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Biomedical subjects

D Shugar

Publications and source records attributed to D Shugar.

At least 127 records · Page 7Linked to original sources
PubMed1979

Correlations of conformational parameters and equilibrium conformational states in a variety of beta-D-arabinonucleosides and their analogues.

H nuclear magnetic resonance spectroscopy has been applied to a study of the conformations of a variety of purine and pyrimidine beta-D-arabinofuranosyl nucleosides. The experimental results, together with data collected from the literature, demonstrated the existence of reasonably good correlations between the coupling constants made it possible to define more accurately, than hitherto possible, the conformational states between which equilibria exist in solution. The equilibrium for the arabinonucleosides differs from that previously established for ribonucleosides; in particular, structural modifications and solvent effects may appreciably modify the conformational states between which equilibria exist. Preliminary measurements on some arabinosides in the syn conformation about the glycosidic bond indicated that these do not conform to the foregoing correlations, and will require separate study. A correlation has also been established between the conformation of the arabinose ring and that of the exocyclic 5'-CH2OH group. For both purine and pyrimidine arabinonucleosides, the conformational state 3E of the arabinose ring coexists to some extent with a gauche-gauche conformation of the exocyclic 5'-CH2OH, as in the case of pyrimidine (but not purine) ribonucleosides. Application of the foregoing to some biological problems is described.

Arabinonucleosides↗
PubMed1979

Genetic evidence for the nature, and excision repair, of DNA lesions resulting from incorporation of 5-bromouracil.

Escherichia coli mutants defective in DNA uracil N-glycosidase (ung-) or endonuclease VI active against apurinic/apyrimidinic sites in DNA (xthA-) exhibit enhanced sensitivity towards 5-bromodeoxyuridine relative to the wild type strain, pointing to involvement of these enzymes in repair of bromouracil-induced lesions in DNA. Mutants defective in DNA polymerase I, either in polymerizing activity (polAl-) or (5' leads to 3')-exonuclease activity (polA107-) exhibit unusually high sensitivity (including marked lethality) in the presence of 5-bromodeoxyuridine. The results indicate that DNA polymerase I, and its associated (5'--3')-exonuclease activity, are involved in repair of bromouracil-induced lesions and are not readily replaced, if at all, by DNA polymerases II and III. Thermosensitive mutant in DNA ligase gene (lig ts7) shows high sensitivity towards 5-bromodeoxyuridine at 42 degrees C indicating the role of the enzyme in repair of bromouracil-induced lesions in DNA. Involvement of DNA uracil N-glycosidase, and endonuclease active against apurinic/apyrimidinic sites in recognition and repair of 5-bromouracil-induced damage permits of some inferences regarding the nature of this damage (lesions), in particular dehalogenation of incorporated bromouracil to uracil residues.

Bromodeoxyuridine↗
PubMed1979

Studies on the mechanism of antiviral action of 1-(beta-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (ribavirin).

Syntheses are described for the 5'-phosphates of the 2'- and 3'-O-methylribavirins (2a and 2b) and the methyl ester of ribavirin 5'-phosphate (3). The 5'-phosphate of 1-beta-(D-ribofuranosyl)-1,2,4-triazole (2d) was obtained via the 3-carboxyl derivative of ribavirin 5'-phosphate (2c). Compounds 2a, 2b, and 2d were inactive as inactive as inhibitors of IMP dehydrogenase under conditions where the parent ribavirin 5'-phosphate (2) was an effective inhibitor. Weak inhibitory activity was exhibited by 3 (Ki approximately 200 muM) and 2c (K1 approximately 70 muM). Under conditions where ribavirin (1) is effectively phosphorylated by rat liver nucleoside kinase, the 2'- and 3'-O-methylribavirins (1a and 1b), the 3-carboxylate of ribavirin (1c), and the riboside of 1,2,4-triazole (1d) were totally inactive. The overall results are fully consistent with the lack of antiviral activity of 1a and 1b, while the specificity of ribavirin as an antiviral agent is further underlined by the behavior of the methyl ester 3.

Animals↗
PubMed1979

Relative potencies of different anti-herpes agents in the topical treatment of cutaneous herpes simplex virus infection of athymic nude mice.

