Deconvoluting the Reactivity of Two Intermediates Formed from Modified Pyrimidines

Weng, Liwei; Horvat, Sonia M.; Schiesser, Carl H.; Greenberg, Marc M.

doi:10.1021/ol401472m

Cited by 23 publications

(39 citation statements)

References 21 publications

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“…One explanation for the formation of NMe- 17 (Scheme 9) that is consistent with literature precedent on related molecules involves initial formation of the carbocation NMe- 9 (Scheme 2). 14,15,38–42 Phosphate rearrangement, followed by deprotonation, produces an allylic species analogous to others that undergo nucleophilic substitution by H 2 O.…”

Section: Resultsmentioning

confidence: 97%

Independent Generation and Reactivity of Thymidine Radical Cations

2017

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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.

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Section: Resultsmentioning

confidence: 97%

Independent Generation and Reactivity of Thymidine Radical Cations

2017

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“…21,240,273,274 This discrepancy was resolved by Weng who determined that in addition to generating 102 upon photolysis, 104 and 103c also produce the carbocation ( 112 , Scheme 45 ). 282 Carbocation 112 may arise via heterolytic cleavage of the excited state precursor or electron transfer with the initially formed radical pair. 283 The carbocation is trapped by nucleophiles, including methoxyamine ( 113 ) and t -butyl thiol.…”

Section: Nucleobase Radical Generation and Reactivity In Dna And Rnamentioning

confidence: 99%

“…Computational experiments on free nucleobases corroborated these findings. 282 Addition of (5-uracil)methyl radical to adenine was determined to face a 50 kJ mol −1 barrier, whereas reaction of the corresponding carbocation analogous to 112 was barrierless.…”

Section: Nucleobase Radical Generation and Reactivity In Dna And Rnamentioning

confidence: 99%

Reactivity of Nucleic Acid Radicals

Greenberg

2016

Advances in Physical Organic Chemistry

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Nucleic acid oxidation plays a vital role in the etiology and treatment of diseases, as well as aging. Reagents that oxidize nucleic acids are also useful probes of the biopolymers’ structure and folding. Radiation scientists have contributed greatly to our understanding of nucleic acid oxidation using a variety of techniques. During the past two decades organic chemists have applied the tools of synthetic and mechanistic chemistry to independently generate and study the reactive intermediates produced by ionizing radiation and other nucleic acid damaging agents. This approach has facilitated resolving mechanistic controversies and lead to the discovery of new reactive processes.

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“…23,24 ICLs form via syn - 1 in nonbase paired regions of DNA, because Watson–Crick hydrogen bonds need not be broken in this environment. 17,23,25,26 Hence, adoption of syn - 1 is more facile. Our approach has been to design nucleotide analogues with reduced hydrogen bonding capacity that would encounter lower barriers for adopting conformations that can lead to interstrand cross-link formation.…”

Section: Introductionmentioning

confidence: 99%

Bromopyridone Nucleotide Analogues, Anoxic Selective Radiosensitizing Agents That Are Incorporated in DNA by Polymerases

et al. 2015

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Ionizing radiation is frequently used to kill tumor cells. However, hypoxic solid tumor cells are more resistant to this treatment, providing the impetus to develop molecules that sensitize cells to ionizing radiation. 5-Bromo-2′-deoxyuridine (BrdU) has been investigated as a radiosensitizing agent in the lab and clinic for almost 5 decades. Recent reports that BrdU yields DNA interstrand cross-links (ICLs) in non-base-paired regions motivated us to develop radio-sensitizing agents that generate cross-links in duplex DNA selectively under anoxic conditions. 4-Bromo- and 5-bromopyridone analogues of BrdU were synthesized and incorporated into oligonucleotides via solid-phase synthesis. Upon irradiation, these molecules yield DNA interstrand cross-links under anaerobic conditions. The respective nucleotide triphosphates are substrates for some DNA polymerases. ICLs are produced upon irradiation under anoxic conditions when the 4-bromopyridone is present in a PCR product. Because the nucleoside analogue is a poor phosphorylation substrate for human deoxycytidine kinase, a pro-nucleotide form of the 4-bromopyridone was used to incorporate this analogue into cellular DNA. Despite these efforts, the 4-bromopyridone nucleotide was not detected in cellular DNA. Although these molecules are improvements over previously reported nucleotide analogues designed to be hypoxic radiosensitizing agents, additional advances are needed to create molecules that function in cells.

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Deconvoluting the Reactivity of Two Intermediates Formed from Modified Pyrimidines

Cited by 23 publications

References 21 publications

Independent Generation and Reactivity of Thymidine Radical Cations

Independent Generation and Reactivity of Thymidine Radical Cations

Reactivity of Nucleic Acid Radicals

Bromopyridone Nucleotide Analogues, Anoxic Selective Radiosensitizing Agents That Are Incorporated in DNA by Polymerases

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