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1.
Curr Protoc ; 4(2): e984, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38327099

RESUMO

A simple, reliable, and efficient method for the gram-scale chemical synthesis of pyrimidine nucleosides functionalized with C5-carboxyl, nitrile, ester, amide, or amidine, starting from unprotected uridine and cytidine, is described. The protocol involves the synthesis of 5-trifluoromethyluridine and 5-trifluoromethylcytidine with Langlois reagent (CF3 SO2 Na) in the presence of tert-butyl hydroperoxide and subsequent transformation of the CF3 group to the C5-C 'carbon substituents' under alkaline conditions. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Synthesis and characterization of 5-trifluoromethyluridine (5-CF3 U) and 5-trifluoromethylcytidine (5-CF3 C) Basic Protocol 2: Conversion of 5-CF3 U and 5-CF3 C to several C5-substituted ribonucleosides.


Assuntos
Química Orgânica , Nucleosídeos de Pirimidina , Citidina/análogos & derivados , Nucleosídeos de Pirimidina/síntese química , Nucleosídeos de Pirimidina/química , Ribonucleosídeos/química , Uridina/análogos & derivados , Química Orgânica/métodos
2.
Eur J Med Chem ; 264: 115991, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38118393

RESUMO

Hepatitis C infection is caused by the bloodborne pathogen hepatitis C virus (HCV) and can lead to serious liver diseases and, ultimately, death if the treatment is ineffective. This work reports the synthesis and preclinical evaluation of 7 novel 9-O/N/S pyrimidine nucleosides, including compound 12, the triphosphate of known compound 7b. The nucleosides are 9-deaza modifications of adenosine and guanosine with ß-2'-C-methyl substituent on the ribose. Within this series of compounds, a 9-deaza furopyrimidine analog of adenosine, compound 7b, showed high anti-HCV activity in vitro, good stability, low toxicity, and low genotoxicity when administrated in low doses, and an adequate pharmacokinetics profile. An improved synthesis of compound 7b compared to a previous study is also reported. Compound 12 was synthesized as a control to verify phosphorylation of 7b occurred in vivo.


Assuntos
Hepatite C , Nucleosídeos de Pirimidina , Humanos , Nucleosídeos/farmacologia , Hepacivirus , RNA Polimerase Dependente de RNA , Nucleosídeos de Pirimidina/farmacologia , Hepatite C/tratamento farmacológico , Adenosina , Antivirais
3.
Carbohydr Res ; 535: 109012, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38157586

RESUMO

To understand the regioselectivity observed in the allylation of pyrimidine nucleosides and to identify the factors directing the reaction, a theoretical study of the regioselective allylation was carried out. Several key points were considered such as: the structure of the deprotonated nucleobase in the presence of Na+; the effect of the solvent on the dissociation and aggregation reactions of thymidine/Na+ ion pair; and the likely allylation reaction mechanisms involved. The results showed that the regioselectivity observed experimentally can be attributed to a greater stability of a dimeric form coupled to an increase of the reaction barrier in THF due to larger Na+ binding to the nucleobase.


Assuntos
Nucleosídeos de Pirimidina , Nucleosídeos de Pirimidina/química , Timidina
4.
Sci Rep ; 13(1): 10787, 2023 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-37402775

RESUMO

The complexation reactions of phosphocholine and pyrimidine nucleosides as well as nucleotides with copper(II) ions were studied in the water system. Using potentiometric methods and computer calculations, the stability constants of the species were determined. Using spectroscopic methods such as UV-vis, EPR, 13C NMR, 31P NMR, FT-IR and CD, the coordination mode was established for complexes created in pH range 2.5-11.0. These studies will lead to a better understanding the role of copper(II) ions in living organisms and explain the interactions between them and the studied bioligands. The differences and similarities between nucleosides and nucleotides in the studied systems were also described, which testify to the significant influence of phosphate groups on the processes of metal ion complexation and interactions between ligands.