Thirteen established anti-herpes compounds have been directly compared in a single assay system for their effects on the development of herpetic skin lesions, and mortality associated therewith, in athymic nude (nu/nu) mice inoculated intracutaneously with herpes simplex virus type 1 (KOS). When applied topically (at 1% in a water-soluble ointment), phosphonoacetic acid, E-5-(2-bromovinyl)-2'-deoxyuridine, acycloguanosine, and trisodium phosphonoformate emerged as the most active agents.

Animals↗
PubMed1979

Conformation of exocyclic amino groups in purines and pyrimidines: crystal structure and conformation of 1-methyl-N4-hydroxycytosine hydrochloride.

The hydrochloride salt of 1-methyl-N4-hydroxycytosine crystallizes in the triclinic space group P1 with cell dimensions: a = 8.232(1), b = 9.293(1), c = 5.416(1) A (1 A = 0.1 nm); alpha = 91.95(1), beta = 91.72(2), gamma = 71.56(1) degrees (SE in parentheses). The structure was solved by direct methods and refined to R = 3.7% for 1514 reflections. Despite the absence of an intramolecular hydrogen bond in the solid state, the N4-hydroxy substituent is syn to the ring N(3). This conformation, which probably prevails also in the neutral form, is of relevance to the mechanism of attack of cytosine by hydroxylamine, known to involve predominantly the cytosine cation, as well as to the mechanism of hydroxylamine mutagenesis. Such conformational aspects are also relevant to other phenomena, including translation and restriction.

Crystallization↗
PubMed1979

Methylation and tautomerism of 1-substituted 5-fluorocytosines.

1. Methylation and thiation of 5-fluorouracil led to 1,3-dimethyl-5-fluoro-4-thiouracil, the amination of which was examined under various conditions. At high dilution, and in the presence of a large excess of NH3, 1,3-dimethyl-5-fluoro-4-thiouracil was converted to 1,3-dimethyl-5-fluorocytosine in 60% yield. 2. Two procedures were employed for methylation of 5-fluoro-1-methylcytosine and 5-fluorocytidine. Treatment of each of these with diazomethane in alcohol-ether gave a complex mixture of products, the major one of which was the desired 3-methyl derivative. By contrast, treatment with methyl iodide in dimethylsulphoxide led exclusively to the 3-methyl derivatives in much better yeilds. 3. Ultraviolet absorption spectra and pKa values are presented for 1-substituted N-methyl-5-fluoro- and 5-bromo-cytosines. The basicity method was applied to determine the tautomeric equilibrium constants of the 1-substituted 5-halogenocytosines. The results show that the proportion of the imino forms of these compounds is of the same order of magnitude as for 1-substituted cytosines, and hence is unlikely to account for the observed mutagenic effects of 1-substituted 5-halogenocytosines.

Amination↗
PubMed1979

Structure and tautomerism of the neutral and monoanionic forms of 2-thiouracil, 2,4-dithiouracil, their nucleosides, and some related derivatives.

Ultraviolet and infrared spectrophotometric techniques have been utilized to demonstrate that the monoanionic form of 2-thiouracil in aqueous medium consists of an equilibrium mixture of two tautomeric monoanions, one due to dissociation of the N1 proton, the other to dissociation of the N3 proton, in the approximate ratio 1:1. In contrast to 2,4-diketopyrimidines, and 4-thiouracil, where monoanion formation involves charge delocalization, the two tautomeric monoanions of 2-thiouracil appear to have the charge localized on the O4 position. The neutral forms of 2,4-dithiouracil and 2,4-dithiouridine are in the dithione form in both aqueous and non-aqueous media. The monoanionic form of 2,4-dithiouracil consists of a mixture of two tautomeric monoanions, the predominant one of which is that with the proton on the ring N3, and with charge delocalization on both isomeric monoanions. Such charge delocalization is also present in the monoanion of 2,4-dithiouridine. For the reference compound 2-methylthiopyrimidone-4, the dominant, virtually exclusive, form in chloroform is that with the hydrogen localized on the ring N3, whereas in aqueous medium there is a 1:1 equilibrium mixture of two neutral tautomeric forms, one with the hydrogen on N3, the other with the hydrogen on N1.

