RESUMO
The hypothesis that life on Earth may have started with a heterogeneous nucleic acid genetic system including both RNA and DNA has attracted broad interest. The recent finding that two RNA subunits (cytidine, C, and uridine, U) and two DNA subunits (deoxyadenosine, dA, and deoxyinosine, dI) can be coproduced in the same reaction network, compatible with a consistent geological scenario, supports this theory. However, a prebiotically plausible synthesis of the missing units (purine ribonucleosides and pyrimidine deoxyribonucleosides) in a unified reaction network remains elusive. Herein, we disclose a strictly stereoselective and furanosyl-selective synthesis of purine ribonucleosides (adenosine, A, and inosine, I) and purine deoxynucleosides (dA and dI), alongside one another, via a key photochemical reaction of thioanhydroadenosine with sulfite in alkaline solution (pH 8-10). Mechanistic studies suggest an unexpected recombination of sulfite and nucleoside alkyl radicals underpins the formation of the ribo C2'-O bond. The coproduction of A, I, dA, and dI from a common intermediate, and under conditions likely to have prevailed in at least some primordial locales, is suggestive of the potential coexistence of RNA and DNA building blocks at the dawn of life.
Assuntos
Desoxirribonucleosídeos/síntese química , Nucleosídeos de Purina/síntese química , Ribonucleosídeos/síntese química , Adenosina/análogos & derivados , Adenosina/efeitos da radiação , Evolução Química , Concentração de Íons de Hidrogênio , Modelos Químicos , Sulfitos/química , Sulfitos/efeitos da radiação , Raios UltravioletaRESUMO
Nucleoside analogs are widely used for the treatment of viral diseases (Hepatitis B/C, herpes and human immunodeficiency virus, HIV) and various malignancies. ALS-8176, a prodrug of the 4'-chloromethyl-2'-deoxy-2'-fluoro nucleoside ALS-8112, was evaluated in hospitalized infants for the treatment of respiratory syncytial virus (RSV), but was abandoned for unclear reasons. Based on the structure of ALS-8112, a series of novel 4'-modified-2'-deoxy-2'-fluoro nucleosides were synthesized. Newly prepared compounds were evaluated against RSV, but also against a panel of RNA viruses, including Dengue, West Nile, Chikungunya, and Zika viruses. Unfortunately, none of the compounds showed marked antiviral activity against these viruses.
Assuntos
Antivirais/síntese química , Desoxicitidina/análogos & derivados , Desoxirribonucleosídeos/síntese química , Pró-Fármacos/síntese química , Animais , Antivirais/farmacologia , Linhagem Celular Tumoral , Vírus Chikungunya/efeitos dos fármacos , Vírus Chikungunya/crescimento & desenvolvimento , Cricetulus , Vírus da Dengue/efeitos dos fármacos , Vírus da Dengue/crescimento & desenvolvimento , Desoxicitidina/síntese química , Desoxicitidina/farmacologia , Desoxirribonucleosídeos/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/virologia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Testes de Sensibilidade Microbiana , Cultura Primária de Células , Pró-Fármacos/farmacologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Vírus Sincicial Respiratório Humano/crescimento & desenvolvimento , Linfócitos T/efeitos dos fármacos , Linfócitos T/virologia , Falha de Tratamento , Replicação Viral/efeitos dos fármacos , Vírus do Nilo Ocidental/efeitos dos fármacos , Vírus do Nilo Ocidental/crescimento & desenvolvimento , Zika virus/efeitos dos fármacos , Zika virus/crescimento & desenvolvimentoRESUMO
We report herein the synthesis and evaluation of a series of ß-d-2'-deoxy-2'-α-chloro-2'-ß-fluoro and ß-d-2'-deoxy-2'-α-bromo-2'-ß-fluoro nucleosides along with their corresponding phosphoramidate prodrugs. Key intermediates, lactols 11 and 12, were obtained by a diastereoselective fluorination of protected 2-deoxy-2-chloro/bromo-ribonolactones 7 and 8. All synthesized nucleosides and prodrugs were evaluated with a hepatitis C virus (HCV) subgenomic replicon system.
