1585199-19-4Relevant academic research and scientific papers
Independent Generation and Reactivity of Thymidine Radical Cations
Sun, Huabing,Taverna Porro, Marisa L.,Greenberg, Marc M.
, p. 11072 - 11083 (2017)
Thymidine radical cation (1) is produced by ionizing radiation and has been invoked as an intermediate in electron transfer in DNA. Previous studies on its structure and reactivity have utilized thymidine as a precursor, which limits quantitative product analysis because thymidine is readily reformed from 1. In this investigation, radical cation 1 is independently generated via β-heterolysis of a pyrimidine radical generated photochemically from an aryl sulfide. Thymidine is the major product (33%) from 1 at pH 7.2. Diastereomeric mixtures of thymidine glycol and the corresponding 5-hydroxperoxides resulting from water trapping of 1 are formed. Significantly lower yields of products such as 5-formyl-2′-deoxyuridine that are ascribable to deprotonation from the C5-methyl group of 1 are observed. Independent generation of the N3-methyl analogue of 1 (NMe-1) produces considerably higher yields of products derived from water trapping, and these products are formed in much higher yields than those attributable to the C5-methyl group deprotonation in NMe-1. N3-Methyl-thymidine is, however, the major product and is produced in as high as 70% yield when the radical cation is produced in the presence of excess thiol. The effects of exogenous reagents on product distributions are consistent with the formation of diffusively free radical cations (1, NMe-1). This method should be compatible with producing radical cations at defined positions within DNA.
Independent Generation of Reactive Intermediates Leads to an Alternative Mechanism for Strand Damage Induced by Hole Transfer in Poly(dA-T) Sequences
Sun, Huabing,Zheng, Liwei,Greenberg, Marc M.
, p. 11308 - 11316 (2018)
Purine radical cations (dA?+ and dG?+) are the primary hole carriers of DNA hole migration due to their favorable oxidation potential. Much less is known about the reactivity of higher energy pyrimidine radical cations. The thymidine radical cation (T?+) was produced at a defined position in DNA from a photochemical precursor for the first time. T?+ initiates hole transfer to dGGG triplets in DNA. Hole localization in a dGGG sequence accounts for ～26% of T?+ formed under aerobic conditions in 9. Reduction to yield thymidine is also quantified. 5-Formyl-2′-deoxyuridine is formed in low yield in DNA when T?+ is independently generated. This is inconsistent with mechanistic proposals concerning product formation from electron transfer in poly(dA-T) sequences, following hole injection by a photoexcited anthraquinone. Additional evidence that is inconsistent with the original mechanism was obtained using hole injection by a photoexcited anthraquinone in DNA. Instead of requiring the intermediacy of T?+, the strand damage patterns observed in those studies, in which thymidine is oxidized, are reproduced by independent generation of 2′-deoxyadenosin-N6-yl radical (dA?). Tandem lesion formation by dA? provides the basis for an alternative mechanism for thymidine oxidation ascribed to hole migration in poly(dA-T) sequences. Overall, these experiments indicate that the final products formed following DNA hole transfer in poly(dA-T) sequences do not result from deprotonation or hydration of T?+, but rather from deprotonation of the more stable dA?+, to form dA?, which produces tandem lesions in which 5′-flanking thymidines are oxidized.
In search of Flavivirus inhibitors part 2: Tritylated, diphenylmethylated and other alkylated nucleoside analogues
Saudi, Milind,Zmurko, Joanna,Kaptein, Suzanne,Rozenski, Jef,Neyts, Johan,Van Aerschot, Arthur
, p. 98 - 109 (2014/03/21)
Several flaviviruses, such as the yellow fever virus and the dengue virus cause severe and potentially lethal infection in man. Following up on our initial hit 3′,5′-bistritylated uridine 1, a series of alkylated nucleoside analogues were synthesized and evaluated for their in vitro antiviral activities against dengue fever virus and yellow fever virus. Hereto, alkyl and aryl groups were attached at various positions of the sugar ring combined with subtle variation of the heterocyclic base. Among the new series of derivatives, 3′,5′-di-O-trityl-5-fluoro-2′-deoxyuridine (39) was the most efficient in this series and inhibited both yellow fever virus and dengue virus replication with a 50% effective concentration (EC50) of ～1 μg/mL without considerable cytotoxicity. The other fluorinated derivatives proved more toxic. Almost all diphenylmethylated pyrimidine nucleosides with 3′,5′-di-O-benzhydryl-2′-deoxyuridine (50) as the example were endowed with strong cytotoxic effects down to 1 μg/mL.
