tolerance and productivity under adverse growth conditions.

• Keywords
• Physcomitrella patens, Zea mays, crystal structure, cytokinin, nitrogen starvation, nucleoside N-ribohydrolase, overexpression, polyamine, purine,
• MeSH
• Arabidopsis * genetics   MeSH
• Nitrogen metabolism   MeSH
• Nucleosides * metabolism   MeSH
• Plants metabolism   MeSH
• Plant Breeding MeSH
• Uridine metabolism   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Nitrogen MeSH
• Nucleosides * MeSH
• Uridine MeSH

Commercially available trans-4-hydroxy-L-proline has been used as a starting material for the synthesis of prolinol-based nucleotide analogues with N-phosphonomethyl moiety attached to the nitrogen atom of prolinol ring. The synthetic methodology based on the inversion of configuration at both 1- and 4- positions led, in result, to all diastereoisomeric O-protected 4-mesyloxyprolinol-N-methylphosphonates. Alkylation of nucleobases using the synthons afforded the nucleotide analogues corresponding to alpha- and beta-nucleotides in both L- and D-series. The NMR-based conformational study of alpha- and beta-nucleotides in aqueous solution performed at two different pH values securing either N-fully protonated or deprotonated forms revealed in both cases occurrence of the same mostly populated conformer. All final prolinol-based nucleoside phosphonic acids were tested for cytotoxic and antiviral properties, but no significant activity was found.

• MeSH
• Deoxyribonucleotides chemical synthesis   chemistry   MeSH
• Nucleosides chemistry   MeSH
• Organophosphonates chemical synthesis   chemistry   MeSH
• Pyrrolidines chemistry   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Deoxyribonucleotides MeSH
• Nucleosides MeSH
• Organophosphonates MeSH
• prolinol MeSH Browser
• Pyrrolidines MeSH

CE methods have been developed for the chiral analysis of new types of six acyclic nucleoside phosphonates, nucleotide analogs bearing [(3-hydroxypropan-2-yl)-1H-1,2,3-triazol-4-yl]phosphonic acid, 2-[(diisopropoxyphosphonyl)methoxy]propanoic acid, or 2-(phosphonomethoxy)propanoic acid moieties attached to adenine, guanine, 2,6-diaminopurine, uracil, and 5-bromouracil nucleobases, using neutral and cationic cyclodextrins as chiral selectors. With the exception of the 5-bromouracil-derived acyclic nucleoside phosphonate with a 2-(phosphonomethoxy)propanoic acid side chain, the R and S enantiomers of the other five acyclic nucleoside phosphonates were successfully separated with sufficient resolutions, 1.51-2.94, within a reasonable time, 13-28 min, by CE in alkaline BGEs (50 mM sodium tetraborate adjusted with NaOH to pH 9.60, 9.85, and 10.30, respectively) containing 20 mg/mL β-cyclodextrin as the chiral selector. A baseline separation of the R and S enantiomers of the 5-bromouracil-derived acyclic nucleoside phosphonate with 2-(phosphonomethoxy)propanoic acid side chain was achieved within a short time of 7 min by CE in an acidic BGE (20:40 mM Tris/phosphate, pH 2.20) using 60 mg/mL quaternary ammonium β-cyclodextrin chiral selector. The developed methods were applied for the assessment of the enantiomeric purity of the above acyclic nucleoside phosphonates. The preparations of all these compounds were found to be synthesized in pure enantiomeric forms. Using UV absorption detection at 206 nm, their concentration detection limits were in the low micromolar range.

• Keywords
• Acyclic nucleoside phosphonates, CE, Chiral analysis, Cyclodextrins / Nucleotide analogs,
• MeSH
• Cyclodextrins chemistry   MeSH
• Electrophoresis, Capillary instrumentation   methods   MeSH
• Molecular Structure MeSH
• Nucleosides chemistry   MeSH
• Organophosphonates chemistry   MeSH
• Stereoisomerism MeSH
• Publication type
• Journal Article MeSH
• Evaluation Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cyclodextrins MeSH
• Nucleosides MeSH
• Organophosphonates MeSH

We report the first evidence that boron-containing nucleoside conjugates have a tendency to associate in water solutions. The size, charge, and exoskeletal pattern of the boron cluster can strongly influence the aggregation. The aggregation of nucleosides with attached boron clusters was observed using light scattering and atomic force microscopy techniques. Although the species containing either the bulky amphiphilic [3-cobalt(III) bis(1,2-dicarbollide)]- anion or the electroneutral dicarba-closo-dodecaboranyl moiety tend to form stable nanoparticles in aqueous solutions, the compounds bearing the smaller, negatively charged dicarba-nido-undecaboranyl moiety as well as the unmodified nucleosides do not aggregate. The light scattering measurements also showed that the aggregated species can interact with nonionic surfactant Triton X-100 in solution. The partition coefficients P in the water-octanol system correlate fairly well with the aggregation tendency observed by light scattering measurements. This finding allows us to predict the association behavior of boron-cluster-containing nucleosides on a qualitative level. The observed phenomenon can contribute to a better understanding of biological properties of boronated nucleosides and the design of boronated nucleoside-based drugs such as boron carriers for boron neutron capture therapy of tumors (BNCT) and antiviral agents.

