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1.
Nat Commun ; 13(1): 5892, 2022 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-36202814

RESUMEN

Dead End (DND1) is an RNA-binding protein essential for germline development through its role in post-transcriptional gene regulation. The molecular mechanisms behind selection and regulation of its targets are unknown. Here, we present the solution structure of DND1's tandem RNA Recognition Motifs (RRMs) bound to AU-rich RNA. The structure reveals how an NYAYUNN element is specifically recognized, reconciling seemingly contradictory sequence motifs discovered in recent genome-wide studies. RRM1 acts as a main binding platform, including atypical extensions to the canonical RRM fold. RRM2 acts cooperatively with RRM1, capping the RNA using an unusual binding pocket, leading to an unusual mode of tandem RRM-RNA recognition. We show that the consensus motif is sufficient to mediate upregulation of a reporter gene in human cells and that this process depends not only on RNA binding by the RRMs, but also on DND1's double-stranded RNA binding domain (dsRBD), which is dispensable for binding of a subset of targets in cellulo. Our results point to a model where DND1 target selection is mediated by a non-canonical mode of AU-rich RNA recognition by the tandem RRMs and a role for the dsRBD in the recruitment of effector complexes responsible for target regulation.


Asunto(s)
Motivo de Reconocimiento de ARN , ARN , Sitios de Unión , Humanos , Proteínas de Neoplasias/metabolismo , Unión Proteica , ARN/metabolismo , Motivo de Reconocimiento de ARN/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo
2.
ACS Cent Sci ; 5(3): 515-523, 2019 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-30937379

RESUMEN

Determining atomic-level characteristics of molecules on two-dimensional surfaces is one of the fundamental challenges in chemistry. High-resolution nuclear magnetic resonance (NMR) could deliver rich structural information, but its application to two-dimensional materials has been prevented by intrinsically low sensitivity. Here we obtain high-resolution one- and two-dimensional 31P NMR spectra from as little as 160 picomoles of oligonucleotide functionalities deposited onto silicate glass and sapphire wafers. This is enabled by a factor >105 improvement in sensitivity compared to typical NMR approaches from combining dynamic nuclear polarization methods, multiple-echo acquisition, and optimized sample formulation. We demonstrate that, with this ultrahigh NMR sensitivity, 31P NMR can be used to observe DNA bound to miRNA, to sense conformational changes due to ion binding, and to follow photochemical degradation reactions.

3.
Chemistry ; 23(57): 14221-14230, 2017 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-28746731

RESUMEN

When used as inhibitors of gene expression in vivo, oligonucleotides require modification of their structures to boost their binding affinity for complementary target RNAs. To date, hundreds of modifications have been designed and tested but few have proven to be useful. Among those investigated are mono- and polyamino-groups. These are positively charged at physiological pH and have been appended to oligonucleotides in an effort to reduce electrostatic repulsion during hybridization to RNAs, but have generally shown relatively minor benefits to binding. We conjugated spermine to uracils in oligonucleotides via a triazole linker so that the polyamine fits in the major groove of a subsequently formed RNA-duplex. The modifications produced large increases in target-binding affinity of the oligonucleotides. Using surface plasmon resonance-based assays, we showed that the increases derived mainly from faster annealing (kon ). We propose that the spermine fragments play a similar role to that of natural polyamines during oligonucleotide-target interactions in cells, and may be advantageous for oligonucleotides that operate catalytic mechanisms.


Asunto(s)
Oligonucleótidos/química , Secuencia de Bases , Línea Celular , Dicroismo Circular , Terapia Genética , Humanos , Cinética , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Conformación de Ácido Nucleico , Hibridación de Ácido Nucleico , Oligonucleótidos/metabolismo , Poliaminas/química , ARN/metabolismo , Espermina/química , Electricidad Estática , Resonancia por Plasmón de Superficie , Triazoles/química , Uracilo/análogos & derivados , Uracilo/química
4.
Nucleic Acids Res ; 45(11): 6717-6728, 2017 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-28369621

