RESUMO
2-Chloro-2'-deoxyadenosine (cladribine, 1) was acylated with valproic acid (2) under various reaction conditions yielding 2-chloro-2'-deoxy-3',5'-O-divalproyladenosine (3) as well as the 3'-O- and 5'-O-monovalproylated derivatives, 2-chloro-2'-deoxy-3'-O-valproyladenosine (4) and 2-chloro-2'-deoxy-5'-O-valproyladenosine (5), as new co-drugs. In addition, 6-azauridine-2',3'-O-(ethyl levulinate) (8) was valproylated at the 5'-OH group (â9). All products were characterized by 1 H- and 13 C-NMR spectroscopy and ESI mass spectrometry. The structure of the by-product 6 (N-cyclohexyl-N-(cyclohexylcarbamoyl)-2-propylpentanamide), formed upon valproylation of cladribine in the presence of N,N-dimethylaminopyridine and dicyclohexylcarbodiimide, was analyzed by X-ray crystallography. Cladribine as well as its valproylated co-drugs were tested upon their cancerostatic/cancerotoxic activity in human astrocytoma/oligodendroglioma GOS-3 cells, in rat malignant neuro ectodermal BT4Ca cells, as well as in phorbol-12-myristate 13-acetate (PMA)-differentiated human THP-1 macrophages. The most important result of these experiments is the finding that only the 3'-O-valproylated derivative 4 exhibits a significant antitumor activity while the 5'-O- as well as the 3',5'-O-divalproylated cladribine derivatives 3 and 5 proved to be inactive.
Assuntos
2-Cloroadenosina/análogos & derivados , Antineoplásicos/farmacologia , Azauridina/farmacologia , Desoxiadenosinas/farmacologia , Ácido Valproico/farmacologia , 2-Cloroadenosina/síntese química , 2-Cloroadenosina/química , 2-Cloroadenosina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Azauridina/síntese química , Azauridina/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desoxiadenosinas/síntese química , Desoxiadenosinas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ácido Valproico/síntese química , Ácido Valproico/químicaRESUMO
To display favorable fluorescent properties, the non-emissive native nucleosides need to be modified. Here we present a motif that relies on conjugating 5-membered aromatic heterocycles (e.g., thiophene) to a 6-azapyrimidine (1,2,4-triazine) core. Synthetic accessibility and desirable photophysical properties make these nucleosides attractive candidates for enzymatic incorporation and biochemical assays. While 6-azauridine triphosphate is known to be poorly tolerated by polymerases in RNA synthesis, we illustrate that conjugating a thiophene ring at position 5 overcomes such limitations, facilitating its T7 RNA polymerase-mediated in vitro transcription incorporation into RNA constructs. We further show that the modified transcripts can be ligated to longer oligonucleotides to form singly modified RNAs, as illustrated for an A-site hairpin model RNA construct, which was employed to visualize aminoglycoside antibiotics binding.
Assuntos
Azauridina/metabolismo , RNA Polimerases Dirigidas por DNA/metabolismo , RNA/biossíntese , Proteínas Virais/metabolismo , Azauridina/síntese química , Azauridina/química , RNA Polimerases Dirigidas por DNA/química , Fluorescência , RNA/química , Proteínas Virais/químicaRESUMO
The emergence of new drug-resistant strains of bacteria necessitates the development of principally new antibacterial agents. One of the novel classes of antibacterial agents is nucleoside analogs. We have developed a fast and simple one-pot method for preparation of α- and ß-anomers of 5-modified 6-aza- and 2-thio-6-aza-2'-deoxyuridine derivatives in high yields. 2-Thio derivatives demonstrated moderate activity against Mycobacterium smegmatis (MIC = 0.2-0.8 mM), Staphylococcus aureus (MIC = 0.03-0.9 mM) and some other Gram-positive bacteria. 2'-Deoxy-2-thio-5-phenyl-6-azauridine (2b) effectively suppressed the growth of Gram-negative bacteria Pseudomonas aeruginosa ATCC 27853 (MIC = 0.03 mM)-the one that causes diseases difficult to treat due to high resistance to antibiotics. 5'-Monophosphates of compounds 2a, b and 3a, b were docked into a binding site of Mycobacterium tuberculosis flavin-dependent thymidylate synthase (ThyX) enzyme. The molecular modeling demonstrates the possibility of binding of the 5-modified 2-thio-6-aza-2'-deoxyuridine 5'-monophosphates within the active site of the enzyme and thereby inhibiting the growth of the bacteria.