Assuntos
Antivirais/farmacologia , Desoxirribonucleosídeos/farmacologia , Hepacivirus/efeitos dos fármacos , Pró-Fármacos/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Linhagem Celular Tumoral , Chlorocebus aethiops , Desoxirribonucleosídeos/síntese química , Desoxirribonucleosídeos/química , Humanos , Pró-Fármacos/síntese química , Pró-Fármacos/química , Estereoisomerismo , Células VeroRESUMO
Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of ß-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 µM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.
Assuntos
Antivirais/farmacologia , Desoxirribonucleosídeos/farmacologia , Nucleotídeos de Desoxiuracil/farmacologia , Hepacivirus/efeitos dos fármacos , Pró-Fármacos/farmacologia , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Linhagem Celular Tumoral , Desoxirribonucleosídeos/síntese química , Desoxirribonucleosídeos/farmacocinética , Nucleotídeos de Desoxiuracil/síntese química , Nucleotídeos de Desoxiuracil/farmacocinética , Cães , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
We developed a versatile access to a series of 4-substituted imidazole 2'-deoxynucleoside triphosphate bearing functionalized phenyl or pyrimidinyl rings. 4-Iodo-1H-imidazole was enzymatically converted into the corresponding 2'-deoxynucleoside, which was then chemically derived into its 5'-triphosphate, followed by 4-arylation via Suzuki-Miyaura coupling using (hetero)arylboronic acids. Both KF (exo-) and Deep Vent (exo-) DNA polymerases incorporated these modified nucleotides in primer-extension assays, adenine being the preferred pairing partner in the template. The 4-(3-aminophenyl)imidazole derivative (3APh) was the most efficiently inserted opposite A by KF (exo-) with only a 37-fold lower efficiency (Vmax/KM) than that of the correct dTTP. No further extension occurred after the incorporation of a single aryl-imidazole nucleotide. Interestingly, the aryl-imidazole dNTPs were found to undergo successive incorporation by calf thymus terminal deoxynucleotidyl transferase with different tailing efficiencies among this series and with a marked preference for 2APyr polymerization.
Assuntos
DNA Polimerase Dirigida por DNA/metabolismo , Desoxirribonucleosídeos/metabolismo , Imidazóis/metabolismo , Polifosfatos/metabolismo , Pirimidinas/metabolismo , Animais , Sequência de Bases , Bovinos , DNA Polimerase I/metabolismo , Desoxirribonucleosídeos/síntese química , Desoxirribonucleosídeos/química , Imidazóis/síntese química , Imidazóis/química , Polimerização , Polifosfatos/síntese química , Polifosfatos/química , Pirimidinas/síntese química , Pirimidinas/químicaRESUMO
The preparation of 2-deoxy-l-ribose derivatives or mirror image deoxyribonucleosides (l-deoxyribonucleosides) from d-ribose is reported. Starting from inexpensive d-ribose, an acyclic d-form carbohydrate precursor was synthesized to study a unique carbonyl translocation process. In this novel radical reaction, not only was the configuration of the sugar transformed from the d-form to the l-form, but also deoxygenation at the C(2) position of the sugar was successfully achieved. This is one of the most practical methods for converting a d-sugar to a 2-deoxy-l-sugar in a one-step reaction. To further identify the reaction product, radical reactions followed by treatment with 1,3-propanedithiol and then benzoylation were performed to afford a dithioacetal derivative. The stereochemistry and configuration of the 2-deoxy-l-ribose dithioacetal derivative were confirmed by its X-ray crystal structure. To further apply this methodology, a diethyl thioacetal derivative was formed, followed by selective benzoyl protection, and an NIS-initiated cyclization reaction to give the desired ethyl S-l-2-deoxyriboside, which can be used as a 2-deoxy-l-ribosyl synthon in the formal total synthesis of various l-deoxyribonucleosides, such as l-dT.
