38716-09-5

Upstream product

• 50-89-5 thymidine 
• 153363-17-8 5-Hydroxy-1-{(2R,4S,5R)-4-hydroxy-5-[(4-methoxy-phenyl)-diphenyl-methoxymethyl]-tetrahydro-furan-2-yl}-5-methyl-imidazolidine-2,4-dione 
• 40733-26-4 3',5'-O-di(tert-butyldimethylsilyl)thymidine 
• 38709-49-8 trans-(5R,6R)-5-hydroperoxy-6-hydroxy-5,6-dihydrothymidine 
• 96221-62-4 trans-(5R,6R)-6-hydroxy-5-(2,2,6,6-tetramethyl-4-oxo-1-piperidinyl-N-oxide)-5,6-dihydrothymidine 
• 96221-62-4 trans-(5S,6S)-6-hydroxy-5-(2,2,6,6-tetramethyl-4-oxo-1-piperidinyl-N-oxide)-5,6-dihydrothymidine 

Relevant academic research and scientific papers

Isomerization of 5-Hydroxy-5-methylhydantoin 2′-Deoxynucleoside into α-Furanose, β-Furanose, α-Pyranose, and β-Pyranose Anomers

Oxidative damage is one of the most frequent types of DNA damage resulting from biologically generated oxygen or nitrogen reactive species. Hydroxyl radicals, one electron oxidants, and various chemical oxidants, such as permanganate and ozone, react with pyrimidine bases in DNA, cytosine and thymine, to produce 5-hydroxyhydantoin derivatives. 5-Hydroxyhydantoin modifications are interesting because they undergo ring-chain tautomerism into a pair of diastereomers via an open chain carbonyl intermediate. Here, we show that purified diastereomers of N1-(2-deoxy-β-d-erythro-pentofuranosyl)-5-hydroxy-5-methylhydantoin not only undergo isomerization into a mixture of 5R and 5S diastereomers of the hydantoin ring but also into three additional pairs of diastereomers, in which the sugar moiety transforms into α-furanose, β-pyranose, and α-pyranose anomers. The novel 5-hydroxy-5-methylhydantoin derivatives were characterized by extensive NMR analyses. Further studies indicate that isomerization is greatly suppressed at pH 6 compared to that at higher pH. A novel mechanism of isomerization is proposed to account for the formation of nucleoside anomers at neutral pH, which involves ring-chain tautomerism of both the hydantoin and sugar moieties. Last, the isomerization of β-furanose into the corresponding α-furanose is shown to take place in purified DNA, albeit to a slower extent than that in solution. The ability of 5-hydroxyhydantoin nucleosides to undergo isomerization may complicate the biological processing of this damage in cellular DNA.

First characterisation of two important postulated intermediates in the formation of a HydT DNA lesion, a thymidine oxidation product

A number of environmental pollutants and endogenous oxidation agents form 1-(2-deoxy-β-d-ribofuranosyl)-5-hydroxy-5-methylhydantoin (HydT), an important DNA lesion resulting from thymidine oxidation. In this paper, two intermediates, postulated in the formation of HydT, have been characterised for the first time. The first, N1-formyl-N3-pyruvoylurea intermediate, was produced by the ozonolysis reaction of 2′,3′,5′-tri-O-acetylribo-, 3′,5′-di-O-TBS- and N3,O3′,O5-tribenzyl-protected thymidines and was shown to produce, upon decomposition and depending on the protecting group and the conditions, HydT alone, or together with protected-β-d-ribofuranosyl-N1-formylurea and formamide products. In addition, the second and long sought, open-chain-pyruvoylurea intermediate, was produced through de novo synthesis in protected β-d-ribofuranosyl-, 2-deoxy-β-d-ribofuranosyl- and 2-deoxy-β-d-ribopyranosyl systems. The conditions that induce the cyclization to the hydantoin ring of HydT have been determined. The chemistry utilised in the de novo synthesis is suitable for generating isotopically labelled HydT, as a reference in isotope-dilution-aided quantification of DNA damage.

The reactions of thymine and thymidine with ozone

The ozonolysis of thymine and thymidine has been investigated by a product study complemented by kinetic studies using spectrophotometry, conductometry and stopped-flow with optical and conductometric detection. Material balance has been obtained. Ozonolysis of thymine (k = 3.4 × 104 dm3 mol-1 s-1) leads to the formation of the acidic (pKa = 4) hydroperoxide 1-hydroperoxymethylene-3-(2-oxopropanoyl)urea 5 (～34%), neutral hydroperoxides (possibly mainly 1-hydroperoxyhydroxymethyl-3-(2-oxopropanoyl)urea 6, total ～41%) and H2O2 (25%, with corresponding formation of 1-formyl-5-hydroxy-5-methylhydantoin 11). The organic hydroperoxides decay (～1.1 × 10-3 s-1 at 20°C, 1.3 × 10-4 s-1 at 3°C) releasing formic acid (formation of 5-hydroperoxy-5-methylhydantoin 18) and also to some extent H2O2 (and 11). After 100 min, the formic acid yield is 75%. Upon treatment at high pH, it increases to 100%. Reduction of the organic hydroperoxides with bis(2-hydroxyethyl) sulfide (k = 50 dm3 mol-1 s-1) leads to 11 whose subsequent treatment with base yields 5-hydroxy-5-methylhydantoin 13 in 100% yield. It is suggested that the Criegee ozonide formed upon reaction with ozone at the C(5)-C(6) double bond opens heterolytically in two directions with subsequent opening of the C(5)-C(6) bond. In the preferred route (75%), the positive charge resides at C(6). Deprotonation at N(1) gives rise to 5, while its reaction with water yields 6. Loss of formic acid yields 5-hydroperoxy-5-methylhydantoin 18. Reduction of 5 and 6 with the sulfide yields 11. In the minor route (25%), the positive charge remains at C(5) followed by a reaction with water. The resulting α-hydroxy hydroperoxide rapidly loses H2O2 (formation of 11). In basic solution, singlet dioxygen is formed (8%). The concomitant product, 5,6-dihydroxy-5,6-dihydrothymine has been detected. In the ozonolysis of thymidine, the rapid formation of conductance (k = 0.55 s-1) is due to the release of acetic acid (18%). In this reaction a short-lived hydroperoxide is destroyed. As a consequence of this, 25 s after ozonolysis the total hydroperoxide yield is only ～78% (including 8% H2O2). The products corresponding to acetic acid are suggested to be CO2 and N-(2-deoxy-β-D-erythropentofuranosyl)formylurea 22. A number of organic hydroperoxides have been detected by HPLC by post-column derivatisation with iodide. An acidic hydroperoxide such as 5 in the case of thymine is not among the products. Upon sulfide reduction, the organic hydroperoxides yield mainly (43-50%) N1-(2-deoxy-β-D-erythropentofuranosyl)-5-hydroxy-5- methylhydantoin 23. The reasons for some striking differences in the ozonolyses of thymine and thymidine are discussed.