Assuntos
Nucleotídeos , Nucleosídeos de Pirimidina , Cobre/química , Fosforilcolina , Estrutura Molecular , Espectroscopia de Infravermelho com Transformada de Fourier , Íons , Concentração de Íons de Hidrogênio
5.
Nat Commun ; 14(1): 3175, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37264059

RESUMO

Concentrative nucleoside transporters (CNTs) are active nucleoside influx systems, but their in vivo roles are poorly defined. By generating CNT1 knockout (KO) mice, here we identify a role of CNT1 in the renal reabsorption of nucleosides. Deletion of CNT1 in mice increases the urinary excretion of endogenous pyrimidine nucleosides with compensatory alterations in purine nucleoside metabolism. In addition, CNT1 KO mice exhibits high urinary excretion of the nucleoside analog gemcitabine (dFdC), which results in poor tumor growth control in CNT1 KO mice harboring syngeneic pancreatic tumors. Interestingly, increasing the dFdC dose to attain an area under the concentration-time curve level equivalent to that achieved by wild-type (WT) mice rescues antitumor efficacy. The findings provide new insights into how CNT1 regulates reabsorption of endogenous and synthetic nucleosides in murine kidneys and suggest that the functional status of CNTs may account for the optimal action of pyrimidine nucleoside analog therapeutics in humans.


Assuntos
Nucleosídeos , Nucleosídeos de Pirimidina , Humanos , Camundongos , Animais , Nucleosídeos/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Eliminação Renal , Proteínas de Transporte/metabolismo , Antimetabólitos , Proteínas de Transporte de Nucleosídeos/metabolismo , Rim/metabolismo
6.
J Biol Chem ; 299(6): 104746, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37094698

RESUMO

Enzymes from thermophilic organisms are interesting biocatalysts for a wide variety of applications in organic synthesis, biotechnology, and molecular biology. Next to an increased stability at elevated temperatures, they were described to show a wider substrate spectrum than their mesophilic counterparts. To identify thermostable biocatalysts for the synthesis of nucleotide analogs, we performed a database search on the carbohydrate and nucleotide metabolism of Thermotoga maritima. After expression and purification of 13 enzyme candidates involved in nucleotide synthesis, these enzymes were screened for their substrate scope. We found that the synthesis of 2'-deoxynucleoside 5'-monophosphates (dNMPs) and uridine 5'-monophosphate from nucleosides was catalyzed by the already known wide-spectrum thymidine kinase and the ribokinase. In contrast, no NMP-forming activity was detected for adenosine-specific kinase, uridine kinase, or nucleotidase. The NMP kinases (NMPKs) and the pyruvate-phosphate-dikinase of T. maritima exhibited a rather specific substrate spectrum for the phosphorylation of NMPs, while pyruvate kinase, acetate kinase, and three of the NMPKs showed a broad substrate scope with (2'-deoxy)nucleoside 5'-diphosphates as substrates. Based on these promising results, TmNMPKs were applied in enzymatic cascade reactions for nucleoside 5'-triphosphate synthesis using four modified pyrimidine nucleosides and four purine NMPs as substrates, and we determined that base- and sugar-modified substrates were accepted. In summary, besides the already reported TmTK, NMPKs of T. maritima were identified to be interesting enzyme candidates for the enzymatic production of modified nucleotides.


Assuntos
Núcleosídeo-Fosfato Quinase , Thermotoga maritima , Nucleotídeos/química , Fosforilação , Nucleosídeos de Pirimidina/química , Especificidade por Substrato , Thermotoga maritima/enzimologia , Thermotoga maritima/genética , Uridina Monofosfato/metabolismo , Núcleosídeo-Fosfato Quinase/genética , Núcleosídeo-Fosfato Quinase/metabolismo
7.
Carbohydr Res ; 527: 108813, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37062106