Assuntos
Desoxirribonucleosídeos/química , Desoxirribonucleosídeos/síntese química , Ribose/química , Técnicas de Química Sintética , Ciclização , EstereoisomerismoRESUMO
The synthesis and characterization of a universal and fluorescent nucleoside, 4-cyanoindole-2'-deoxyribonucleoside (4CIN), and its incorporation into DNA is described. 4CIN is a highly efficient fluorophore with quantum yields >0.90 in water. When incorporated into duplex DNA, 4CIN pairs equivalently with native nucleobases and has uniquely high quantum yields ranging from 0.15 to 0.31 depending on sequence and hybridization contexts, surpassing that of 2-aminopurine, the prototypical nucleoside fluorophore. 4CIN constitutes a new isomorphic nucleoside for diverse applications.
Assuntos
DNA/análise , Desoxirribonucleosídeos/síntese química , Corantes Fluorescentes/síntese química , Indóis/síntese química , Nitrilas/síntese química , Isomerismo , Luz , Hibridização de Ácido NucleicoRESUMO
2'-Deoxyribonucleoside triphosphates (dNTPs) containing 5-(hydroxymethyl)cytosine (5hmC) protected with photocleavable groups (2-nitrobenzyl or 6-nitropiperonyl) were prepared and studied as substrates for the enzymatic synthesis of oligonucleotides and DNA containing a photocaged epigenetic 5hmC base. DNA probes containing photocaged or free 5hmC in the recognition sequence of restriction endonucleases were prepared and used for the study of the photorelease of caged DNA by UV or visible light at different wavelengths. The nitrobenzyl-protected dNTP was a slightly better substrate for DNA polymerases in primer extension or PCR, whereas the nitropiperonyl-protected nucleotide underwent slightly faster photorelease at 400 nm. However, both photocaged building blocks can be used in polymerase synthesis and the photorelease of 5hmC in DNA.
Assuntos
5-Metilcitosina/análogos & derivados , DNA/química , Desoxirribonucleosídeos/química , Polifosfatos/química , 5-Metilcitosina/síntese química , 5-Metilcitosina/química , DNA/síntese química , Desoxirribonucleosídeos/síntese química , Luz , Processos Fotoquímicos , Polifosfatos/síntese química , Raios UltravioletaRESUMO
Milligram quantities of α-D-ribofuranosyl 1-phosphate (sodium salt) (αR1P) were prepared by the phosphorolysis of inosine, catalyzed by purine nucleoside phosphorylase (PNPase). The αR1P was isolated by chromatography in >95% purity and characterized by 1H and 13C NMR spectroscopy. Aqueous solutions of αR1P were stable at pH 6.4 and 4 °C for several months. The isolated αR1P was N-glycosylated with different nitrogen bases (adenine, guanine and uracil) using PNPase or uridine phosphorylase (UPase) to give the corresponding ribonucleosides in high yield based on the glycosyl phosphate. This methodology is attractive for the preparation of stable isotopically labeled ribo- and 2'-deoxyribonucleosides because of the ease of product purification and convenient use and recycling of nitrogen bases. The approach eliminates the need for separate reactions to prepare individual furanose-labeled ribonucleosides, since only one ribonucleoside (inosine) needs to be labeled, if desired, in the furanose ring, the latter achieved by a high-yield chemical N-glycosylation. 2'-Deoxyribonucleosides were prepared from 2'-deoxyinosine using the same methodology with minor modifications.