Repair and coding properties of 5-hydroxy-5-methylhydantoin nucleosides inserted into DNA oligomers

1-(2-Deoxy-β-D-erythro-pentofuranosyl)-5-hydroxy-5-methylhydantoin (5- OH-5-Me-dHyd) (3) has been shown to be a major oxidation product of thymidine formed upon exposure of DNA to ·OH-radical and excited photosensitizers. To investigate the biological and

Thymidine hydroperoxides: Structural assignment, conformational features, and thermal decomposition in water

The primary products of DNA oxidation by free radicals are thymidine hydroperoxides, which include eight diastereomers of 5(6)-hydroxy-6(5)-hydroperoxy-5,6-dihydrothymidine and 5-(hydroperoxymethyl)-2'-deoxyuridine. The hydroperoxides were prepared by trifluoroperacetic acid oxidation of thymidine, which gave the four trans and ics diastereomers of 5-hydroxy-6-hydroperoxy-5,6-dihydrothymidine, and sensitized photooxidation of thymidine with 2-methyl-l,4-naphthoquinone and near-UV light, which gave the four trans and cis diasteromers of 5-hydroperoxy-6-hydroxy-5,6-dihydrothymidine as well as 5-(hydroperoxymethyl)-2'-deoxyuridine. 1H and 13C NMR analyses suggested that the pyrimidine ring of thymidine 5,6-hydroxyhydroperoxides adopts four puckered conformations in which the orientations of the C6 hydroxy or hydroperoxy substituents are predominantly axial. The kinetics of decomposition of 5(6)-hydroxy-6(5)-hydroperoxy-5,6-dihydrothymidine were studied at 22, 37, and 55°C in ultrapure water. The cis diastereomers of each group were generally found to more stable than the corresponding trans diastereomers. The enthalpy (ΔH≠) and entropy (ΔS≠) of decomposition were in the range of 22.9-25.2 kcal mol-1 (ΔH≠) and -7.4-+3.7 cal mol-1 deg-1 (ΔS≠) for 5-hydroxy-6-hydroperoxy-5,6-dihydrothymidine and in the range 28.5-35.2 kcal mol-1 (ΔH≠) and +9.7-+30 cal mol-1 deg-1 (ΔS≠) for 5-hydroperoxy-6-hydroxy-5,6-dihydrothymidine. The mechanism of decomposition was studied by analysis of stable and intermediate products: the major decomposition products of the trans and cis diasteromers of 5-hydroxy-6-hydroperoxy-5,6-dihydrothymidine were N-(2-deoxy-β-D-erythro-pentofuranosyl)-5-hydroxy-5-methylbarbituric acid and N1-(2-deoxy-β-D-erythro-pentofuranosyl-N3-tartronoylurea in neutral aqueous solutions; in contrast, the trans and cis diastereomers of 5-hydroperoxy-6-hydroxy-5,6-dihydrothymidine were observed to undergo isomerization and ultimately decomposed into the 5R* and 5S* diastereomers of N-(2-deoxy-β-d-erythro-pentofuranosyl)-5-hydroxy-5-methylhydantoin. On the basis of the above results, the mechanism of decomposition was proposed to involve either dehydration for 5-hydroxy-6-hydroperoxy-5,6-dihydrothymidine or ring-chain tautomerism followed by α-cleavage of an intermediate hydroperoxy aldehyde and subsequent ring closure for 5-hydroperoxy-6-hydroxy-5,6-dihydrothymidine.

Oxydation de la thymidine par l'ozone: comparaison avec l'action des radicaux hydroxyles

The reaction of the base moiety of the thymidine, one of the pyrimidinyl nucleosides, with ozone was examined.This reaction gives rise to five nucleosides which were isolated and characterised.The comparison with the current knowledge of the hydroxyl radical-mediated oxidations of thymidine, in aerated aqueous solution, shows that the ozone oxidation is specific.Indeed, the identified products obtained by the ozonolysis resulted from the opening of the C5-C6 bond.

Ozonolysis of pyrimidine nucleosides

Cytidine, uridine, and thymidine are transformed into the ring-contracted 1-substituted derivatives by ozone. A plausible mechanism is proposed.