A Platinum(IV) Complex Oxidizes Guanine to 8-Oxo-Guanine in DNA and RNA
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A platinum(IV) complex with a high reduction potential, d,l-1,2-diaminocyclohexyltetrachloroplatinum(IV) (PtIV(dach)Cl4), oxidizes guanine in guanosine-5'-monophosphate (GMP), 2'-deoxyguanosine-5'-monophosphate (dGMP), d(GG), and a double-stranded oligonucleotide to 8-oxo-guanine. To the best of our knowledge, this is the first report that provides unambiguous evidence of DNA oxidation by a PtIV complex. This oxidative damage may differentiate the anticancer activity of PtIV complexes from their PtII analogues.Keywords:
Deoxyguanosine
Guanosine monophosphate
Deoxyguanosine
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The intermediates in the browning reaction of triose reductone (I) with guanine, guanosine, 2′(3′)- or 5′-guanylic acid were isolated. The reaction of I with guanine in 4 n HCl at 65°C for about 1 hr produced only a brown tricyclic compound, 1 ,N2-(2-hydroxypropenylidene)- guanine or 7-hydroxy-10-oxo-9,10-dihydropyrimido[1,2-a]purine (III) with the analogous structure to natural occurring Y bases, whereas that at room temperature yielded a labile light yellow intermediate, N2-(3-oxo-2-hydroxypropenyl)guanine (II) with the enaminol structure as a mixture with III. The ratio of II to III was about 1:1. The isolation of II in pure form was difficult because of its instability. On the other hand, the reaction of I with guanosine, 2′(3′)- or 5′-guanylic acid in 4 n HCl at room temperature gave the reductive intermediate with the same enaminol structure as II, N2-(3-oxo-2-hydroxypropenyl)guanosine (IV), N2-(3-oxo-2-hydroxypropenyl)2′(3′)-guanyIic acid (V) or N2-(3-oxo-2-hydroxypropenyl)5′-guanylic acid (VI), respectively.
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Deoxyguanosine
Inosine
Deoxycytidine kinase
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Intermediates in the browning reaction of triose reductone with guanine, guanosine or guanylic acid.
The intermediates in the browning reaction of triose reductone (I) with guanine, guanosine, 2'(3')- or 5'-guanylic acid were isolated. The reaction of I with guanine in 4 N HCI at 65°C for about 1 hr produced only a brown tricyclic compound, 1, N2-(2-hydroxypropenylidene)-guanine or 7-hydroxy-10-oxo-9, 10-dihydropyrimido[1, 2-a] purine (III) with the analogous structure to natural occurring Y bases, whereas that at room temperature yielded a labile light yellow intermediate, N2-(3-oxo-2-hydroxypropenyl)guanine (II) with the enaminol structure as a mixture with III. The ratio of II to III was about 1:1. The isolation of II in pure form was difficult because of its instability. On the other hand, the reaction of I with guanosine, 2'(3')- or 5'-guanylic acid in 4 N HCl at room temperature gave the reductive intermediate with the same enaminol structure as II, N2-(3-oxo-2-hydroxypropenyl)guanosine (IV), N2-(3-oxo-2-hydroxypropenyl) 2' (3')-guanylic acid (V) or N2-(3-oxo-2-hydroxypropenyl) 5'-guanylic acid (VI), respectively.