Assuntos
Desoxirribonucleosídeos/química , Desoxirribonucleosídeos/síntese química , Furanos/química , Fosfatos/química , Purina-Núcleosídeo Fosforilase/metabolismo , Biocatálise , Técnicas de Química Sintética , Glicosilação , Marcação por Isótopo , CinéticaRESUMO
Reported is an efficient synthesis of adenyl and uridyl 5'-tetrachlorophthalimido-5'-deoxyribonucleosides, and guanylyl 5'-azido-5'-deoxyribonucleosides, which are useful in solid-phase synthesis of phosphoramidate and ribonucleic guanidine oligonucleotides. Replacement of 5'-hydroxyl with tetrachlorophthalimido group was performed via Mitsunobu reaction for adenosine and uridine. An alternative method was applied for guanosine which replaced the 5'-hydroxyl with an azido group. The resulting compounds were converted to 5'-amino-5'-deoxyribonucleosides for oligonucleotide synthesis. Synthetic intermediates were tested as antimicrobials against six bacterial strains. All analogs containing the 2',3'-O-isopropylidine protecting group demonstrated antibacterial activity against Neisseria meningitidis, and among those analogs with 5'-tetrachlorophthalimido and 5'-azido demonstrated increased antibacterial effect.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Adenosina/química , Antibacterianos/síntese química , Azidas/química , Técnicas de Química Sintética , Desoxirribonucleosídeos/síntese química , Desoxirribonucleosídeos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Testes de Sensibilidade Microbiana , Neisseria meningitidis/efeitos dos fármacos , Ftalimidas/química , Uridina/químicaRESUMO
Four 6-substituted 4-amino-pyrimido[4,5-b]indole 2'-deoxyribonucleoside triphosphates (dA(BX)TPs) were prepared by glycosylation of 4,6-dichloropyrimidoindole followed by ammonolysis, cross-coupling and triphosphorylation. They were found to be moderate to good substrates for DNA polymerases in primer extension. They also exerted fluorescence with emission maxima 335-378nm. When incorporated to oligonucleotide probes, they did not show significant mismatch discrimination but the 6-benzofuryl 4-amino-pyrimido[4,5-b]indole nucleotide displayed a useful sensitivity to protein binding in experiment with SSB protein.
Assuntos
Nucleotídeos de Desoxiadenina/química , Desoxirribonucleosídeos/química , Corantes Fluorescentes/química , Indóis/química , Sondas de Oligonucleotídeos/química , Pareamento Incorreto de Bases , Sequência de Bases , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , DNA Polimerase Dirigida por DNA/metabolismo , Nucleotídeos de Desoxiadenina/síntese química , Nucleotídeos de Desoxiadenina/metabolismo , Desoxirribonucleosídeos/síntese química , Desoxirribonucleosídeos/metabolismo , Escherichia coli/química , Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Indóis/síntese química , Indóis/metabolismo , Sondas de Oligonucleotídeos/síntese química , Sondas de Oligonucleotídeos/metabolismo , Espectrometria de FluorescênciaRESUMO
The objective of this work was to design conjugates of anti-HIV nucleosides conjugated with fatty acids and cell-penetrating poly-L-arginine (polyArg) peptides. Three conjugates of polyArg cell-penetrating peptides with fatty acyl derivatives of alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC) were synthesized. In general, the compounds exhibited anti-HIV activity against X4 and R5 cell-free virus with EC50 values of 1.5-16.6 µM. FLT-CO-(CH2)12-CO-(Arg)7 exhibited EC50 values of 2.9 µM and 3.1 µM against X4 and R5 cell-free virus, respectively. The FLT conjugate was selected for further preformulation studies by determination of solution state degradation and lipid solubility. The compound was found to be stable in neutral and oxidative conditions and moderately stable in heated conditions.
Assuntos
Fármacos Anti-HIV/síntese química , Desoxirribonucleosídeos/síntese química , Peptídeos/química , Inibidores da Transcriptase Reversa/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Peptídeos Penetradores de Células/química , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxirribonucleosídeos/química , Desoxirribonucleosídeos/farmacologia , Ácidos Dicarboxílicos/química , Didesoxinucleosídeos/química , Emtricitabina , Humanos , Lamivudina/análogos & derivados , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologiaRESUMO
The synthesis of 2'-deoxyribonucleoside triphosphates (dNTPs) either by classical triphosphorylation of nucleosides or by aqueous cross-coupling reactions of halogenated dNTPs is discussed. Different enzymatic methods for synthesis of modified oligonucleotides and DNA by polymerase incorporation of modified nucleotides are summarized, and the applications in redox or fluorescent labeling, as well as in bioconjugations and modulation of interactions of DNA with proteins, are outlined.
