Site specific N6-(2-hydroxy-3,4-epoxybut-1-yl)adenine oligodeoxynucleotide adducts of 1,2,3,4-diepoxybutane: synthesis and stability at physiological pH.
Identifieur interne : 002191 ( PubMed/Curation ); précédent : 002190; suivant : 002192Site specific N6-(2-hydroxy-3,4-epoxybut-1-yl)adenine oligodeoxynucleotide adducts of 1,2,3,4-diepoxybutane: synthesis and stability at physiological pH.
Auteurs : Sergey Antsypovich [États-Unis] ; Danaè Quirk-Dorr ; Crystal Pitts ; Natalia TretyakovaSource :
- Chemical research in toxicology [ 0893-228X ] ; 2007.
Descripteurs français
- KwdFr :
- Adduits à l'ADN (), Adduits à l'ADN (métabolisme), Adénosine (), Adénosine (analogues et dérivés), Chromatographie en phase liquide à haute performance, Composés époxy (), Concentration en ions d'hydrogène, Désoxyadénosine (), Spectrométrie de masse ESI, Spectroscopie par résonance magnétique, Structure moléculaire.
- MESH :
- analogues et dérivés : Adénosine.
- métabolisme : Adduits à l'ADN.
- Adduits à l'ADN, Adénosine, Chromatographie en phase liquide à haute performance, Composés époxy, Concentration en ions d'hydrogène, Désoxyadénosine, Spectrométrie de masse ESI, Spectroscopie par résonance magnétique, Structure moléculaire.
English descriptors
- KwdEn :
- Adenosine (analogs & derivatives), Adenosine (chemistry), Chromatography, High Pressure Liquid, DNA Adducts (chemistry), DNA Adducts (metabolism), Deoxyadenosines (chemistry), Epoxy Compounds (chemistry), Hydrogen-Ion Concentration, Magnetic Resonance Spectroscopy, Molecular Structure, Spectrometry, Mass, Electrospray Ionization.
- MESH :
- chemical , analogs & derivatives : Adenosine.
- chemical , chemistry : Adenosine, DNA Adducts, Deoxyadenosines, Epoxy Compounds.
- chemical , metabolism : DNA Adducts.
- Chromatography, High Pressure Liquid, Hydrogen-Ion Concentration, Magnetic Resonance Spectroscopy, Molecular Structure, Spectrometry, Mass, Electrospray Ionization.
Abstract
1,2,3,4-Diepoxybutane (DEB) is an important metabolite of 1,3-butadiene, a high volume industrial chemical classified as a human and animal carcinogen. DEB is a bifunctional alkylating agent that exhibits both mutagenic and cytotoxic activity, presumably a result of its ability to form bifunctional DNA adducts. Initial reactions of DEB with DNA produce 2-hydroxy-3,4-epoxybut-1-yl (HEB) lesions at guanine and adenine nucleobases. The epoxy group of the monoadduct is inherently reactive and can then undergo further reactions, for example, hydrolysis to the corresponding 2,3,4-trihydroxybutyl adducts and/or second alkylation to yield 2,3-butanediol cross-links. In the present work, synthetic DNA 16-mers containing structurally defined racemic N6-(2-hydroxy-3,4-epoxybut-1-yl)-2'-deoxyadenosine (N6-HEB-dA) adducts (5'-AATTATGTXACGGTAG-3', where X = N6-HEB-dA) were prepared by coupling 6-chloropurine-containing oligodeoxynucleotides with 1-amino-2-hydroxy-3,4-epoxybutane. The latter was generated in situ from the corresponding Fmoc-protected amino epoxide. The N6-HEB-dA-containing DNA oligomer was isolated by reverse-phase HPLC, and the presence of N6-HEB-dA in its structure was confirmed by molecular weight determination and by HPLC-UV-ESI+-MS/MS analyses of enzymatic digests. An independently prepared N6-HEB-dA nucleoside served as an authentic standard. The fate of N6-HEB-dA within DNA at physiological conditions in the presence of various nucleophiles (e.g., cysteine, dG, and the complementary DNA strand) was investigated. Under all conditions tested, N6-HEB-dA rapidly cyclized to produce previously unidentified exocyclic dA lesions (t1/2 < 2 h at physiological conditions). Only trace amounts of hydrolyzed and cross-linked products were detected, suggesting that the rate of cyclization was much greater than the rates of other reactions at the epoxide ring. These results indicate that DEB-induced alkylation of N6-adenine in DNA is unlikely to lead to DNA-DNA cross-linking but instead can result in the formation of exocyclic dA adducts.
