Chemical Biology of N-Substituted Formamidopyrimidine DNA Adducts.

Citation data:

Chemical research in toxicology, ISSN: 1520-5010, Vol: 30, Issue: 1, Page: 434-452

Publication Year:
2017
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PMID:
27959490
DOI:
10.1021/acs.chemrestox.6b00392
Author(s):
Pujari, Suresh S, Tretyakova, Natalia
Publisher(s):
American Chemical Society (ACS)
Tags:
Pharmacology, Toxicology and Pharmaceutics
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article description
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 N-substituted formamidopyrimidine (N-R-FAPy) lesions. Me-FAPy-dG adducts induced by exposure to methylating agents and AFB-FAPy-dG lesions formed by aflatoxin B have been shown to persist in cells and to contribute to toxicity and mutagenicity. In contrast, the biological outcomes of other N-substituted FAPy lesions have not been fully elucidated. To enable their structural and biological evaluation, N-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. N-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 N-R-FAPy adducts and summarize the strategies for their synthesis and structural elucidation. We will also summarize the chemical biology studies conducted with N-R-FAPy-containing DNA to elucidate their effects on DNA replication and to identify the mechanisms of N-R-FAPy repair.

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