Assuntos
Antibacterianos/síntese química , Azauridina/análogos & derivados , Azauridina/síntese química , Animais , Antibacterianos/farmacologia , Azauridina/farmacologia , Domínio Catalítico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Timidilato Sintase/efeitos dos fármacosRESUMO
Condensation of 6-azauridine with ethyl levulinate, followed by saponification or phosphorylation, leads to 2',3'-O-[1-(2-carboxyethyl)ethylidene]-6-azauridine and its 5'-monophosphate. The latter was coupled to 6-aminohexylagarose via its carboxylic group. Using the same synthetic route, agarose-linked uridine 5'-monophosphate has been prepared. Both polymers show specific binding toward orotidine-5'-monophosphate decarboxylase. The immobilized inhibitor (6-azauridine 5'-monophosphat) binds the enzyme more strongly than the immobilized uridine 5'-monophosphate. Both resins have been used to separate orotidine-5'-monophosphate decarboxylase from orotidine-5'-monophosphate pyrophosphorylase.
Assuntos
Azauridina/análogos & derivados , Carboxiliases/antagonistas & inibidores , Orotidina-5'-Fosfato Descarboxilase/antagonistas & inibidores , Resinas Sintéticas/síntese química , Nucleotídeos de Uracila/síntese química , Uridina Monofosfato/síntese química , Azauridina/síntese química , Azauridina/farmacologia , Cromatografia de Afinidade , Orotidina-5'-Fosfato Descarboxilase/metabolismo , Resinas Sintéticas/farmacologia , Uridina Monofosfato/análogos & derivados , Uridina Monofosfato/farmacologiaRESUMO
The biotechnological method of synthesis of ribavirin, vidarabin, and 6-azauridine by the use of immobilized recombinant enzymatic preparations of nucleoside phosphorylase was improved. The effect of ribavirin and its combinations with the other synthesized nucleosides on the reproduction of Vaccinia virus was studied using cultures of Vero cells. The combination of ribavirin and vidarabin was shown to provide an antiviral effect at lesser concentrations than when these compounds were taken separately. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 6; see also http://www.maik.ru.
Assuntos
Antivirais/síntese química , Nucleosídeos/síntese química , Ribavirina/análogos & derivados , Ribavirina/síntese química , Vaccinia virus/efeitos dos fármacos , Animais , Antivirais/farmacologia , Azauridina/análogos & derivados , Azauridina/síntese química , Azauridina/farmacologia , Catálise , Chlorocebus aethiops , Interações Medicamentosas , Enzimas Imobilizadas , Nucleosídeos/farmacologia , Purina-Núcleosídeo Fosforilase/química , Ribavirina/farmacologia , Uridina Fosforilase/química , Células Vero , Vidarabina/análogos & derivados , Vidarabina/síntese química , Vidarabina/farmacologia , Replicação Viral/efeitos dos fármacosRESUMO
A family of extended 5-modified-6-aza-uridines was obtained via Suzuki coupling reactions with a common brominated precursor. Extending the conjugated-6-aza-uridines with substituted aryl rings increases the push-pull interactions yielding enhanced bathochromic shifts and solvatochromism compared to the parent nucleosides. For example, the methoxy substituted derivative 1d displays λmax abs around 375 nm, with visible emission maxima at 486 nm (Φ = 0.74) and 525 nm (Φ = 0.02) in dioxane and water, respectively.
Assuntos
Azauridina , Corantes Fluorescentes , Nucleosídeos/síntese química , Azauridina/análogos & derivados , Azauridina/síntese química , Azauridina/química , Cristalografia por Raios X , Corantes Fluorescentes/síntese química , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Nucleosídeos/químicaAssuntos
Oxirredutases do Álcool/metabolismo , Fígado/enzimologia , Açúcares de Uridina Difosfato/farmacologia , Oxirredutases do Álcool/antagonistas & inibidores , Animais , Azauridina/síntese química , Azauridina/farmacologia , Bovinos , Humanos , Concentração de Íons de Hidrogênio , Hidroxilação , Cinética , Nitrobenzenos/farmacologia , Proteínas/metabolismo , Saccharomyces cerevisiae/enzimologia , Fatores de Tempo , Xilose/metabolismoRESUMO
Inosine (I) when acetylated with acetic anhydride in the presence of acetyl chloride in acetic acid solution (the so called "acid acetylation"), affords an acetylated nucleoside III (75%) along with cleavage products of the nucleoside (hypoxanthine, 19%). The reaction of I with acetyl chloride (7 days) results in the formation of hypoxanthine (95%) and triacetylribofuranosyl chloride (IV) isolated in the form of tetraacetylribofuranose (47%). The acetylated purine nucleoside affords a similar result by reaction with acetyl chloride or acetyl bromide. 2'-Deoxyuridine gives a diacetyl derivative (80%) by reaction with acetyl bromide. On treatment with acetyl bromide, the nucleoside bond of purine nucleosides is quantitatively cleavaged (4 h, 20 degrees C) with the formation of tri-O-acetyl-D-ribofuranosyl bromide (X). The halogenose X affords pure beta-anomers, namely, 1,2,3,5-tetra-O-acetyl-beta-D-ribofuranose (75%), the triacetyl derivatives of 5-methyluridine (XVIIa; 75%, referred to guanosine), 6-azauridine (XVIII; 71%), and 5-fluorouridine (XIXa; 75%).