RESUMO

A greener chemo-enzymatic methodology has been developed for the synthesis of conformationally restricted diastereomeric homolyxofuranosyl pyrimidines (AZT analogue), i.e., (5'R)-3'-azido-3'-deoxy-2'-O,5'-C-bridged-ß-d-homolyxofuranosyl-uracil and thymine starting from inexpensive diacetone-d-glucofuranose in 18% and 21% overall yields, respectively. In one of the key steps in multistep synthesis of bicyclic AZT analogues, the primary hydroxyl group of 3'-azido-3'-deoxy-ß-d-glucofuranosyl pyrimidines has been acetylated using Novozyme® 435 in THF in 92% and 97% yields, respectively. The monoacetylated nucleoside was converted to desired bicyclic AZT analogue in two steps in an overall yield of 82% and 83%, respectively.


Assuntos
Nucleosídeos de Pirimidina , Nucleosídeos , Timina , Uracila , Antivirais
8.
Sci Adv ; 9(5): eade4361, 2023 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-36735785

RESUMO

Cytidine deaminases (CDAs) catalyze the hydrolytic deamination of cytidine and 2'-deoxycytidine to uridine and 2'-deoxyuridine. Here, we report that prokaryotic homo-tetrameric CDAs catalyze the nucleophilic substitution at the fourth position of N4-acyl-cytidines, N4-alkyl-cytidines, and N4-alkyloxycarbonyl-cytidines, and S4-alkylthio-uridines and O4-alkyl-uridines, converting them to uridine and corresponding amide, amine, carbamate, thiol, or alcohol as leaving groups. The x-ray structure of a metagenomic CDA_F14 and the molecular modeling of the CDAs used in this study show a relationship between the bulkiness of a leaving group and the volume of the binding pocket, which is partly determined by the flexible ß3α3 loop of CDAs. We propose that CDAs that are active toward a wide range of substrates participate in salvage and/or catabolism of variously modified pyrimidine nucleosides. This identified promiscuity of CDAs expands the knowledge about the cellular turnover of cytidine derivatives, including the pharmacokinetics of pyrimidine-based prodrugs.


Assuntos
Nucleosídeos de Pirimidina , Nucleosídeos de Pirimidina/metabolismo , Citidina Desaminase/metabolismo , Uridina/metabolismo , Citidina , Desoxicitidina
9.
Arch Pharm (Weinheim) ; 356(6): e2200382, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36792964

RESUMO

Influenza viruses belong to the Orthomyxoviridae family and cause acute respiratory distress in humans. The developed drug resistance toward existing drugs and the emergence of viral mutants that can escape vaccines mandate the search for novel antiviral drugs. Herein, the synthesis of epimeric 4'-methyl-4'-phosphonomethoxy [4'-C-Me-4'-C-(O-CH2 P═O)] pyrimidine ribonucleosides, their phosphonothioate [4'-C-Me-4'-C-(O-CH2 P═S)] derivatives, and their evaluation against an RNA viral panel are described. Selective formation of the α- l-lyxo epimer, [4'-C-(α)-Me-4'-C-(ß)-(O-CH2 -P(═O)(OEt)2 )] over the ß- d-ribo epimer [4'-C-(ß)-Me-4'-C-(α)-(O-CH2 -P(═O)(OEt)2 )] was explained by DFT equilibrium geometry optimizations studies. Pyrimidine nucleosides having the [4'-C-(α)-Me-4'-C-(ß)-(O-CH2 -P(═O)(OEt)2 )] framework showed specific activity against influenza A virus. Significant anti-influenza virus A (H1N1 California/07/2009 isolate) was observed with the 4'-C-(α)-Me-4'-C-(ß)-O-CH2 -P(═O)(OEt)2 -uridine derivative 1 (EC50 = 4.56 mM, SI50 > 56), 4-ethoxy-2-oxo-1(2H)-pyrimidin-1-yl derivative 3 (EC50 = 5.44 mM, SI50 > 43) and the cytidine derivative 2 (EC50 = 0.81 mM, SI50 > 13), respectively. The corresponding thiophosphonates 4'-C-(α)-Me-4'-C-(ß)-(O-CH2 -P( S)(OEt)2 ) and thionopyrimidine nucleosides were devoid of any antiviral activity. This study shows that the 4'-C-(α)-Me-4'-(ß)-O-CH2 -P(═O)(OEt)2 ribonucleoside can be further optimized to provide potent antiviral agents.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Nucleosídeos de Pirimidina , Ribonucleosídeos , Humanos , Relação Estrutura-Atividade , Antivirais/farmacologia
10.
mBio ; 14(2): e0028723, 2023 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-36853041

