Nucleosides. 124. 3-Amino-3-deoxyhexopyranosyl Nucleosides. 7. 1-(3-Deoxy-3-Nitro-β-D-glucopyranosyl) Uracil and Its Galactopyranosyl Isomer1

Abstract

Crystalline 1-(3-deoxy-3-nitro-β-D-glucopyranosyl) uracil (3), originally prepared by nitromethane condensation of “uridine dialdehyde,” was found to contain the galactosyl isomer (4). Each isomer was obtained in pure form by 4′,6′-O-benzylidenation of the mixture of 3 and 4, followed by chromatographic separation and subsequent O-debenzylidenation. The structure of each isomer was established by chemical conversion of the isomer into the corresponding known 3′-acetamido-2′,4′,6′-tri-O-acetyl derivative.     

Synthesis of 7-(tetrahydropyran-2-yl)- and 7-(4-acetoxytetrahydropyran-2-yl)-ε-rhodomycinone and 7-(tetrahydropyran-2-yl)-ε-pyrromycinone

The ¹³C.n.m.r spectra of water-soluble and -insoluble glucans synthesized by enzymes isolated from six strains of Streptococcus mutans are interpreted. The glucans are shown to be composed primarily of α(1→3)- and α-(1→6)-linked glucosyl residues, and the relative abundance of each linkage is estimated from peak areas. Treatment of water-insoluble glucans with dextranase is found to result in water-soluble and -insoluble products, the former enriched in α-(1→6)-linkages and the latter in α-(1→3)-linkages. The structural conclusions arrived at by ¹³C-n.m.r. spectroscopy are consistent with data from methylation analysis and ¹H-n.m.r. spectroscopy.     

Synthesis of Two 3-(7′-Theophyllyl)glycals, 3-Deoxy-3-(7′-theophyllyl)-d-xylo-hex-1-enopyranose and Methyl 3-Deoxy-3-(7′-theophyllyl)-d-xylo-hex-1-enopyranuronate,and their Derivatives

Two 3-(7′-theophyllyl)glycals, (IV) and (V), were synthesized by fusion of theophylline and the appropriate glycals in the presence of p-toluenesulfonic acid. The structure and stereochemistry of the glycals were determined mainly from NMR analysis of their dihydro and 1,6-anhydro derivatives.     

Reaction of Azide Ion with 1-(2,3-Anhydrolyxofuranosyl)Uracil. Isolation of 1-(2-Amino-2-deoxy-β-D-Xylo-Furanosyl)uracil and 1-(3-Amino-3-deoxy-β-D-arabinofuranosyl)uracil

Abstract

The reaction of the 2′,3′-lyxoepoxide (1) with ammonium azide gives two products; namely, the 3′-arabino azide (2a) and in low yield 2′-xylo azide (3a). After debenzoylation and reduction the resulting mixture of amines was resolved by chromatography on a weak cation exchanger, Amberlite IRC-50, and afforded crystalline 1-(3-amino-3-deoxy-β-D-arabinofuranosyl)uracil (2c) and 1-(2-amino-2-deoxy-β-D-xylofuranosyl)uracil (3c) in the ratio of 4:1.     

Microsolvation and hydration enthalpies of CaC2O4(H2O) n (n = 0-16) and C2O4 2-(H2O) n (n = 0-14): an ab initio study

We studied hydrated calcium oxalate and its ions at the restricted Hartree–Fock RHF/6-31G* level of theory. Performing a configurational search seems to improve the fit of the HF/6-31G* level to experimental data. The first solvation shell of calcium oxalate contains 13 water molecules, while the first solvation shell of oxalate ion is formed by 14 water molecules. The first solvation shell of Ca(II) is formed by six water molecules, while the second shell contains five. At 298.15 K, we estimate the asymptotic limits (infinite dilution) of the total standard enthalpies of hydration for Ca(II), oxalate ion and calcium oxalate as ?480.78, –302.78 and –312.73 kcal mol^?1, resp. The dissociation of hydrated calcium oxalate is an endothermic process with an asymptotic limit of +470.84 kcal mol^?1.