RESUMEN

The nascent peptide exit tunnel has recently been identified as a functional region of ribosomes contributing to translation regulation and co-translational protein folding. Inducible expression of the erm resistance genes depends on ribosome stalling at specific codons of an upstream open reading frame in the presence of an exit tunnel-bound macrolide antibiotic. The molecular basis for this translation arrest is still not fully understood. Here, we used a nucleotide analog interference approach to unravel important functional groups on 23S rRNA residues in the ribosomal exit tunnel for ribosome stalling on the ErmC leader peptide. By replacing single nucleobase functional groups or even single atoms we were able to demonstrate the importance of A2062, A2503 and U2586 for drug-dependent ribosome stalling. Our data show that the universally conserved A2062 and A2503 are capable of forming a non-Watson-Crick base pair that is critical for sensing and transmitting the stalling signal from the exit tunnel back to the peptidyl transferase center of the ribosome. The nucleobases of A2062, A2503 as well as U2586 do not contribute significantly to the overall mechanism of protein biosynthesis, yet their elaborate role for co-translational monitoring of nascent peptide chains inside the exit tunnel can explain their evolutionary conservation.


Asunto(s)
Antibacterianos/química , Macrólidos/química , ARN Ribosómico 23S/química , Proteínas de Escherichia coli/biosíntesis , Proteínas de Escherichia coli/química , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Biosíntesis de Proteínas/efectos de los fármacos , ARN Bacteriano/química , Thermus
5.
Chemistry ; 23(22): 5210-5213, 2017 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-28295757

RESUMEN

Long structured RNAs are useful biochemical and biological tools. They are usually prepared enzymatically, but this precludes their site-specific modification with functional groups for chemical biology studies. One solution is to perform solid-phase synthesis of multiple RNAs loaded with 5'-terminal phosphate groups, so that RNAs can be concatenated using template ligation reactions. However, there are currently no readily available reagents suitable for the incorporation of the phosphate group into long RNAs by solid-phase synthesis. Here we describe an easy-to-prepare phosphoramidite reagent suitable for the chemical introduction of 5'-terminal phosphate groups into long RNAs. The phosphate is protected by a dinitrobenzhydryl group that serves as an essential lipophilic group for the separation of oligonucleotide by-products. The phosphate is unmasked quantitatively by brief UV irradiation. We demonstrate the value of this reagent in the preparation of a library of long structured RNAs that are site-specifically modified with functional groups.


Asunto(s)
Oligonucleótidos/química , Compuestos Organofosforados/química , Fosfatos/química , ARN/síntesis química , ARN/química , Técnicas de Síntesis en Fase Sólida
6.
Chembiochem ; 17(21): 2012-2017, 2016 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-27577972

RESUMEN

Functionalized oligoribonucleotides are essential tools in RNA chemical biology. Various synthetic routes have been developed over recent years to conjugate functional groups to oligoribonucleotides. However, the presence of the functional group on the oligoribonucleotide backbone can lead to partial or total loss of biological function. The limited knowledge concerning the positioning of functional groups therefore represents a hurdle for the development of oligoribonucleotide chemical tools. Here we describe a systematic investigation of site-specific labeling of pre-miRNAs to identify positions for the incorporation of functional groups, in order not to hinder their processing into active mature miRNAs.


Asunto(s)
MicroARNs/química , Oligorribonucleótidos/química , MicroARNs/metabolismo , Estructura Molecular , Oligorribonucleótidos/síntesis química , Oligorribonucleótidos/metabolismo , Relación Estructura-Actividad
7.
ACS Chem Biol ; 11(10): 2773-2781, 2016 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-27548809