RESUMO

When microbes grow in foreign nutritional environments, selection may enrich mutations in unexpected pathways connecting growth and homeostasis. An evolution experiment designed to identify beneficial mutations in Burkholderia cenocepacia captured six independent nonsynonymous substitutions in the essential gene tilS, which modifies tRNAIle2 by adding a lysine to the anticodon for faithful AUA recognition. Further, five additional mutants acquired mutations in tRNAIle2, which strongly suggests that disrupting the TilS-tRNAIle2 interaction was subject to strong positive selection. Mutated TilS incurred greatly reduced enzymatic function but retained capacity for tRNAIle2 binding. However, both mutant sets outcompeted the wild type by decreasing the lag phase duration by ~3.5 h. We hypothesized that lysine demand could underlie fitness in the experimental conditions. As predicted, supplemental lysine complemented the ancestral fitness deficit, but so did the additions of several other amino acids. Mutant fitness advantages were also specific to rapid growth on galactose using oxidative overflow metabolism that generates redox imbalance, not resources favoring more balanced metabolism. Remarkably, 13 tilS mutations also evolved in the long-term evolution experiment with Escherichia coli, including four fixed mutations. These results suggest that TilS or unknown binding partners contribute to improved growth under conditions of rapid sugar oxidation at the predicted expense of translational accuracy. IMPORTANCE There is growing evidence that the fundamental components of protein translation can play multiple roles in maintaining cellular homeostasis. Enzymes that interact with transfer RNAs not only ensure faithful decoding of the genetic code but also help signal the metabolic state by reacting to imbalances in essential building blocks like free amino acids and cofactors. Here, we present evidence of a secondary function for the essential enzyme TilS, whose only prior known function is to modify tRNAIle(CAU) to ensure accurate translation. Multiple nonsynonymous substitutions in tilS, as well as its cognate tRNA, were selected in evolution experiments favoring rapid, redox-imbalanced growth. These mutations alone decreased lag phase and created a competitive advantage, but at the expense of most primary enzyme function. These results imply that TilS interacts with other factors related to the timing of exponential growth and that tRNA-modifying enzymes may serve multiple roles in monitoring metabolic health.


Assuntos
Aminoacil-tRNA Sintetases , Nucleosídeos de Pirimidina , Lisina/metabolismo , Aminoacil-tRNA Sintetases/genética , Aminoacil-tRNA Sintetases/metabolismo , Nucleosídeos de Pirimidina/metabolismo , Bactérias/genética , RNA de Transferência/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Mutação , Aminoácidos/metabolismo
11.
Chem Rec ; 23(1): e202200182, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36166699

RESUMO

Several naturally occurring purine and pyrimidine nucleosides contain an amide linkage as part of the heterocyclic aglycone. Enolization of the amide and conversion to leaving groups at the amide carbon atom permits base modification by addition-elimination types of processes. Although a number of methods have been developed over the years for accomplishing such conversions, the present Personal Account describes efforts from the Lakshman laboratories. Facile activation of the amido groups in nucleobases can be achieved with peptide-coupling agents. Subsequent reaction with nucleophiles then accomplishes the base modifications. In many cases, the activation and displacement steps can be done as two-step, one-pot processes, whereas in other cases, discrete storable activated nucleosides can be isolated for subsequent displacement reactions. Using such an approach a wide range of nucleoside base modifications is readily achievable. In many instances, mechanistic investigations have been conducted so as to understand the activation process.