Assuntos
DNA Polimerase Dirigida por DNA/química , DNA/química , Desoxirribonucleosídeos/síntese química , Nucleosídeos/síntese química , Nucleotídeos/síntese química , Oligonucleotídeos/química , Sequência de Bases , Fenômenos Bioquímicos , DNA/metabolismo , DNA Polimerase Dirigida por DNA/metabolismo , Desoxirribonucleosídeos/química , Estrutura Molecular , Nucleosídeos/química , Nucleotídeos/química , FosforilaçãoRESUMO
Upon reacting 3',4'-unsaturated cytosine (8 and 9) and adenine nucleosides (13 and 14) with XeF(2)/BF3 · OEt(2), the respective novel 3',4'-difluoro-3'-deoxyribofuranosyl nucleosides (10-12 and 15-18) could be obtained. Formation of anti-adducts (11, 16 and 18) revealed that the fluorination involved oxonium ions as incipient intermediates. TBDMS-protected 3',4'-unsaturated adenosine provided the ß-face adducts as sole stereoisomers whereas α-face-selectivity was observed with the TBDPS-protected adenosine 14. The evaluation of the novel 3'-deoxy-3',4'-difluororibofuranosylcytosine-(19-21) and adenine nucleosides (22-25) against antitumor and antiviral activities revealed that 3',4'-difluorocordycepin (24) was found to possess anti-HCV activity. The SI of 24 was comparable to that of the anti-HCV drug ribavirin. However, sofosbuvir, FDA-approved novel anti-HCV drug, showed better SI value. Our finding revealed that the introduction of the fluoro-substituent into the 4'-position of cordycepin derivatives decreased the cytotoxicity to the host cell with retention of the antiviral activity.
Assuntos
Antivirais/química , Antivirais/farmacologia , Desoxirribonucleosídeos/química , Desoxirribonucleosídeos/farmacologia , Hepacivirus/efeitos dos fármacos , Antivirais/síntese química , Linhagem Celular , Desoxiadenosinas/síntese química , Desoxiadenosinas/química , Desoxiadenosinas/farmacologia , Desoxirribonucleosídeos/síntese química , Halogenação , Hepatite C/tratamento farmacológico , Humanos , Relação Estrutura-AtividadeRESUMO
Oligonucleotides with 3-ethynyl-5-nitroindole and 3-octadiynyl-5-nitroindole 2'-deoxyribonucleosides were prepared by solid-phase synthesis. To this end, nucleoside phosphoramidites with clickable side chains were synthesized. The 3-ethynylated 5-nitroindole nucleoside was hydrated during automatized DNA synthesis to 3-acetyl-5-nitroindole 2'-deoxyribonucleoside. Side product formation was circumvented by triisopropylsilyl protection of the ethynyl side chain and was removed with TBAF after oligonucleotide synthesis. All compounds with a clickable 5-nitroindole skeleton show universal base pairing and can be functionalized with almost any azide in any position of the DNA chain. Functionalization of the side chain with 1-azidomethylpyrene afforded click adducts in which the fluorescence was quenched by the 5-nitroindole moieties. However, fluorescence was slightly recovered during duplex formation. Oligonucleotides with a pyrene residue and a long linker arm are stabilized over those with non-functionalized side chains. From the UV red shift of the pyrene residue in oligonucleotides and modelling studies, pyrene intercalation was established for the long linker adduct showing increased duplex stability over those with a short side chain.
Assuntos
Indóis/química , Oligonucleotídeos/síntese química , Pirenos/química , Pareamento de Bases , Sequência de Bases , Química Click , DNA/síntese química , DNA/química , Desoxirribonucleosídeos/síntese química , Desoxirribonucleosídeos/química , Modelos Moleculares , Oligonucleotídeos/química , Técnicas de Síntese em Fase SólidaRESUMO
Synthetic routes to 5'-azidoribonucleosides are reported for adenosine, cytidine, guanosine, and uridine, resulting in a widely applicable one-pot methodology for the synthesis of these and related compounds. The target compounds are appropriate as precursors in a variety of purposive syntheses, as the synthetic and therapeutic relevance of azido- and amino-modified nucleosides is expansive. Furthermore, in the conversion of alcohols to azides, these methods offer a tractable alternative to the Mitsunobu and other more difficult reactions.
