- A serendipitous synthesis of 8-dimsyl-2′-deoxyguanosine
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A serendipitous synthesis of 8-dimsyl-dG (2) has been achieved along with the known 8-benzyloxy-dG (3) in a nucleophilic substitution reaction of 8-bromo-dG (1) with in situ generated dimsyl and benzyloxy sodium. Compound 3 was directly converted into the
- Nampalli, Satyam,Livshin, Inna,Kumar, Shiv
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- Efficient synthesis of 8-oxo-dGTP: A mutagenic nucleotide
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An efficient synthesis of mutagenic and oxidative DNA damage product, 8-oxo-dGTP (4) has been achieved in high yield, along with a serendipitous generation of 8-dimsyl-dG (2). In combination with dPTP (5), 8-oxo-dGTP (4) can be formulated into a kit for investigating DNA random mutagenesis. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Nampalli, Satyam,Kumar, Shiv
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- Oxidation of 5′-dGMP, 5′-dGDP, and 5′-dGTP by a platinum(IV) complex
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We previously reported that a Pt(IV) complex, [PtIV(dach)Cl4] [trans-d,l-1,2-diaminocyclohexanetetrachloroplatinum(IV)] binds to the N7 of 5′-dGMP (deoxyguanosine-5′-monophosphate) at a relatively fast rate and oxidizes it to 8-oxo-5′-dGMP. Here, we further studied the kinetics of the oxidation of 5′-dGMP by the PtIV complex. The electron transfer rate constants between 5′-dGMP and PtIV in [H8-5′-dGMP-PtIV] and [D8-5′-dGMP-PtIV] were similar, giving a small value of the kinetic isotope effect (KIE: 1.2 ± 0.2). This small KIE indicates that the deprotonation of H8 in [H8-5′-dGMP-PtIV] is not involved in the rate-determining step in the electron transfer between guanine (G) and PtIV. We also studied the reaction of 5′-dGDP (deoxyguanosine-5′-diphosphate) and 5′-dGTP (deoxyguanosine-5′-triphosphate) with the PtIV complex. Our results showed that [PtIV(dach)Cl4] oxidized 5′-dGDP and 5′-dGTP to 8-oxo-5′-dGDP and 8-oxo-5′-dGTP, respectively, by the same mechanism and kinetics as for 5′-dGMP. The PtIV complex binds to N7 followed by a two-electron inner sphere electron transfer from G to PtIV. The reaction was catalyzed by PtII and occurred faster at higher pH. The electron transfer was initiated by either an intramolecular nucleophilic attack by any of the phosphate groups or an intermolecular nucleophilic attack by free OH- in the solution. The rates of reactions for the three nucleotides followed the order: 5′-dGMP > 5′-dGDP > 5′-dGTP, indicating that the bulkier the phosphate groups are, the slower the reaction is, due to the larger steric hindrance and rotational barrier of the phosphate groups.
- Kipouros, Ioannis,Fica-Contreras, Sebastian Matias,Bowe, Gregory Joon Kee,Choi, Sunhee
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- Induction of 8-oxo-dGTPase activity in human lymphoid cells and normal fibroblasts by oxidative stress
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The pre-mutagen 8-Oxo-2'-deoxyguanosine-5'-triphosphate (8-oxo-dGTP) is formed during normal cellular metabolism and its incorporation into DNA leads to transversion mutations. Human cells possess the hMTH-1 gene encoding the enzyme 8-oxo-dGTPase, which catalyzes the hydrolysis of 8-oxo-dGTP to the corresponding 8-oxo-dGMP, preventing mutations. To elucidate the involvement of 8-oxo-dGTPase in carcinogenesis, we studied hMTH-1 gene expression and enzyme activity in response to oxidative stress to human skin fibroblasts and Jurkat cells. In fibroblasts, ranges from 0 to 100 μM H2O2 caused a 2-fold induction of hMTH-1-mRNA expression and a 3-fold induction of enzyme activity. A 1.7-fold induction of mRNA expression and a 3.5-fold induction of enzyme activity was obtained in Jurkat cells after treatment ranging from 0 to 300 μM H2O2. Cytotoxic concentrations of hydrogen peroxide lead to an almost complete loss of enzyme activity and an inhibition of hMTH-1 mRNA expression. Induction of hMTH-1 gene expression was prevented by addition of actinomycin D and cycloheximide. These data indicate the inducibility of the hMTH-1 gene expression and enzyme activity by prooxidative molecules, such as hydrogen peroxide. These parameters can thus be used as a marker of oxidative stress. (C) 2000 Elsevier Science Ireland Ltd.
- Meyer, Frauke,Fiala, Emerich,Westendorf, Johannes
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