Assuntos
Nucleosídeos , Nucleosídeos de Pirimidina , Peptídeos , Amidas
12.
Org Lett ; 24(49): 8931-8935, 2022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36331529

RESUMO

An efficient two-step procedure for the syntheses of pyrimidine nucleosides is presented. A series of glycosyl 5-(aminomethylene)-1,3-dioxane-4,6-dione derivatives were prepared from ß-anomeric isonitriles by reaction with Meldrum's acid or by allowing aminomethylene Meldrum's acid to react with an 1-aldofuranosyl halide or acetate. The resultant 5-(aminomethylene)-1,3-dioxane-4,6-dione derivatives underwent reaction with benzyl- or 2,4-dimethoxybenzyl isocyanate via transacylation to provide uridine-5-carboxylic acid derivatives and related nucleosides. These nucleoside carboxylic acids were converted into other C-5 derivatives by bromo-decarboxylation with N-bromosuccinimide.


Assuntos
Dioxanos , Nucleosídeos de Pirimidina , Uridina , Nucleosídeos
13.
Org Biomol Chem ; 20(47): 9469-9489, 2022 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-36408761

RESUMO

Analogues of the canonical nucleosides have a longstanding presence and proven capability within medicinal chemistry and drug discovery research. The synthesis reported herein successfully replaces furanose oxygen with CF2 and CHF in pyrimidine nucleosides, granting access to an alternative pharmacophore space. Key diastereoselective conjugate addition and fluorination methodologies are developed from chiral pool materials, establishing a robust gram-scale synthesis of 6'-(R)-monofluoro- and 6'-gem-difluorouridines. Vital intermediate stereochemistries are confirmed using X-ray crystallography and NMR analysis, providing an indicative conformational preference for these fluorinated carbanucleosides. Utilising these 6'-fluorocarbauridine scaffolds enables synthesis of related cytidine, ProTide and 2'-deoxy analogues alongside a preliminary exploration of their biological capabilities in cancer cell viability assays. This synthetic blueprint offers potential to explore fluorocarbanucleoside scaffolds, indicatively towards triphosphate analogues and as building blocks for oligonucleotide synthesis.


Assuntos
Nucleosídeos , Nucleosídeos de Pirimidina , Nucleosídeos/farmacologia , Química Farmacêutica , Nucleosídeos de Pirimidina/farmacologia
14.
Bioorg Med Chem ; 76: 117065, 2022 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-36436488

RESUMO

Molecular docking of N-1,4-disubstituted-1,2,3-triazole tethered carboxymethylated thymidine and uridine with ribonuclease A, indicated their possible binding with the P1, B1 and P2 subsites with varied efficiencies. This theoretical study in combination of our earlier experimental observations was used as the guiding principles for designing a range of 1,4-disubstituted 1, 2, 3- triazole tethered carboxymethylated pyrimidine nucleosides. Triazoles are biologically important molecules and at the same time easily accessible through less complicated synthetic routes as reported about two decades back in the context of "click" reactions. Regioselective propargylation of the nucleosides under controlled conditions followed by the use of CuAAC strategy afforded mono-, bis-, tris- and tetratriazolyl pyrimidine nucleosides. Although the characteristics of nucleosides were lost in these densely functionalized polyheterocycles, the catalytic efficiency of ribonuclease A was significantly reduced by these molecules which were investigated experimentally and by docking studies. Triazoles as linkers helped one or more acidic groups to reach the P1 subsite of ribonuclease A. Enzyme kinetics showed that the efficiency of inhibition reached the highest point with an optimum number of functional groups and were not linearly dependent on the number of triazole tethered carboxymethyl groups. The location of the triazole ring in the molecule affected the efficiency and nature of inhibition which were the result of the overall structure of the modified nucleosides. Thus, the tris-triazolylated thymidine derivative (T-3', 5', N-tris-CH2TzCH2COOH) as opposed to tetra-triazolylated uridine (U-2', 3', 5', N-tetrakis-CH2TzCH2COOH) emerged as the best inhibitor with an inhibition constant value of 2.3 ±â€¯0.05 µM.