Assuntos
Azidas/química , Desoxirribonucleosídeos/química , Adenosina/química , Álcoois/química , Azidas/síntese química , Citidina/química , Desoxirribonucleosídeos/síntese química , Uridina/químicaRESUMO
Threose nucleic acid (TNA) is a potential alternative genetic material that may have played a role in the early evolution of life. We have developed a novel synthesis of 2'-amino modified TNA nucleosides (2'-NH2-TNA) based on a cycloaddition reaction between a glycal and an azodicarboxylate, followed by direct nucleosidation of the cycloadduct. Using this route, we synthesized the thymine and guanine 2'-NH2-TNA nucleosides in seven steps with 24% and 12% overall yield, respectively. We then phosphorylated the guanine nucleoside on the 3'-hydroxyl, activated the phosphate as the 2-methylimidazolide, and tested the ability of the activated nucleotide to copy C4 RNA, DNA, and TNA templates by nonenzymatic primer extension. We measured pseudo-first-order rate constants for the first nucleotide addition step of 1.5, 0.97, and 0.57 h(-1) on RNA, DNA, and TNA templates, respectively, at pH 7.5 and 4 °C with 150 mM NaCl, 100 mM N-(hydroxylethyl)imidazole catalyst, and 5 mM activated nucleotide. The activated nucleotide hydrolyzed with a rate constant of 0.39 h(-1), causing the polymerization reaction to stall before complete template copying could be achieved. These extension rates are more than 1 order of magnitude slower than those for amino-sugar ribonucleotides under the same conditions, and copying of the TNA template, which best represented a true self-copying reaction, was the slowest of all. The poor kinetics of 2'-NH2-TNA template copying could give insight into why TNA was ultimately not used as a genetic material by biological systems.
Assuntos
Desoxirribonucleosídeos/síntese química , Moldes Genéticos , Tetroses/química , Cristalografia por Raios X , Reação de Cicloadição , Desoxirribonucleosídeos/química , Desoxirribonucleosídeos/genética , Hidrólise , Estrutura Molecular , Tetroses/genéticaRESUMO
During the synthesis of a series of 2'-deoxy-9-deaza nucleosides using Heck methodology, the necessity for a pyrrole protecting group was discovered. The results of this brief study revealed that the benzyloxymethyl (BOM) group proved optimal, and Heck coupling using Jeffery conditions increased the coupling yield significantly. The results are reported herein.
Assuntos
Desoxiguanosina/análogos & derivados , Desoxirribonucleosídeos/síntese química , Desoxiguanosina/síntese química , Desoxiguanosina/química , Desoxirribonucleosídeos/química , Conformação MolecularRESUMO
2-Bromo-6-chloro- and 6-bromo-2-chloropyridin-3-yl deoxyribonucleosides were prepared by the Heck coupling of bromo-chloro-iodopyridines with TBS-protected deoxyribose glycal. Some of their Pd-catalyzed cross-coupling reactions proceeded chemoselectively at the position of the bromine, whereas nucleophilic substitutions were unselective and gave mixtures of products. The mono-substituted intermediates were used for another coupling or nucleophilic substitution giving rise to a small library of title 2,6-disubstituted pyridine C-deoxyribonucleosides. The title nucleosides did not exert antiviral or cytostatic effects.
Assuntos
Desoxirribonucleosídeos/química , Desoxirribonucleosídeos/síntese química , Piridinas/química , Técnicas de Química Sintética , Especificidade por SubstratoRESUMO
Convenient and efficient methods of the synthesis of N(6)- and N(4)-substituted derivatives of adenine and cytosine and their 2'-deoxyribosides were developed. The reactions of either unprotected nucleobases (adenine, cytosine) or unprotected 2'-deoxyribosides with aryl or alkyl aldehydes give corresponding Schiff bases that can be reduced to the target title compounds with high overall yields. In the case of aryl aldehydes the imine derivatives are obtained in the presence of methoxides in methanol and reduced with sodium borohydride. The corresponding reactions with alkyl aldehydes require the use of acetic acid and borane dimethyl sulfide complex instead.