Synthesis of 5′,9-anhydro-3-(β-d-ribofuranosyl)xanthine, and 3,5′-anhydro-xanthosine as potential anti-hepatitis C virus agents

5′,9-Anhydro-3-(β-d-ribofuranosyl)xanthine and 3,5′-anhydro-xanthosine were prepared as potential anti-hepatitis C virus (HCV) agents from uridine and xanthosine, respectively.     

Retention studies of 2′-2′-difluorodeoxycytidine and 2′-2′-difluorodeoxyuridine nucleosides and nucleotides on porous graphitic carbon: Development of a liquid chromatography–tandem mass spectrometry method

The development of a method for the separation of 2′-2′-difluorodeoxycytidine (gemcitabine, dFdC), 2′-2′-difluorodeoxyuridine (dFdU) and their mono-, di- and triphosphates using a porous graphitic carbon column (Hypercarb), without ion-pairing agent, is described. The retention of dFdC and dFdU could be controlled with an organic modifier (acetonitrile, CH₃CN) and the retention of the anionic nucleotides with an eluting ion (bicarbonate). Separation of all analytes was achieved using a 0–25 mM ammonium bicarbonate gradient in CH₃CN–H₂O (15:85, v/v). Under these conditions, however, very long re-equilibration times were required. Injection of an acidic solution (100 μL 10% formic acid in H₂O, v/v; 2.65 M) after running a gradient directly restored the separation capabilities of the column. Still, separation between the analytes slowly deteriorated over a period of months. These problems were solved by preconditioning the column with a pH buffered hydrogen peroxide (H₂O₂) solution (0.05% H₂O₂ in CH₃CN–H₂O (15:85, v/v), pH 4) before starting an analytical run. The oxidation of the stationary phase with H₂O₂ prevented its slow reduction, which most likely caused the decreasing retention times. The analytes were detected using tandem mass spectrometry.     

Efficient synthesis of 3-cyanovinylcarbazole-1′-β-deoxyriboside-5′-triphosphate: a reversible photo-cross-linking probe

We describe an efficient synthesis of 3-cyanovinylcarbazole-1′-β-deoxyriboside-5′-triphosphate containing light-responsive artificial nucleobase 3-cyanovinylcarbazole, which can be used as a reversible photo-cross-linking probe with nucleic acid compounds for various biological applications. A three-step synthesis of 3-cyanovinylcarbazole-1′-β-deoxyriboside starting from 3-cyanovinylcarbazole, followed by ‘one-pot, three-step’ procedure is presented to accomplish the title compound 3-cyanovinylcarbazole-1′-β-deoxyriboside-5′-triphosphate in good yields.     

Synthesis of 2′-β-C-methyl-neplanocin derivatives as anti-HCV agents

The synthesis of 2′-β-C-methyl-neplanocin derivatives is described. The key intermediate cyclopentenyl alcohol 12 is prepared from sugar 5 in 12 steps. Coupling of 12 with appropriately protected purine, 7-deaza pyrimidine, uracil and pyrimidine bases via the Mitsunobu reaction followed by deprotection afforded the target cyclopentenyl nucleosides (18-23, 27). The synthesized compounds were evaluated as potential inhibitors of the hepatitis C virus (HCV) in vitro. Unfortunately, none of them show anti-HCV activity below EC₅₀ 100 μM.     

Synthesis and anti-HIV activity of l-β-3′-C-cyano-2′,3′-unsaturated nucleosides and l-3′-C-cyano-3′-deoxyribonucleosides

An efficient synthetic method was developed for l-β-3′-C-cyano-2′,3′-unsaturated nucleosides and l-3′-C-cyano-3′-deoxyribonucleosides. The key intermediate 11 was obtained from l-xylose, from which a series of pyrimidine and purine nucleosides were prepared in high yield by the coupling of 11 and various silyl-protected bases in the presence of TMSOTf. These nucleosides were eliminated, followed by deprotecting to give l-β-3′-C-cyano-2′,3′-unsaturated nucleosides. When selectively deprotected by hydrazine hydrate in buffered acetic acid-pyridine followed by treatment with potassium carbonate in methanol, l-3′-C-cyano-3′-deoxyribonucleosides were obtained. The synthesized nucleosides were tested for anti-HIV activity.     

Synthesis and transformations of [1,2-O-isopropylidene-α-d-erythro (and α-d-ribo)furanose]-3-spiro-3′-(4′-amino-5′H-2′,3′-dihydroisothiazole-1′,1′-dioxide) derivatives

The carbanion-mediated sulfonamide cyclisations (CSIC protocols) of glyco-α-sulfonamidonitriles derived from readily available uloses 1A and 1B have been investigated using different bases (potassium carbonate, cesium carbonate, LDA and n-BuLi). As a result, a series of enantiomerically pure [1,2-O-isopropylidene-α-d-erythro (and α-d-ribo)furanose]-3-spiro-3′-(4′-amino-5′H-2′,3′-dihydroisothiazole-1′,1′-dioxide) derivatives have been prepared and isolated in good yields.     