Assuntos
Nucleosídeos , Nucleosídeos de Pirimidina , Triazóis/farmacologia , Ribonucleases , Ribonuclease Pancreático , Simulação de Acoplamento Molecular , Uridina/farmacologia , Timidina
15.
Int J Mol Sci ; 23(20)2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36293420

RESUMO

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 ß-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.


Assuntos
COVID-19 , Nucleosídeos de Pirimidina , Tioaçúcares , Humanos , Camundongos , Animais , Arabinonucleosídeos/química , Arabinonucleosídeos/farmacologia , Nucleosídeos/farmacologia , Nucleosídeos/química , Antivirais/farmacologia , Acetais , Compostos de Sulfidrila/química , Purinas , Relação Estrutura-Atividade
16.
Biochem Pharmacol ; 204: 115207, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35961402

RESUMO

Elevated thymidine phosphorylase (TP) levels, a key enzyme in the pyrimidine nucleoside salvage pathway, in cancer cells, are related to a poor prognosis in a variety of cancers. Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is involved in the stabilization and maturation of many oncogenic proteins. The aim of this study is to elucidate whether Hsp90 inhibitor 17-AAG could enhance tamoxifen- and erlotinib-induced cytotoxicity in nonsmall cell lung cancer (NSCLC) cells via modulating TP expression in two squamous NSCLC cell lines, H520 and H1703. We found that 17-AAG reduced TP expression via inactivating the MKK1/2-ERK1/2-mitogen-activated protein kinase (MAPK) pathway. TP knockdown with siRNA or ERK1/2 MAPK inactivation with the pharmacological inhibitor U0126 could enhance the cytotoxic and growth inhibitory effects of 17-AAG. In contrast, MKK1-CA or MKK2-CA (a constitutively active form of MKK1/2) vector-enforced expression could reduce the cytotoxic and cell growth inhibitory effects of 17-AAG. Furthermore, 17-AAG enhanced the cytotoxic and cell growth inhibitory effects of tamoxifen and erlotinib in NSCLC cells, which were associated with TP expression downregulation and MKK1/2-ERK1/2 signal inactivation. Taken together, Hsp90 inhibition downregulates TP, enhancing the tamoxifen- and erlotinib-induced cytotoxicity in H520 and H1703 cells.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Nucleosídeos de Pirimidina , Antineoplásicos/farmacologia , Benzoquinonas/farmacologia , Benzoquinonas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Cloridrato de Erlotinib/uso terapêutico , Proteínas de Choque Térmico HSP90 , Humanos , Lactamas Macrocíclicas , Pulmão , Neoplasias Pulmonares/patologia , Nucleosídeos de Pirimidina/uso terapêutico , RNA Interferente Pequeno , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Timidina Fosforilase/genética
17.
J Org Chem ; 87(14): 9330-9342, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35759615

RESUMO

Functionalized nucleosides bearing pyrimidine or purine bases can be prepared by activation of accessible pyrimidine nucleosides and subsequent transglycosylation. Nitration of lumicitabine, a 2'-fluoro-2'-deoxycytidine class antiviral agent, and its 2'-fluoro-2'-deoxyuridine precursor produce the same 5-nitro-2'-fluoro-2'-deoxyuridine. Under Vorbrüggen conditions, 5-nitrouracil serves as the leaving nucleobase and enables exchange with pyrimidine and purine nucleobases to anomeric 2'-fluoro-2'-deoxyribonucleosides in favor of ß-anomers generally. The strategy is also applied in the isotopic labeling of 2'-fluoro-2'-deoxyuridines.