• MeSH
• Boron chemistry   MeSH
• Nucleic Acid Conformation MeSH
• Nucleosides chemistry   MeSH
• Surface Properties MeSH
• Solutions chemistry   MeSH
• Particle Size MeSH
• Water chemistry   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Boron MeSH
• Nucleosides MeSH
• Solutions MeSH
• Water MeSH

Nucleoside analogs represent the largest class of small molecule-based antivirals, which currently form the backbone of chemotherapy of chronic infections caused by HIV, hepatitis B or C viruses, and herpes viruses. High antiviral potency and favorable pharmacokinetics parameters make some nucleoside analogs suitable also for the treatment of acute infections caused by other medically important RNA and DNA viruses. This review summarizes available information on antiviral research of nucleoside analogs against arthropod-borne members of the genus Flavivirus within the family Flaviviridae, being primarily focused on description of nucleoside inhibitors of flaviviral RNA-dependent RNA polymerase, methyltransferase, and helicase/NTPase. Inhibitors of intracellular nucleoside synthesis and newly discovered nucleoside derivatives with high antiflavivirus potency, whose modes of action are currently not completely understood, have drawn attention. Moreover, this review highlights important challenges and complications in nucleoside analog development and suggests possible strategies to overcome these limitations.

• Keywords
• Nucleoside analog, antiviral agent, antiviral therapy, arthropod-borne flavivirus, inhibitor,
• MeSH
• Antiviral Agents chemistry   pharmacology   MeSH
• Culicidae virology   MeSH
• Flavivirus drug effects   MeSH
• Flavivirus Infections drug therapy   virology   MeSH
• Microbial Sensitivity Tests MeSH
• Molecular Structure MeSH
• Nucleosides chemistry   pharmacology   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antiviral Agents MeSH
• Nucleosides MeSH

OBJECTIVE: The review covers basic principles of the prodrug strategy applied to antiviral nucleoside drugs or drug candidates. Specific role of amino acids as promoieties is explained with respect to transport mechanisms, pharmacokinetics and a low toxicity of compounds. Synthetic approaches to the most important representatives (compounds under clinical investigations or available on the market) are described, including valacyclovir, valganciclovir, valomaciclovir stearate, valcyclopropavir, valtorcitabine, valopicitabine and several attempts to amino acid modifications of antiretroviral nucleosides. METHOD: A special attention is paid to acyclic nucleoside phosphonates, where the phosphonic acid residue is esterified with a side-chain hydroxyl group of appropriate amino acid (serine, tyrosine) which can be used as single amino acid or as a part of dipeptides further modified on the terminal carboxyl function. The most advantageous pharmacokinetic profile and the best oral bioavailability were found in tyrosinebased prodrugs. RESULTS & CONCLUSION: Studies were performed successfully on 1-(S)-[3-hydroxy-2-(phosphonomethoxy) propyl]cytosine (cidofovir), 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine and some (R)-2- (phosphonomethoxy)propyl and 2-(phosphonomethoxy)ethyl derivatives including adefovir.

• Keywords
• Acyclic nucleoside analogues, antiherpetics, antiretrovirals, cidofovir, peptidomimetics, prodrugs, tyrosine esters, valacyclovir,
• MeSH
• Adenine analogs & derivatives   chemistry   pharmacology   MeSH
• Antiviral Agents chemistry   pharmacology   MeSH
• Cidofovir MeSH
• Cytomegalovirus drug effects   MeSH
• Cytosine analogs & derivatives   chemistry   pharmacology   MeSH
• Humans MeSH
• Nucleosides chemistry   pharmacology   MeSH
• Nucleotides chemistry   pharmacology   MeSH
• Organophosphonates chemistry   pharmacology   MeSH
• Prodrugs chemistry   pharmacology   MeSH
• Herpesvirus 3, Human drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• adefovir MeSH Browser
• Adenine MeSH
• Antiviral Agents MeSH
• Cidofovir MeSH
• Cytosine MeSH
• Nucleosides MeSH
• Nucleotides MeSH
• Organophosphonates MeSH
• Prodrugs MeSH