RESUMEN

New discoveries in RNA biology underscore a need for chemical tools to clarify their roles in pathophysiological mechanisms. In certain cancers, synthesis of the let-7 microRNA tumor suppressor is blocked by an RNA binding protein (RBP) Lin28, which docks onto a conserved sequence in let-7 precursor RNA molecules and prevents their maturation. Thus, the Lin28/let-7 interaction might be an attractive drug target, if not for the well-known difficulty in targeting RNA-protein interactions with drugs. Here, we describe a protein/RNA FRET assay using a GFP-Lin28 donor and a black-hole quencher (BHQ)-labeled let-7 acceptor, a fluorescent protein/quencher combination which is rarely used in screening despite favorable spectral properties. We tested 16 000 molecules and identified N-methyl-N-[3-(3-methyl[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide, which blocked the Lin28/let-7 interaction, rescued let-7 processing and function in Lin28-expressing cancer cells, induced differentiation of mouse embryonic stem cells, and reduced tumor-sphere formation by 22Rv1 and Huh7 cells. A biotinylated derivative captured Lin28 from cell lysates consistent with an on-target mechanism in cells, though the compound also showed some activity against bromodomains in selectivity assays. The Lin28/let-7 axis is presently of high interest not only for its role as a bistable switch in stem-cell biology but also because of its prominent roles in numerous diseases. We anticipate that much can be learned from the use of this first reported small molecule antagonist of Lin28, including the potential of the Lin28/let-7 interaction as a new drug target for selected cancers. Furthermore, this approach to assay development may be used to identify antagonists of other RBP/RNA interactions suspected to be operative in pathophysiological mechanisms.


Asunto(s)
Proteínas de Unión al ARN/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas , Animales , Diferenciación Celular/efectos de los fármacos , Línea Celular , Humanos , Ratones
8.
Bioconjug Chem ; 27(3): 681-7, 2016 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-26806029

RESUMEN

Modified oligonucleotides bearing multiple functional labels are valuable tools in RNA biology. Efficient synthetic access to singly modified short DNAs and RNAs has been developed in the past years and paved the way to a first generation of oligonucleotide tools. Here, we describe an efficient procedure for the site-specific hetero bis-labeling of long RNAs. We exemplified the method with the preparation of Cy3/Cy5 pre-microRNAs labeled at selected internal sites as probes for microRNA maturation.


Asunto(s)
MicroARNs/química , Sondas de Oligonucleótidos/química
9.
J Med Chem ; 58(8): 3445-58, 2015 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-25849312

RESUMEN

The conversion of selected ß-D-2,6-diaminopurine nucleosides (DAPNs) to their phosphoramidate prodrug (PD) substantially blocks the conversion to the G-analog allowing for the generation of two bioactive nucleoside triphosphates (NTPs) in human hepatocytes. A variety of 2'-C-methyl DAPN-PDs were prepared and evaluated for inhibition of HCV viral replication in Huh-7 cells, cytotoxicity in various cell lines, and cellular pharmacology in both Huh-7 and primary human liver cells. The DAPN-PDs were pan-genotypic, effective against various HCV resistant mutants, and resistant variants could not be selected. 2'-C-Me-DAPN-TP and 2'-C-Me-GTP were chain terminators for genotype 1b HCV-pol, and single nucleotide incorporation assays revealed that 2'-C-Me-DAPN-TP was incorporated opposite U. No cytotoxicity was observed with our DAPN-PD when tested up to 50 µM. A novel, DAPN-PD, 15c, has been selected for further evaluation because of its good virologic and toxicologic profile and its ability to deliver two active metabolites, potentially simplifying HCV treatment.


Asunto(s)
2-Aminopurina/análogos & derivados , Antivirales/química , Antivirales/farmacología , Guanosina Trifosfato/química , Guanosina Trifosfato/farmacología , Hepacivirus/efectos de los fármacos , 2-Aminopurina/química , 2-Aminopurina/metabolismo , 2-Aminopurina/farmacología , Amidas/química , Amidas/metabolismo , Amidas/farmacología , Antivirales/metabolismo , Línea Celular , Células Cultivadas , Guanosina Trifosfato/metabolismo , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Humanos , Metilación , Ácidos Fosfóricos/química , Ácidos Fosfóricos/metabolismo , Ácidos Fosfóricos/farmacología , Profármacos/química , Profármacos/metabolismo , Profármacos/farmacología , Ribonucleósidos/química , Ribonucleósidos/metabolismo , Ribonucleósidos/farmacología
10.
Nucleic Acids Res ; 43(2): e9, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25378324