Chemical Phenomena↗
PubMed1979

Solution conformations of the antimetabolite 9-beta-D-xylofuranosyladenine and its 8-bromo analogue.

An analysis has been made, with the aid of 1H NMR spectroscopy, of the solution conformation of the known antimetabolite, 9-beta-D-xylofuranosyladenine (xyloA), and of its 8-bromo analogue. For xyloA, the results point to a strong preference for the sugar ring of the conformation type N (C(3') endo), a relatively low population of the gauche-gauche rotamer of the exocyclic 5'-CH2OH, and a preference for the conformation anti about the glycosidic bond. For 8-bromo-xyloA, the preference for the type N conformation of the sugar ring is less marked, and the preferred conformation about the glycosidic bond is syn. The conformation of the sugar ring in the foregoing xylonucleosides consequently differs appreciably from that for the corresponding ribonucleosides, which adopt preferentially the type S (C(2')endo) and gauche-gauche conformations. Comparison with previously reported results for O'-methyl derivatives of xyloA points to the similarity in conformational properties of all of these. In contrast to arabinonucleosides with free 2' and 5' hydroxyls, the conformation of xyloA is relatively unaffected in strongly alkaline medium where the sugar hydroxyl(s) dissociate. Under these conditions, there is no formation of an intramolecular hydrogen bond such as might have been anticipated from X-ray diffraction studies in the solid state.

Adenosine↗
PubMed1978

A purine nucleoside unequivocally constrained in the syn form. Crystal structure and conformation of 8-(alpha-hydroxyisopropyl)-adenosine.

Crystals of 8-(alpha-hydroxyisopropyl)-adenosine dihydrate, C13H19N5O5.2H2O, belong to the monoclinic space group P21. Cell dimensions are a = 8.259 (1), b = 11.117 (2), c = 9.663 (1) A, beta = 109.65 (2) degrees. Intensity data were collected on a four-circle diffractometer and the structure was solved by direct methods. Block diagonal least-squares refinement led to R = 0.031 for 1467 reflections. The glycosyl torsion angle chiCN is 241.4 degrees, corresponding to a syn conformation. The conformation of the exocyclic C(4')-C(5') bond is gauche-gauche and the sugar pucker is C(2') endo. It is considered that the bulky, tetrahedral, neutral 8-substituent, with an effective van der Waals radius of 3.5--4.0 A, provides an adenosine analogue which should exhibit the syn conformation about the glycosidic bond in solution as well as in solid state, irrespective of the nature of the sugar pucker. It should therefore be suitable for studies of interactions with enzyme systems requiring the anti conformation of the nucleoside or nucleotide.

Adenosine↗
PubMed1978

5-Propyl-2'-deoxyuridine: a specific anti-herpes agent.

In both primary rabbit kidney cells and human skin fibroblasts, 5-propyl-2'-deoxyuridine proved inhibitory to herpes simplex virus at a concentration as low as 1 micrograms/ml, whereas concentrations higher than 200 micrograms/ml were required to inhibit vaccinia virus replication or normal cell metabolism.

Animals↗
PubMed1977

alpha-Nucleosides in biological systems. Crystal structure and conformation of alpha-cytidine.

The structure of alpha-cytidine, C9H13N3O5, monoclinic with space group C2 and cell parameters a = 20.064 (3) A, b = 7.100 (1) A, c = 7.860 (2) A, beta = 104.60 (2) degrees, Z = 4, was determined by X-ray diffraction using a combination of direct methods, Patterson and difference Fourier techniques and refined by block-diagonal least-squares to a final R of 0.033 for 1002 reflections measured on a diffractometer. The glycosidic torsional angle, chiCN = -28.4 degrees, is in the anti region; the sugar pucker is C(2')exo-C(3')endo in a nearly pure 32H twist; and the conformation of C(4')-C(5') is gauche-gauche. The molecules are bound by hydrogen bonds in the lattice with little likelihood of base-stacking interactions. The molecular features of the compound are compared and contrasted with those of its naturally occurring beta-anomer, and some biological implications of this structure, and alpha-nucleosides in general, are discussed.

Cytidine↗