Site-Specific Synthesis and Characterization of Oligonucleotides Containing an N6-(2-Deoxy-<scp>d</scp>-erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5-N-methylformamidopyrimidine Lesion, the Ring-Opened Product from N7-Methylation of Deoxyguanosine

Christov, Plamen P.; Brown, Kyle L.; Kozekov, Ivan D.; Stone, Michael P.; Harris, Thomas M.; Rizzo, Carmelo J.

doi:10.1021/tx800352a

Cited by 28 publications

(85 citation statements)

References 58 publications

(110 reference statements)

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“…41,55 It was hypothesized that the two phases represented the α- and β-anomers of the Fapy-dGuo adduct. Attempts to characterize the thermal melting profile of the NM-Fapy-dGuo containing 12-mer gave inconsistent results in our hands.…”

Section: Results and Discussionmentioning

confidence: 99%

Synthesis and Characterization of Oligonucleotides Containing a Nitrogen Mustard Formamidopyrimidine Monoadduct of Deoxyguanosine

Christov

Son

Rizzo

2014

Chem. Res. Toxicol.

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N5-Substituted formamidopyrimidine adducts have been observed from the reaction of dGuo or DNA with aziridine containing electrophiles, including nitrogen mustards. However, the role of substituted Fapy-dGuo adducts in the biological response to nitrogen mustards and related species has not been extensively explored. We have developed chemistry for the site-specific synthesis of oligonucleotides containing an N5-nitrogen mustard Fapy-dGuo using the phosphoramidite approach. The lesion was found to be a good substrate for Escherichia coli endonuclease IV and formamidopyrimidine glycosylase.

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Section: Results and Discussionmentioning

confidence: 99%

Synthesis and Characterization of Oligonucleotides Containing a Nitrogen Mustard Formamidopyrimidine Monoadduct of Deoxyguanosine

Christov

Son

Rizzo

2014

Chem. Res. Toxicol.

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“…7, 103 Therefore, during nucleoside and phosphoramidite synthesis of FAPy adducts, the formation of pyranose isomers can be minimized by protecting the 5′position of the sugar, typically using the DMT group. 57 …”

Section: Structural Identification and Synthesis Of N5-substitutedmentioning

confidence: 99%

“…57 Upon HPLC analysis of enzymatic digests, five Me-FAPy-dG peaks were observed (Figure 11), of which one peak was the pyranose form (Peak 1) whereas other four peaks corresponded to furanose nucleosides in an α and β anomeric forms. 57 …”

Section: Synthesis Of Dna Oligodeoxynucleotides Containing N5-r-famentioning

confidence: 99%

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Chemical Biology of N⁵-Substituted Formamidopyrimidine DNA Adducts

Pujari

Tretyakova

2016

Chem. Res. Toxicol.

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DNA nucleobases are the prime targets for chemical modifications by endogenous and exogenous electrophiles. Alkylation of the N7 position of guanine and adenine in DNA triggers base-catalyzed imidazole ring opening and the formation of N5-substituted formamidopyrimidine (N5-R-FAPy) lesions. Me-FAPy-dG adducts induced by exposure to methylating agents and AFB-FAPy-dG lesions formed by aflatoxin B1 have been shown to persist in cells and to contribute to toxicity and mutagenicity. In contrast, the biological outcomes of other N5-substituted FAPy lesions have not been fully elucidated. To enable their structural and biological evaluation, N5-R-FAPy adducts must be site-specifically incorporated into synthetic DNA strands using phosphoramidite building blocks, which can be complicated by their unusual structural complexity. N5-R-FAPy exist as a mixture of rotamers and can undergo isomerization between α, β anomers and furanose-pyranose forms. In this Perspective, we will discuss the main types of N5-R-FAPy adducts and summarize the strategies for their synthesis and structural elucidation. We will also summarize the chemical biology studies conducted with N5-R-FAPy-containing DNA to elucidate their effects on DNA replication and to identify the mechanisms of N5-R-FAPy repair.

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“…26 These researchers incorporated monomeric phosphoramidites into oligonucleotides containing as many as 29 nucleotides via solid phase synthesis, and purified the desired furanose isomers by HPLC. This methodology is very attractive, and could greatly improve the synthesis of Fapy containing oligonucleotides if it is applicable to the parent lesions.…”

Section: Synthesis Of Oligonucleotides Containing Formamidopyrimidmentioning

confidence: 99%

The Formamidopyrimidines: Purine Lesions Formed in Competition With 8-Oxopurines From Oxidative Stress

Greenberg

2011

Acc. Chem. Res.