RESUMEN

MicroRNAs (miRNAs) originate from stem-loop-containing precursors (pre-miRNAs, pri-miRNAs) and mature by means of the Drosha and Dicer endonucleases and their associated factors. The let-7 miRNAs have prominent roles in developmental differentiation and in regulating cell proliferation. In cancer, the tumor suppressor function of let-7 is abrogated by overexpression of Lin28, one of several RNA-binding proteins that regulate let-7 biogenesis by interacting with conserved motifs in let-7 precursors close to the Dicer cleavage site. Using in vitro assays, we have identified a binding site for short modified oligoribonucleotides ('looptomirs') overlapping that of Lin28 in pre-let-7a-2. These looptomirs selectively antagonize the docking of Lin28, but still permit processing of pre-let-7a-2 by Dicer. Looptomirs restored synthesis of mature let-7 and inhibited growth and clonogenic potential in Lin28 overexpressing hepatocarcinoma cells, thereby demonstrating a promising new means to rescue defective miRNA biogenesis in Lin28-dependent cancers.


Asunto(s)
MicroARNs/metabolismo , Neoplasias/genética , Oligorribonucleótidos/metabolismo , Procesamiento Postranscripcional del ARN , Proteínas de Unión al ARN/antagonistas & inhibidores , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular , Células HEK293 , Humanos , MicroARNs/química , Neoplasias/enzimología , Neoplasias/patología , Oligorribonucleótidos/química , Precursores del ARN/química , Precursores del ARN/metabolismo , Proteínas de Unión al ARN/metabolismo , Ribonucleasa III/metabolismo
14.
Eur J Med Chem ; 57: 126-33, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23047229

RESUMEN

Seventeen hitherto unknown bis(POM) prodrugs of novel (E)-[4'-phosphono-but-2'-en-1'-yl]purine nucleosides were prepared in a straight approach and at good yields. Those compounds were synthesized by the reaction of purine nucleobases directly with the phosphonate synthon 3 bearing POM biolabile groups under Mitsunobu conditions. All obtained compounds were evaluated for their antiviral activities against a large number of DNA and RNA viruses including herpes simplex viruses 1 and 2, varicella zoster virus, Feline herpes virus, human cytomegalovirus, HIV-1 and HIV-2. Among these molecules, some of them exhibit anti-VZV and anti-HIV activity at submicromolar concentrations. This class of compound will be of further interest for lead optimization as anti-infectious agents.


Asunto(s)
Antivirales/síntesis química , Virus ADN/efectos de los fármacos , Organofosfonatos/síntesis química , Profármacos/síntesis química , Nucleósidos de Purina/síntesis química , Virus ARN/efectos de los fármacos , Animales , Antivirales/farmacología , Chlorocebus aethiops , Virus ADN/crecimiento & desarrollo , Perros , Diseño de Fármacos , Descubrimiento de Drogas , Células HeLa , Humanos , Células de Riñón Canino Madin Darby , Organofosfonatos/farmacología , Profármacos/farmacología , Nucleósidos de Purina/farmacología , Virus ARN/crecimiento & desarrollo , Células Vero , Ensayo de Placa Viral
15.
Org Lett ; 14(17): 4426-9, 2012 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-22917194

RESUMEN

A new and facile synthetic pathway to metabolically stable 5'-methylene-bis(pivaloyloxymethyl)(POM)phosphonate furanonucleoside prodrugs is reported. The key step involves a Horner-Wadsworth-Emmons reaction of a tetra(pivaloyloxymethyl) bisphosphonate salt with appropriately protected 5'-aldehydic nucleosides. This efficient approach was applied for the synthesis HCV related 2'-deoxy-2'-α-fluoro-2'-ß-C-methyl nucleosides.


Asunto(s)
Hepacivirus/efectos de los fármacos , Nucleósidos/síntesis química , Profármacos/síntesis química , Amidas/química , Amidas/farmacología , Antivirales/síntesis química , Metano/análogos & derivados , Estructura Molecular , Nucleósidos/química , Nucleósidos/farmacología , Ácidos Fosfóricos/química , Ácidos Fosfóricos/farmacología , Profármacos/química , Profármacos/farmacología
16.
Mol Pharmacol ; 82(1): 125-33, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22513406