Enzymic glycosphingolipid synthesis on polymer supports. III. Synthesis of GM3, its analog [NeuNAcα(2-3)Galβ(1-4)Glcβ(1-3)Cer] and their lyso-derivatives

Two water-soluble polymers, carrying 0.24 meq g–1 of lactosyl-(1-1)-sphingosine (7) and 0.13 meq g–1 of lactosyl-(1-3)-sphingosine (8) were prepared. The polymers served as acceptors in the -(2-3)-sialyltransferase reaction (up to 55.3 and 38.5% transfer yields, respectively). Subsequent photolysis, released compounds 11 (lyso-GM3) and 12 (lyso-GM3 analog), respectively; acylation and chromatography afforded (5-acetamido-3,5-dideoxy-D-glycero--D-galacto-2-nonulopyranosylonic acid)-(2-3)--D-galactopyranosyl-(1-4)--D-glucopyranosyl-(1-1)-(2S, 3R, 4E)-2-octadecanoylamino-4-octadecene-1,3-diol (13, GM3) and (5-acetamido-3,5-dideoxy-D-glycero--D-galacto-2-nonulopyranosylonic acid)-(2-3)--D-galactopyranosyl-(1-4)--D-glucopyranosyl-(1-3)-(2S, 3R, 4E)-2-octadecanoylamino-4-octadecene-1,3-diol (14, GM3 analogue), respectively, thus presenting a route to glycosphingolipids possessing the unusual glycosyl-(1-3)-spingosine linkage.     

Synthesis of 1-(β-D-Glycopyranosyl)-3-Deazapyrimidines from 2-Hydroxy and 2-Mercaptopyridines

Abstract

The synthesis of new 4- and 5-substituted-3-cyanopyridine nucleosides has been performed by reacting the silylated pyridines and penta-O-acetyl-α -D-glycopyranose in dichloroethane in the presence of SnCl₄. The free nucleosides were tested for their potential activity against HIV and different types of tumor.     

Cu(Nor)2·5H2O, a complex of Cu(II) with Norfloxacin: theoretic approach and biological studies. Cytotoxicity and genotoxicity in cell cultures

Norfloxacin is a fluoroquinolone antibiotic used in the treatment of bacterial infections. In this article, we studied the potential antitumoral action of a complex of Norfloxacin with Cu(II), Cu(Nor)₂·5H₂O on osteosarcoma cells (UMR106) and calvaria-derived cells (MC3T3-E1), evaluating its cytotoxicity and genitoxicity. We have also elucidated the more stable conformation of this complex under physiologic conditions by Molecular Dynamic simulations based on the model of the canonical ensemble and PM6 force field. When solvent effect was taken into account, the complex conformation with both carbonyl groups in opposite sides displayed lower energy. Cu(Nor)₂·5H₂O caused an inhibitory effect on the proliferation on both cell lines from 300 μM (P < 0.01). Nevertheless, the decline on cell proliferation of UMR106 cells was more pronounced (45 % vs basal) than in MC3T3-E1 cells (20 % vs basal) at 300 μM (P < 0.01). Cu(Nor)₂·5H₂O altered lysosomal metabolism (Neutral Red assay) in a dose-dependent manner from 300 μM (P < 0.001). Morphological studies showed important transformations that correlated with a decrease in the number of cells in a dose-dependent manner. Moreover, Cu(Nor)₂·5H₂O caused statistically significant genotoxic effects on both osteoblast cell lines in a lower range of concentrations (Micronucleus assay) (P < 0.05 at 10 μM, P < 0.001 from 25 to 50 μM). UMR106 cells displayed a dose-related genotoxic effect between 5 and 25 μM while the MC3T3-E1 cells showed a narrower concentration dependent range. Altogether, these results suggest that Cu(Nor)₂·5H₂O is a good candidate to be further evaluated for alternative therapeutics in cancer treatment.     

Photogeneration of singlet oxygen (1O2) and free radicals (Sen·-, O·-2) by tetra-brominated hypocrellin B derivative

To improve photodynamic activity of the parent hypocrellin B (HB), a tetra-brominated HB derivative (compound 1) was synthesized in high yield. Compared with HB, compound 1 has enhanced red absorption and high molar extinction coefficients. The photodynamic action of compound 1, especially the generation mechanism and efficiencies of active species (Sen^·-, O^·-₂ and ¹O₂) were studied using electron paramagnetic resonance (EPR) and spectrophotometric methods. In the deoxygenated DMSO solution of compound 1, the semiquinone anion radical of compound 1 is photogenerated via the self-electron transfer between the excited and ground state species. The presence of electron donor significantly promotes the reduction of compound 1. When oxygen is present, superoxide anion radical (O^·-₂) is formed via the electron transfer from Sens^·- to the ground state molecular oxygen. The efficiencies of Sens^·- and O^·-₂ generation by compound 1 are about three and two times as much as that of HB, respectively. Singlet oxygen (¹O₂) can be produced via the energy transfer from triplet compound 1 to ground state oxygen molecules. The quantum yield of singlet oxygen (¹O₂) is 0.54 in CHCl₃ similar to that of HB. Furthermore, it was found that the accumulation of Sens^·- would replace that of O^·-₂ or ¹O₂ with the depletion of oxygen in the sealed system.     

