Synthesis of Oligonucleotides Containing Trans Mitomycin C DNA Adducts at N

Adenine DNA Adducts Guanine Mitomycin Oligonucleotides
alkylation conformational studies deoxyadenosine adducts interstrand crosslinks site-specific mitomycin C

Journal

Chemistry (Weinheim an der Bergstrasse, Germany)
ISSN: 1521-3765
Titre abrégé: Chemistry
Pays: Germany
ID NLM: 9513783

Informations de publication

Date de publication:
13 Oct 2021
Historique:
received: 29 06 2021
pubmed: 29 7 2021
medline: 15 10 2021
entrez: 28 7 2021
Statut: ppublish

Résumé

Mitomycin C, (MC), an antitumor drug, is a DNA alkylating agent currently used in the clinics. Inert in its native form, MC is reduced to reactive mitosenes, which undergo nucleophilic attack by guanine or adenine bases in DNA to form monoadducts as well as interstrand crosslinks (ICLs). Although ICLs are considered the most cytotoxic lesions, the role of each individual adduct in the drug's cytotoxicity is still not fully understood. Synthetic routes have been developed to access modified oligonucleotides containing dG MC-monoadducts and dG-MC-dG ICL at a single position of their base sequences to investigate the biological effects of these adducts. However, until now, oligonucleotides containing monoadducts formed by MC at the adenine base had not been available, thus preventing the examination of the role played by these lesions in the toxicity of MC. Here, we present a route to access these substrates. Structural proof of the adducted oligonucleotides were provided by enzymatic digestion to nucleosides and high-resolution mass spectral analysis. Additionally, parent oligonucleotides containing a dG monoadduct and a dG-MC-dG ICL were also produced. The stability and physical properties of all substrates were compared via CD spectroscopy and UV melting temperature studies. Finally, virtual models were created to explore the conformational space and structural features of these MC-DNA complexes.

Identifiants

DOI: 10.1002/chem.202102338 PMID: 34319608 PMC: PMC8516704
pubmed: 34319608
doi: 10.1002/chem.202102338
pmc: PMC8516704
mid: NIHMS1730410
doi:

Substances chimiques

DNA Adducts 0
Oligonucleotides 0
mitomycin C-DNA adduct 0
Mitomycin 50SG953SK6
Guanine 5Z93L87A1R
Adenine JAC85A2161

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

14263-14272

Subventions

Organisme : NIGMS NIH HHS
ID : SC3 GM105460
Pays : United States
Organisme : NIGMS NIH HHS
ID : 2SC3GM105460-07
Pays : United States

Informations de copyright

© 2021 Wiley-VCH GmbH.

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Auteurs

Owen Zacarias (O)

Science Department, John Jay College of Criminal Justice, 524 West 59th street, New York, NY, 10019, USA.

Ana G Petrovic (AG)

New York Institute of Technology, 1855 Broadway, EGGC 405 A, New York, NY, 10023, USA.

Rinat Abzalimov (R)

City University of New York, Advanced Research Center, 85 St Nicholas Terrace, New York, NY, 10031, USA.
Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, NY, 10016, USA.

Padmanava Pradhan (P)

The City College, 138th Street at Convent Avenue, New York, New York, 10031, USA.

Elise Champeil (E)

Science Department, John Jay College of Criminal Justice, 524 West 59th street, New York, NY, 10019, USA.
Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, NY, 10016, USA.

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Classifications MeSH

questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Purines › Adénine › Synthesis of Oligonucleotides Containing Trans...
questionsmedicales.fr › Phénomènes génétiques › Altération de l'ADN › Adduits à l'ADN › Synthesis of Oligonucleotides Containing Trans...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Purines › Purinones › Hypoxanthines › Guanine › Synthesis of Oligonucleotides Containing Trans...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Indoles › Indolequinones › Mitomycines › Mitomycine › Synthesis of Oligonucleotides Containing Trans...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Polynucléotides › Oligonucléotides › Synthesis of Oligonucleotides Containing Trans...