RESUMEN

Two novel thymidine analogs, 3'-fluoro-3'-deoxythymidine (FLT) and 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine (Ed4T), have been investigated as nucleoside reverse transcriptase inhibitors (NRTIs) for treatment of HIV infection. Ed4T seems very promising in phase II clinical trials, whereas toxicity halted FLT development during this phase. To understand these different molecular mechanisms of toxicity, pre-steady-state kinetic studies were used to examine the interactions of FLT and Ed4T with wild-type (WT) human mitochondrial DNA polymerase γ (pol γ), which is often associated with NRTI toxicity, as well as the viral target protein, WT HIV-1 reverse transcriptase (RT). We report that Ed4T-triphosphate (TP) is the first analog to be preferred over native nucleotides by RT but to experience negligible incorporation by WT pol γ, with an ideal balance between high antiretroviral efficacy and minimal host toxicity. WT pol γ could discriminate Ed4T-TP from dTTP 12,000-fold better than RT, with only an 8.3-fold difference in discrimination being seen for FLT-TP. A structurally related NRTI, 2',3'-didehydro-2',3'-dideoxythymidine, is the only other analog favored by RT over native nucleotides, but it exhibits only a 13-fold difference (compared with 12,000-fold for Ed4T) in discrimination between the two enzymes. We propose that the 4'-ethynyl group of Ed4T serves as an enzyme selectivity moiety, critical for discernment between RT and WT pol γ. We also show that the pol γ mutation R964C, which predisposes patients to mitochondrial toxicity when receiving 2',3'-didehydro-2',3'-dideoxythymidine to treat HIV, produced some loss of discrimination for FLT-TP and Ed4T-TP. These molecular mechanisms of analog incorporation, which are critical for understanding pol γ-related toxicity, shed light on the unique toxicity profiles observed during clinical trials.


Asunto(s)
Fármacos Anti-VIH/farmacología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/enzimología , Nucleótidos/antagonistas & inhibidores , Inhibidores de la Transcriptasa Inversa/farmacología , ADN Polimerasa gamma , ADN Mitocondrial/efectos de los fármacos , ADN Mitocondrial/metabolismo , ADN Polimerasa Dirigida por ADN/metabolismo , Didesoxinucleósidos/farmacología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/metabolismo , Humanos , Cinética , Estavudina/análogos & derivados , Estavudina/farmacología
17.
Nucleic Acids Res ; 40(1): 381-90, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21914723

RESUMEN

ß-D-3'-Azido-2',3'-dideoxyguanosine (3'-azido-ddG) is a potent inhibitor of HIV-1 replication with a superior resistance profile to zidovudine. Recently, we identified five novel 6-modified-3'-azido-ddG analogs that exhibit similar or superior anti-HIV-1 activity compared to 3'-azido-ddG in primary cells. To gain insight into their structure-activity-resistance relationships, we synthesized their triphosphate (TP) forms and assessed their ability to inhibit HIV-1 reverse transcriptase (RT). Steady-state and pre-steady-state kinetic experiments show that the 6-modified-3'-azido-ddGTP analogs act as adenosine rather than guanosine mimetics in DNA synthesis reactions. The order of potency of the TP analogs against wild-type RT was: 3'-azido-2,6-diaminopurine >3'-azido-6-chloropurine; 3'-azido-6-N-allylaminopurine > 2-amino-6-N,N-dimethylaminopurine; 2-amino-6-methoxypurine. Molecular modeling studies reveal unique hydrogen-bonding interactions between the nucleotide analogs and the template thymine base in the active site of RT. Surprisingly, the structure-activity relationship of the analogs differed in HIV-1 RT ATP-mediated excision assays of their monophosphate forms, suggesting that it may be possible to rationally design a modified base analog that is efficiently incorporated by RT but serves as a poor substrate for ATP-mediated excision reactions. Overall, these studies identify a promising strategy to design novel nucleoside analogs that exert profound antiviral activity against both WT and drug-resistant HIV-1.