Guanosine monophosphate
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Convenient synthesis of rac-glycidaldehyde from rac-but-3-ene-1,2-diol and (R)-glycidaldehyde from D-mannitol are described. (R)-Glycidaldehyde (1) reacts with guanosine in water (pH 4-11, faster reaction at higher pH) to give initially 6(S)-hydroxy-7(S)-(hydroxymethyl)-3-(beta-D-ribofuranosyl)-5,6,7- trihydroimidazo[1,2-alpha]purin-9(3H)-one (7a) and 6(S),7(R)-dihydroxy-3-(beta-D-ribofuranosyl)-5,6,7,8- tetrahydropyrimido[1,2- alpha]purin-10(3H)-one (8a). The former decomposes to 7-(hydroxymethyl)-5,9-dihydro-9-oxo-3-(beta-D-ribofuranosyl)imidazo[1,2- alpha]purine (3a), 5,9-dihydro-9-oxo-3-(beta-D-ribofuranosyl)imidazo[1,2-alpha]purine (5a, 1,N2-ethenoguanosine), and formaldehyde, while the latter adduct is relatively stable. The position of the hydroxymethyl group on the imidazo ring of 7-(hydroxymethyl)-5,9-dihydro-9-oxo-3-(beta-D-ribofuranosyl)imidazo-[1,2 - alpha]purine was proved by 13C NMR analysis of adducts derived from [1-15N]guanosine and [amino-15N]guanosine. At longer reaction times, the adduct 7,7'-methylenebis[5,9-dihydro-9-oxo-3-(beta-D-ribofuranosyl)imidazo[1,2- alpha]purine (4a) is formed from guanosine and glycidaldehyde. The structure analysis of this adduct was also aided by 13C NMR analysis of the 15N-labeled adduct derived from [1-15N]guanosine. Analogous adducts were obtained from the reaction between glycidaldehyde and deoxyguanosine. Mechanisms of formation of the adducts from glycidaldehyde and guanosine/deoxyguanosine are proposed and supported by model studies with simple amines. The formaldehyde produced in the reactions described reacts with guanosine to give the known adduct N2-(hydroxymethyl)guanosine (9).
Deoxyguanosine
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Abstract— The uptake of [ 14 C]guanine and some of its [ 14 C]‐labelled derivatives into rat brain was studied in vivo and in vitro. In vivo guanine, guanosine, and hypoxanthine penetrated the brain of adult rats to a very small extent. Inosine was taken up somewhat better. In young animals, also, guanosine was taken up poorly, but guanine was taken up fairly well. When guanine was administered to adult animals, only guanine was found in the brain. In young animals, by contrast, radioactivity from guanine appeared in guanosine and in guanine nucleotides, but no free guanine was found. In vitro guanine was taken up much better and, in fact, remained mostly as guanine in slices from 10‐day‐old rats. The in vitro conversion of guanine to GMP and its incorporation into RNA was unimpaired by the addition of unlabelled guanosine, an indication that guanine was converted directly to GMP. The uptake of guanine in vitro was not subject to competitive inhibition or influenced by the presence of dinitrophenol. This finding suggested that guanine entered the slice by simple diffusion.
Hypoxanthine
Inosine
Xanthine
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Guanosine deaminase and guanine deaminase were partially purified from tea leaves. The optimum activity of guanosine deaminase was observed at pH 7.5 and that of guanine deaminase was at pH 7.0–7.5 and 8.5. Guanosine deaminase was an unstable enzyme. The activities of these deaminases were significantly inhibited by heavy metals. Molecular weights of guanosine deaminase and guanine deaminase as measured by gel filtration were about 18,000 and 54,000, respectively. The Km for the respective substrates, guanosine and guanine, were 9.5 μm and 41.7 μm. Guanosine deaminase was considered to catalyze the deamination of 2′-deoxyguanosine besides guanosine. It is suggested that guanosine deaminase as well as guanine deaminase in tea leaves not only acts on the catabolic pathway, but also is involved in the biosynthesis of caffeine from guanosine or guanine nucleotides.
AMP deaminase
Deoxyguanosine
Guanosine monophosphate
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A platinum(IV) complex with a high reduction potential, d,l-1,2-diaminocyclohexyltetrachloroplatinum(IV) (PtIV(dach)Cl4), oxidizes guanine in guanosine-5'-monophosphate (GMP), 2'-deoxyguanosine-5'-monophosphate (dGMP), d(GG), and a double-stranded oligonucleotide to 8-oxo-guanine. To the best of our knowledge, this is the first report that provides unambiguous evidence of DNA oxidation by a PtIV complex. This oxidative damage may differentiate the anticancer activity of PtIV complexes from their PtII analogues.
Deoxyguanosine
Guanosine monophosphate
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Citations (35)