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Conspectus DNA is constantly exposed to agents that induce structural damage, from sources both internal and external to an organism. Endogenous species, such as oxidizing chemicals, and exogenous agents, such as ultraviolet rays in sunlight, together produce more than 70 distinct chemical modifications of native nucleotides. Of these, about 15 of the lesions have been detected in cellular DNA. This kind of structural DNA damage can be cytotoxic, carcinogenic, or both, and is being linked to an increasingly lengthy list of diseases. The formamidopyrimidine (Fapy) lesions are a family of DNA lesions that result after purines undergo oxidative stress. The Fapy lesions are produced in yields comparable to the 8-oxopurines, which, owing in part to a perception of mutagenicity in some quarters, have been subjected to intense research scrutiny. But despite the comparable abundance of the formamidopyrimidines and the 8-oxopurines, until recently very little was known about the effects of Fapy lesions on biochemical processes involving DNA or on the structure and stability of the genomic material. In this Account, we discuss the detection of Fapy lesions in DNA and the mechanism proposed for their formation. We also describe methods for the chemical synthesis of oligonucleotides containing Fapy•dA or Fapy•dG and the outcomes of chemical and biochemical studies utilizing these compounds. These experiments reveal that the formamidopyrimidines decrease the fidelity of polymerases and are substrates for DNA repair enzymes. The mutation frequency of Fapy•dG in mammals is even greater than that of 8-oxodGuo (8-oxo-7,8-dihydro-2′-deoxyguanosine, one of the 8-oxopurines), suggesting that this lesion could be a useful biomarker and biologically significant. Despite clear similarities, the formamidopyrimidines have lived in the shadow of the corresponding 8-oxopurine lesions. But the recent development of methods for synthesizing oligonucleotides containing Fapy•dA or Fapy•dG has accelerated research on these lesions, revealing that the formamidopyrimidines are repaired as efficiently and, in some cases, more rapidly than the 8-oxopurines. Fapy•dG appears to be a lesion of biochemical consequence, and further study of its mutagenicity, repair, and interactions with DNA structure will better define the cellular details involving this important product of DNA stress.

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Site-Specific Synthesis and Characterization of Oligonucleotides Containing an N⁶-(2-Deoxy-d-erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5-N-methylformamidopyrimidine Lesion, the Ring-Opened Product from N7-Methylation of Deoxyguanosine

Cited by 28 publications

References 58 publications

Synthesis and Characterization of Oligonucleotides Containing a Nitrogen Mustard Formamidopyrimidine Monoadduct of Deoxyguanosine

Synthesis and Characterization of Oligonucleotides Containing a Nitrogen Mustard Formamidopyrimidine Monoadduct of Deoxyguanosine

Chemical Biology of N⁵-Substituted Formamidopyrimidine DNA Adducts

The Formamidopyrimidines: Purine Lesions Formed in Competition With 8-Oxopurines From Oxidative Stress

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Site-Specific Synthesis and Characterization of Oligonucleotides Containing an N6-(2-Deoxy-d-erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5-N-methylformamidopyrimidine Lesion, the Ring-Opened Product from N7-Methylation of Deoxyguanosine

Cited by 28 publications

References 58 publications

Synthesis and Characterization of Oligonucleotides Containing a Nitrogen Mustard Formamidopyrimidine Monoadduct of Deoxyguanosine

Synthesis and Characterization of Oligonucleotides Containing a Nitrogen Mustard Formamidopyrimidine Monoadduct of Deoxyguanosine

Chemical Biology of N5-Substituted Formamidopyrimidine DNA Adducts

The Formamidopyrimidines: Purine Lesions Formed in Competition With 8-Oxopurines From Oxidative Stress

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Product

Resources

About

Site-Specific Synthesis and Characterization of Oligonucleotides Containing an N⁶-(2-Deoxy-d-erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5-N-methylformamidopyrimidine Lesion, the Ring-Opened Product from N7-Methylation of Deoxyguanosine

Chemical Biology of N⁵-Substituted Formamidopyrimidine DNA Adducts