Asunto(s)
Fármacos Anti-VIH/química , Didesoxinucleósidos/química , Didesoxinucleótidos/química , Transcriptasa Inversa del VIH/química , Inhibidores de la Transcriptasa Inversa/química , Adenosina/análogos & derivados , Adenosina Trifosfato/química , Fármacos Anti-VIH/metabolismo , Dominio Catalítico , Didesoxinucleótidos/metabolismo , Transcriptasa Inversa del VIH/genética , Transcriptasa Inversa del VIH/metabolismo , Modelos Moleculares , Imitación Molecular , Mutación , Inhibidores de la Transcriptasa Inversa/metabolismo
18.
J Med Chem ; 54(1): 222-32, 2011 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-21128666

RESUMEN

Acyclic nucleoside phosphonates (ANPs) are at the cornerstone of DNA virus and retrovirus therapies. They reach their target, the viral DNA polymerase, after two phosphorylation steps catalyzed by cellular kinases. New pyrimidine ANPs have been synthesized with unsaturated acyclic side chains (prop-2-enyl-, but-2-enyl-, pent-2-enyl-) and different substituents at the C5 position of the uracil nucleobase. Several derivatives in the but-2-enyl- series 9d and 9e, with (E) but not with (Z) configuration, were efficient substrates for human thymidine monophosphate (TMP) kinase, but not for uridine monophosphate-cytosine monophosphate (UMP-CMP) kinase, which is in contrast to cidofovir. Human TMP kinase was successfully crystallized in a complex with phosphorylated (E)-thymidine-but-2-enyl phosphonate 9e and ADP. The bis-pivaloyloxymethyl (POM) esters of (E)-9d and (E)-9e were synthesized and shown to exert activity against herpes virus in vitro (IC(50) = 3 µM) and against varicella zoster virus in vitro (IC(50) = 0.19 µM), in contrast to the corresponding inactive (Z) derivatives. Thus, their antiviral activity correlates with their ability to act as thymidylate kinase substrates.


Asunto(s)
Antivirales/síntesis química , Nucleósido-Fosfato Quinasa/metabolismo , Organofosfonatos/síntesis química , Profármacos/síntesis química , Nucleósidos de Pirimidina/síntesis química , Timidina/análogos & derivados , Antivirales/química , Antivirales/farmacología , Dominio Catalítico , Células Cultivadas , Cristalografía por Rayos X , Herpesviridae/efectos de los fármacos , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Nucleósido-Fosfato Quinasa/antagonistas & inhibidores , Organofosfonatos/química , Organofosfonatos/farmacología , Profármacos/química , Profármacos/farmacología , Nucleósidos de Pirimidina/química , Nucleósidos de Pirimidina/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Especificidad por Sustrato , Timidina/síntesis química , Timidina/química , Timidina/farmacología , Timidina Quinasa/antagonistas & inhibidores
19.
Future Med Chem ; 2(2): 177-92, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21426185

RESUMEN

In recent decades, nucleosides analogs have been the cornerstone in the treatment of various diseases, such as AIDS, herpes and hepatitis. More than 40 modified nucleosides are officially approved by the US FDA and represent the major compound class for inhibition of viral replication. By comparison with traditional conditions, microwave irradiation offers a powerful tool that can increase yields and decrease reaction time, with simple manipulation and an environmentally friendly way. Here, we report the latest progress in nucleoside synthesis using microwave irradiation.


Asunto(s)
Antivirales/síntesis química , Microondas , Nucleósidos de Purina/síntesis química , Nucleósidos de Pirimidina/síntesis química , Adenina/química , Antimetabolitos Antineoplásicos/síntesis química , Catálisis , Paladio/química , Purinas/química , Timina/química , Factores de Tiempo
20.
Tetrahedron ; 64(38): 9044-9051, 2008 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-34321698

RESUMEN

In this study, we described the synthesis of 1,4- and 1,5-disubstituted-1,2,3-triazolo-nucleosides from various alkynes with 1'-azido-2',3',5'-tri-O-acetylribose using either copper-catalyzed azide-alkyne cycloaddition (CuAAC) or ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC), respectively. Optimized RuAAC conditions were realized with the commercially available [Cp*RuCl(PPh3)2] under microwave heating, which allows a significant acceleration of the reaction times (from 6 h to 5 min). This reaction can work under water-containing system. RuAAC and CuAAC are useful tools for the synthesis of 1,2,3-triazolyl-nucleosides small libraries.

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