- Self-sacrificing acetylation observed during attempted desilylation of 1-[4-benzenesulfonyl-3-O-(tert-butyldimethylsilyl)-2-deoxy-5-O-methanesulfonyl- α-l-threo-pentofuranosyl]thymine
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Desilylation of 1-[4-benzenesulfonyl-3-O-(tert-butyldimethylsilyl)-2-deoxy- 5-O-methanesulfonyl-α-l-threo-pentofuranosyl]thymine (4) with Bu 4NF/THF, when carried out at room temperature, gave four products. Among these, there were 1-[3-O-acetyl-4-benzenesulfonyl-2-deoxy-5-O- methanesulfonyl-α-l-threo-pentofuranosyl]thymine (7) and thymine. A possible reaction mechanism is proposed, which suggests the origin of 3′-O-acetyl group of 7 and thymine as well as structures of the other two products (9a and 9b).
- Shimada, Hisashi,Kubota, Yutaka,Tanaka, Hiromichi
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p. 4253 - 4255
(2010/09/07)
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- Identification of the oxidized products formed upon reaction of Chromium(V) with thymidine nucleotides
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Two pathways have been observed for Cr(V)-mediated nucleotide oxidation in reactions of bis(2-ethyl-2-hydroxybutyrato)oxochromate(V) [CrO(ehba)2]- with thymidine nucleotides dTMP, dTDP, and dTTP. The extent of Cr(V)-induced nucleotide oxidation was greatest for thymidine diphosphate (dTDP), as measured by the production of thiobarbituric acid reactive species (TBARS; indicative of pathway 1) and thymine release (indicative of pathway 2). The nucleoside thymidine showed no reaction, suggesting a phosphate-dependent oxidation. Amounts of TBARS and thymine were maximal at a pH range of 6.0-6.5, and both TBARS formation and thymine release correlated with decay of the Cr(V) EPR signal. Formation of TBARS was maximal in 100% O2 but decreased markedly under argon, whereas thymine release was maximal under argon, but remained the major product observed under aerobic conditions. Pathway 1 for the reaction of Cr(V) with dTDP led to formation of glycolic acid and trans-thymine propenal at approximately equimolar amounts, consistent with a mechanism involving oxygen-dependent sugar oxidation following hydrogen atom abstraction at the C-4' carbon of the deoxyribose sugar. Pathway 2 led to release of free thymine, but much less (barely detectable) 2-deoxy-D-pentitol was formed from postreduction of the reactive aldehydic sugar fragment. Thus, the oxygen-independent release of thymine does not appear to result from reaction at the C-4' hydrogen unless decomposition of the aldehydic intermediate occurred. Determination of the oxidation state of chromium responsible for the observed oxidative damage was carried out using Mn(II), a Cr(IV)-specific reductant. Mn(II) essentially abolished all activity for both TBARS formation (pathway 1) and thymine release (pathway 2). These results suggest that Cr(IV), formed upon disproportionation of Cr(V), oxidizes the nucleotide deoxyribose sugar moiety via a phosphate-bound intermediate. pathway 1 involves oxygen-dependent oxidation at the C-4' position; however, the mechanism for oxygen-independent thymine release (pathway 2) is still unclear.
- Sugden, Kent D.,Wetterhahn, Karen E.