Assuntos
Desoxirribonucleosídeos , Nucleosídeos de Pirimidina , Antivirais , Desoxiuridina , Purinas
18.
Molecules ; 27(9)2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35566215

RESUMO

Pyrimidine nucleoside analogues are widely used to treat infections caused by the human immunodeficiency virus (HIV) and DNA viruses from the herpes family. It has been shown that 5-substituted uracil derivatives can inhibit HIV-1, herpes family viruses, mycobacteria and other pathogens through various mechanisms. Among the 5-substituted pyrimidine nucleosides, there are not only the classical nucleoside inhibitors of the herpes family viruses, 2'-deoxy-5-iodocytidine and 5-bromovinyl-2'-deoxyuridine, but also derivatives of 1-(benzyl)-5-(phenylamino)uracil, which proved to be non-nucleoside inhibitors of HIV-1 and EBV. It made this modification of nucleoside analogues very promising in connection with the emergence of new viruses and the crisis of drug resistance when the task of creating effective antiviral agents of new types that act on other targets or exhibit activity by other mechanisms is very urgent. In this paper, we present the design, synthesis and primary screening of the biological activity of new nucleoside analogues, namely, 5'-norcarbocyclic derivatives of substituted 5-arylamino- and 5-aryloxyuracils, against RNA viruses.


Assuntos
HIV-1 , Herpesviridae , Nucleosídeos de Pirimidina , Antivirais/farmacologia , Humanos , Nucleosídeos/farmacologia , Nucleosídeos de Pirimidina/farmacologia , Relação Estrutura-Atividade , Uracila
19.
FEMS Microbiol Lett ; 369(1)2022 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-35641197

RESUMO

Co-exposure to aflatoxin and fumonisin is a health concern where corn is a staple food, and a method to prevent co-contamination of these mycotoxins in foods is urgently needed. Polyoxins are chitin synthase inhibitors produced by Streptomyces cacaoi var. asoensis. The aflatoxin production inhibitory activity of a commercially available polyoxin D and four polyoxins purified from polyoxin AL water-soluble powder, an agricultural chemical containing polyoxins, was tested. The five polyoxins dose-dependently inhibited aflatoxin production by Aspergillus parasiticus and the IC50 values of polyoxin A, B, D, K and L were 16, 74, 110, 9 and 280 µmol L-1, respectively. Polyoxins also inhibited fumonisin production by Fusarium fujikuroi, and the IC50 values of polyoxin B, D, K and L were 270, 42, 65 and 62 µmol L-1, respectively. Polyoxins repressed the transcription of genes encoding proteins required for aflatoxin biosynthesis in A. parasiticus and fumonisin biosynthesis in F. fujikuroi. Polyoxin K and D also inhibited conidiation in A. parasiticus and F. fujikuroi, respectively. These results suggest that a mixture of polyoxins may effectively prevent co-contamination of aflatoxin and fumonisin in foods.


Assuntos
Aflatoxinas , Fumonisinas , Fusarium , Aspergillus , Fumonisinas/metabolismo , Fusarium/genética , Nucleosídeos de Pirimidina
20.
Viruses ; 14(4)2022 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-35458500

RESUMO

The bicyclic nucleoside analogue (BCNA) Cf1743 and its orally bioavailable prodrug FV-100 have unique potential as varicella-zoster virus (VZV) inhibitors to treat herpes zoster (shingles) and the therewith associated pain, including post-herpetic neuralgia (PHN). The anti-VZV activity of Cf1743 depends on a specific phosphorylation by the VZV-encoded thymidine kinase (TK). The target of antiviral action is assumed to be the viral DNA polymerase (or DNA synthesis in the virus-infected cells).


Assuntos
Varicela , Herpes Zoster , Antivirais/farmacologia , Antivirais/uso terapêutico , Herpes Zoster/tratamento farmacológico , Herpesvirus Humano 3 , Humanos , Nucleosídeos/uso terapêutico , Nucleosídeos de Pirimidina
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