Highly stereoselective synthesis of 2′-deoxy-β-ribonucleosides via a 3′-(N-acetyl)-glycyl-directing group

A facile synthesis of 2′-deoxy-β-ribonucleosides from 3′-O-(N-acetyl)-glycyl-protected 2′-deoxyribofuranose has been developed. The coupling reactions between the protected 2′-deoxyribose and silylated bases exhibited β-selectivity up to 98% presumably via a 1′,3′-participation mechanism. The 3′-directing group can be introduced and removed easily under mild conditions. This approach provides an efficient and highly stereoselective entry for the synthesis of 2′-deoxy-ribonucleosides.     

Synthesis and anti-HCV activity of 1-(1′,3′-O-anhydro-3′-C-methyl-β-d-psicofuranosyl)uracil

Synthesis of a novel 1′,2′-oxetane-uridine bearing a 2′-C-methyl substituent, [1-(1′,3′-O-anhydro-3′-C-methyl-β-d-psicofuranosyl)uracil], is described. Key to its construction was the use of 6-O-(p-toluoyl)-1,2:3,4-di-O-isopropylidene-3-C-methyl-d-psicofuranose as a nucleosidation substrate, which itself was derived from d-fructose. Anti-HCV activity was examined for the corresponding triphosphate which was not found to be an inhibitor of HCV NS5B 1b wild type polymerase in vitro. The 1′,2′-oxetane uridine triphosphate without 2′-C-methyl substitution was similarly inactive, however, the guanosine analog displayed modest inhibition (IC₅₀ = 10 μM).     

Solubility of Oxygen in Some 1-1, 2-1, 1-2, and 2-2 Electrolytes as a Function of Concentration at 25°C

The solubility of oxygen has been measured in a number of electrolytes [(LiCl, KCl, RbCl, CsCl, NaF, NaBr, NaI, NaNO₃, KBr, KI, KNO₃, CaCl₂, SrCl₂, BaCl₂, Li₂SO₄, K₂SO₄, Mn(NO₃)₃)] as a function of concentration at 25°C. The solubilities, mol (kg-H₂O)^–1, have been fitted to a function of the molality m (standard deviation < 3mol-kg^–1)

Chemo-enzymatic synthesis of 2′,3′-dideoxy-3′-fluoro-β-d-guanosine via 2,3-dideoxy-3-fluoro-α-d-ribose 1-phosphate

2,3-Dideoxy-3-fluoro-α-d-ribose 1-phosphate 2 was stereoselectively synthesized and converted to 2′,3′-dideoxy-3-fluoro-β-d-guanosine 1 by enzymatic reaction using purine nucleoside phosphorylase. This chemo-enzymatic strategy was first applied to the synthesis of 1.     

Staudinger and retro-Staudinger reactions. The dichloro-β-lactam moiety as a useful handle for the synthesis of 4-aryl-2H-1,3-benzothiazine 1,1-dioxides

The dichloro-β-lactam ring, obtained via Staudinger reaction of 4-aryl-2H-1,3-benzothiazines, proved to be a useful protecting strategy for the synthesis of 4-aryl-2H-1,3-benzothiazine 1,1-dioxides. After oxidation of the 1,1-dichloroazeto[2,1-c][1,3]-benzothiazin-2-ones, the thiazine ring could be recovered selectively and in good yield by treatment with base. Thus, novel 4-aryl-2H-1,3-benzothiazine 1,1-dioxides were obtained efficiently.     

Synthesis of 1-aryl-3-（3,4-dihydro-2H-chromen-5-yl） ureas as TNF-α inhibitors

A new series of compounds,1-aryl-3-(3,4-dihydro-2H-chromen-5-yl) ureas,have been synthesized and their structures were confirmed by FAB-MS and ~1H NMR.The preliminary pharmacological screening showed that these compounds inhibited TNF-αproduction in lipopolysaccharide (LPS)-stimulated THP-1 cells.     

Reassignment of the structures of condensation products of α-keto α′-formylarylhydrazones with ethyl cyanoacetate: a novel route to ethyl 5-arylazo-2-hydroxynicotinates

The condensation of α-keto α′-formylarylhydrazones with ethyl cyanoacetate afforded ethyl 5-arylazo-2-hydroxy-6-aryl (or alkyl) nicotinates. The structures of the reaction products could be established based on X-ray crystal structure determination.     