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p. 10811 - 10818
(2007/10/03)
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- Acyl Migration in the Production of Thymine Propenal from 3'-O-Benzoyl-5'-deoxy-4'-hydroperoxythymidine: A Reinterpretation of a Putative Model for Bleomycin-Mediated DNA Degradation
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Studies of Saito et al. (Saito, I.; Morii, T.; Matsuura, T.J.Org.Chem. 1987, 52, 1008) analyzing the decomposition of 3'-O-benzoyl-5'-deoxy-4'-hydroperoxythymidine (7) claimed to model the decomposition of the putative 4'-hydroxyperoxynucleotide intermediate in the bleomycin (BLM) mediated production of base propenal, 3'-phosphoglycolate, and 5'-phosphate termini from double-stranded DNA.A number of puzzling observations reported in this paper prompted a reinvestigation of this model system in detail. 18O2>-7 and its 4'-epimer 8 were prepared and their fate in aqueous solution as a function of pH was examined.Compound 7 decompos ed in aqueous solution to produce thymine propenal accompanied by stoichiometric formation of benzoate containing 1 atom of 18O.In addition, thymine accompanied by stoichiometric amounts of malondialdehyde and 18O>benzoate was also observed.Acetate containing 1 atom of 18O accompanied production of both thymine and thymine propenal.The ratio of thymine propenal to thymine varied as a function of pH and temperature.Production of 18O>benzoate and a detailed kinetic analysis of the decomposition of 7 unequivocally demonstrated that conversion of 7 to thymine propenal required the intermediacy of a 4'-perbenzoate ester.This perester produced by migration of the 3'-benzoyl blocking group of 7 to the terminal oxygen of its 4'-hydroperoxy moiety would then greatly facilitate heterolytic cleavage of the oxygen-oxygen bond.For stereochemical reasons a similar intramolecular benzoyl migration cannot occur with 8, explaining its lack of reactivity.These results call into question the relevance of the Model proposed by Saito et al. to understanding the base propenal pathway in the BLM-catalyzed degradation of DNA.In addition, preparation of a second model of a putative intermediate in the base propenal pathway, oxy>-3-oxopropyl>thymine (12) is reported.The detailed kinetics of its decomposition as well as identification of the products accompanying ist decomposition are reported.The relevance of these two model systems to the mechanism of degradation of DNA by BLM is discussed.
- McGall, Glenn H.,Stubbe, JoAnne,Kozarich, John W.
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- Chemistry of 4'-Hydroperoxy Nucleosides as a Model for the Intermediate in Bleomycin-Induced Degradation of DNA
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The reaction of 1-(3-O-benzoyl-2,5-dideoxy-β-D-glycero-pent-4-enofuranosyl)thymine (5) with anhydrous hydrogen peroxide in the presence of trifluoroacetic acid gave two isomeric 4'-hydroperoxides (6 and 7).The structure of the major product was assigned as 3'-O-benzoyl-5'-deoxy-4'-hydroperoxythymine (6) on the basis of spectral data.It has been demonstrated that the 4'-hydroperoxide 6 is capable of undergoing a Criegee-type rearrangement in an aqueous buffered solution to give trans-3-(thymin-1'-yl)propenal (10) stereospecifically, whereas the more stable isomer 7 does not produce 10 under the same conditions.These model experiments suggest that once a 4'-hydroperoxy intermediate of β-D-deoxyribo configuration is formed by action of the activated bleomycin on DNA, it spontaneously decomposes to afford DNA strand scission and trans base propenal.Reduction of these 4'-hydroperoxy nucleosides with dimethyl sulfide in methanol gave thymine and γ-keto aldehyde 14 quantitatively.The result indicates that the 4'-hydroxy nucleoside might be the precursor of alkali-labile lesion in DNA.
- Saito, Isao,Morii, Takashi,Matsuura, Teruo
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p. 1008 - 1012
(2007/10/02)
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- Synthesis and biological activity of a new class of cytotoxic agents: N-(3-oxoprop-1-enyl)-substituted pyrimidines and purines
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The 1-(3-oxoprop-1-enyl) derivatives of thymine and cytosine and the corresponding 9-substituted derivatives of adenine and guanine (products of degradation of DNA by bleomycin, Fe2+, and O2) have been synthesized and tested for biological activity. The thymine and adenine compounds are highly cytotoxic to a variety of tumor cell lines and inhibit macromolecular synthesis in cultured HeLa cells. Structure-activity studies, based primarily on the pyrimidine derivatives, reveal that the most potent inhibition occurs when the propenal group is located on the 3-nitrogen of a 2'-deoxyribonucleoside. The 3-(3-oxoprop-1-enyl) derivatives of thymidine, 2'-deoxyuridine, and 5-iodo-2'-deoxyuridine powerfully and selectively inhibit incorporation of thymidine into DNA at concentrations (IC50 ? 0.5 μM) comparable to those observed with idoxuridine. Active compounds in this series react readily with nucleophiles containing primary amino and sulfhydryl groups. The results of this study provide a basis for the development of a new class of cytotoxic agents.
- Johnson,Pillai,Grollman,et al.
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p. 954 - 958
(2007/10/02)
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