Stereoselective Synthesis of 1- and 2-O-α-d-Cellotriosyl-3-deoxy-2(R)- and 2(S)-glycerols Related to Rhynchosporoside

The stereoselective synthesis of 1- and 2-O-α-d-cellotriosyl-3-deoxy-2(R)- and 2(S)-glycerols, which determined the structure of rhynchosporoside produced by Rhynchosporium secalis, and their phytotoxicity toward the host plant (Hordeum vulgare) are described in detail.     

Synthetic mucin fragments. Methyl 6-O-(2-acetamido-2-deoxy-β-D-glycopyranosyl)-β-D-galactopyranoside,methyl 3,4-di-O-(2-acetamido-2-deoxy-β-D-glycopyranosyl)-β-D-galactopyranoside,and methyl O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-(1 å 3)-O-β-D-galactopyranosyl-(1 å 3)-O-(2-acetamido-2-deoxy-β- D-glucopyranosyl)-(1 å 3)-β-D-galactopyranoside

Condensation of methyl 2,6-di-O-benzyl-β-d-galactopyranoside with 2-methyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-α-d-glucopyrano)-[2,1,-d]-2-oxazoline (1) in 1,2-dichloroethane, in the presence of p-toluenesulfonic acid, afforded a trisaccharide derivative which, on deacetylation, gave methyl 3,4-di-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-2,6-di-O-benzyl-β-d- glactopyranoside (5). Hydrogenolysis of the benzyl groups of 5 furnished the title trisaccharide (6). A similar condensation of methyl 2,3-di-O-benzyl-β-d-galactopyranoside with 1 produced a partially-protected disacchraide derivative, which, on O-deacetylation followed by hydrogenolysis, gave methyl 6-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-β-d-glactopyranoside (10). Condensation of methyl 3-O-(2-acetamido-4,6-O-benzylidene-2-deoxy-β-d-glucopyranosyl)-2,4,6-tri-O-benzyl-β-d- galactopyranoside with 3-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-2,4,6-tri-O-acetyl-α-d-galactopyranosyl bromide in 1:1 benzene-nitromethane in the presence of powdered mercuric cyanide gave a fully-protected tetrasaccharide derivative, which was O-deacetylated and then subjected to catalytic hydrogenation to furnish methyl O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-(1→3)-O-β-d-galactopyranosyl-(1å3)-O-(2-acetamido-2-deoxy- β-d-glucopyranosyl)-(1å3)-β-d-galactopyranoside (15). The structures of 6, 10, and 15 were established by ¹³C-n.m.r. spectroscopy.     

Synthesis of 7-(β-D-Glucopyranosyl)-6-Thiotheophylline and 7-(α-D-Arabinopyranosyl)-6-Thiotheopwlline. Conformational Study of the Peracetyl Derivatives.

Abstract

The synthesis of two 7-glycosyl-6-thiotheophylline nucleosides where the sugar moieties are β-D-glucose (1b) and α-D-arabinose (2b) is reported. The syn-anti equilibrium of the peracetyl derivatives was studied by the line-shape and the ¹H-NMR nOe methods, and molecular mechanics analysis.     

Discovery of trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,a potent and orally active neuropeptide Y Y5 receptor antagonist

A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1 mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.     

2-Phenyl and 2-heterocyclic-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridines as inhibitors of TGF-β1 and activin A signalling

Novel inhibitors of TGF-β1 and activin A signalling based on a 2-aryl-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridine pharmacophore have been synthesised. Compounds containing phenyl or aromatic nitrogen heterocycle substituents inhibited both types of signalling with HEK-293T cells in culture, with a selectivity preference for TGF-β1. Synthetic compounds containing pyridin-3-yl, pyrazol-4-yl, pyrazol-1-yl or 1H-imidazoyl-1-yl substituents exhibited structural and functional attributes suitable for further investigation related to the development of more potent TGF-β inhibitors.     

Synthesis and biological evaluation of 3-(azolylmethyl)-1H-indoles and 3-(α-azolylbenzyl)-1H-indoles as selective aromatase inhibitors

This present study identifies a number of azolyl-substituted indoles as potent inhibitors of aromatase. In the sub-series of 3-(azolylmethyl)-1H-indoles, four imidazole derivatives and their triazole analogues were tested. Imidazole derivatives 11 and 14 in which the benzyl moiety was substituted by 2-chloro and 4-cyano groups, respectively, were the most active, with IC₅₀ values ranging between 0.054 and 0.050 μM. In the other sub-series, eight 3-(α-azolylbenzyl)-1H-indoles were prepared and tested. Compound 30, the N-ethyl imidazole derivative, proved to be an aromatase inhibitor, showing an IC₅₀ value of 0.052 μM. All target compounds were further evaluated against 17α-hydroxylase/C17,20-lyase to determine their selectivity profile.