A convenient method for 14C-labeling of 2-methylthio-1-[4-N-α-ethoxycarbonylbenzyl)-amino-benzyl]-5-hydroxymethyl-2-[14C]-1H-imidazole and 1-[4-N-α-ethoxy-carbonylbenzyl)-aminobenzyl]-5-hydroxymethyl-2-[14C]-1H-imidazole as potential antihypertensives

The key synthetic intermediate, (2-mercapto-1-(4-nitrobenzyl)-1H-imidazol-5-yl)methanol-[2-¹⁴C], has been synthesized by using one pot procedure from potassium[¹⁴C]-thiocyanate. It was converted to two nonpeptide angiotensin II receptor antagonists, 2-methylthio-1-[4-N-α-ethoxycarbonyl benzyl)-aminobenzyl]-5-hydroxymethyl-1H-imidazole-[2-¹⁴C] and 1-[4-N-α-ethoxy-carbonylbenzyl)-aminobenzyl]-5-hydroxymethyl-1H-imidazole-[2-¹⁴C] via a 3-step sequence synthetic pathway.     

Chimeric oligonucleotides based on 2"-O-modified oligoribonucleotides with the terminal 3"—3" internucleotide linkage as potential inhibitors of MDR 1 gene expression

Chimeric constructs were synthesized based on oligoribonucleotides modified at the 2"-position of the ribose (2"-O-tetrahydropyranyl- or 2"-O-methyl-) and at the 3"-terminus of the oligonucleotide chain (terminal 3"—3" internucleotide linkage), which are complementary to a region of MDR 1 mRNA. A comparative study of the properties of these chimeric constructs was performed. The chimeric oligomers with the modified 3"-terminus are characterized by high stability with respect to 3"-exonucleases, form stable complementary complexes with RNA, and can activate RNase H in a duplex with RNA.     

Crystal structure of a new π-complex of AgClO4 with 1-allyl-5-(2-pyridyl)-1H-tetrazole of the composition [Ag2(C9H6N5)2](ClO4)2

By the AgClO₄ interaction with 1-allyl-5-(2-Pyridyl)-1H-tetrazolee (1aPyt) in a methanol solution, an [Ag₂(1aPyt)₂](ClO₄)₂ π-complex is obtained, which is studied using single crystal X-ray diffraction.     

β-Cyclodextrin as a photostabilizer of the plant growth regulator 2-(1-naphthyl) acetamide in aqueous solution

The plant growth regulator 2-(1-naphthyl) acetamide (NAAm) is susceptible to degradation by sunlight and UV light in aqueous solution. Its inclusion complex with β-cyclodextrin (β-CD) was characterized by absorption and fluorescence spectroscopy and its photodegradation was compared with that of aqueous solutions of NAAm. The complex was formed with a stoichiometric ratio of 1:1 with a binding constant of 651 M^?1. The photodegradation behavior of NAAm in the inclusion complex NAAm:β-CD was investigated using both UV (λ = 254 nm) and simulated solar light (Suntest) irradiation. It was found that the NAAm:β-CD complex increases NAAm photostability towards photochemical degradation markedly. In addition, an influence of β-CD concentration was also observed on NAAm degradation rate: higher β-CD concentrations lead to a slower photoinduced transformation. Moreover, some differences were found in the photoproducts in the presence and absence of the cyclodextrin, indicating inhibition of some of the mechanistic pathways. β-CD stabilizes NAAm photodegradation towards sunlight and UV irradiation, enhancing its efficient application on formulations for the treatment of fruits and vegetables.     

The relevance of the fluorine interactions in the supramolecular structure of a complex constructed from copper(II) hexafluoroacetylacetonate and the 4′-(3-pyridyl)-2,2′:6′,2″-terpyridine ligand. Novel C-F/π synthons involving the π-system of the terpyridine moieties and those of the hexafluoroacetylacetonate chelate rings

Reaction of 4′-(3-pyridyl)-2,2′:6′,2′′-terpyridine (pyterpy) with Cu(hfacac)₂ (hfacac = hexafluoroacetylacetonate) led to the formation of the novel compound [Cu₃(hfacac)₄(μ-pyterpy)₂][Cu(hfacac)₃]₂ (1). The structure is composed of a trinuclear [Cu₃(hfacac)₄(μ-pyterpy)₂]²⁺ cation and two [Cu(hfacac)₃]⁻ anionic species. The cation consists of a chain of three Cu^II atoms connected by bridging pyterpy ligands. The [Cu(hfacac)₃]⁻ anions have the hfacac ligands coordinated in their usual chelating manner through their carbonyl O donors. Besides the coulombian forces, the ionic species are fixed by C-H?O, C-H?F, F?F and a variety of unusual inter-ion C-F?π interactions that control the packing motif. These π-interactions involve the terpyridine groups from the pyterpy ligand and the five-membered rings of the chelating hexafluoroacetylacetonate anions.