DOI: 10.1021/tx060178k
PubMed: 17355152
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uniqKey="Pitts C" first="Crystal" last="Pitts">Crystal Pitts</name></author><author><name sortKey="Tretyakova, Natalia" sort="Tretyakova, Natalia" uniqKey="Tretyakova N" first="Natalia" last="Tretyakova">Natalia Tretyakova</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2007">2007</date><idno type="RBID">pubmed:17355152</idno><idno type="pmid">17355152</idno><idno type="doi">10.1021/tx060178k</idno><idno type="wicri:Area/PubMed/Corpus">002191</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002191</idno><idno type="wicri:Area/PubMed/Curation">002191</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">002191</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Site specific N6-(2-hydroxy-3,4-epoxybut-1-yl)adenine oligodeoxynucleotide adducts of 1,2,3,4-diepoxybutane: synthesis and stability at physiological pH.</title><author><name sortKey="Antsypovich, Sergey" sort="Antsypovich, Sergey" uniqKey="Antsypovich S" first="Sergey" last="Antsypovich">Sergey Antsypovich</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry and The Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicinal Chemistry and The Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455</wicri:regionArea></affiliation></author><author><name sortKey="Quirk Dorr, Danae" sort="Quirk Dorr, Danae" uniqKey="Quirk Dorr D" first="Danaè" last="Quirk-Dorr">Danaè Quirk-Dorr</name></author><author><name sortKey="Pitts, Crystal" sort="Pitts, Crystal" uniqKey="Pitts C" first="Crystal" last="Pitts">Crystal Pitts</name></author><author><name sortKey="Tretyakova, Natalia" sort="Tretyakova, Natalia" uniqKey="Tretyakova N" first="Natalia" last="Tretyakova">Natalia Tretyakova</name></author></analytic><series><title level="j">Chemical research in toxicology</title><idno type="ISSN">0893-228X</idno><imprint><date when="2007" type="published">2007</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adenosine (analogs & derivatives)</term><term>Adenosine (chemistry)</term><term>Chromatography, High Pressure Liquid</term><term>DNA Adducts (chemistry)</term><term>DNA Adducts (metabolism)</term><term>Deoxyadenosines (chemistry)</term><term>Epoxy Compounds (chemistry)</term><term>Hydrogen-Ion Concentration</term><term>Magnetic Resonance Spectroscopy</term><term>Molecular Structure</term><term>Spectrometry, Mass, Electrospray Ionization</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adduits à l'ADN ()</term><term>Adduits à l'ADN (métabolisme)</term><term>Adénosine ()</term><term>Adénosine (analogues et dérivés)</term><term>Chromatographie en phase liquide à haute performance</term><term>Composés époxy ()</term><term>Concentration en ions d'hydrogène</term><term>Désoxyadénosine ()</term><term>Spectrométrie de masse ESI</term><term>Spectroscopie par résonance magnétique</term><term>Structure moléculaire</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Adenosine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Adenosine</term><term>DNA Adducts</term><term>Deoxyadenosines</term><term>Epoxy Compounds</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>DNA Adducts</term></keywords><keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Adénosine</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Adduits à l'ADN</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Chromatography, High Pressure Liquid</term><term>Hydrogen-Ion Concentration</term><term>Magnetic Resonance Spectroscopy</term><term>Molecular Structure</term><term>Spectrometry, Mass, Electrospray Ionization</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adduits à l'ADN</term><term>Adénosine</term><term>Chromatographie en phase liquide à haute performance</term><term>Composés époxy</term><term>Concentration en ions d'hydrogène</term><term>Désoxyadénosine</term><term>Spectrométrie de masse ESI</term><term>Spectroscopie par résonance magnétique</term><term>Structure moléculaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">1,2,3,4-Diepoxybutane (DEB) is an important metabolite of 1,3-butadiene, a high volume industrial chemical classified as a human and animal carcinogen. DEB is a bifunctional alkylating agent that exhibits both mutagenic and cytotoxic activity, presumably a result of its ability to form bifunctional DNA adducts. Initial reactions of DEB with DNA produce 2-hydroxy-3,4-epoxybut-1-yl (HEB) lesions at guanine and adenine nucleobases. The epoxy group of the monoadduct is inherently reactive and can then undergo further reactions, for example, hydrolysis to the corresponding 2,3,4-trihydroxybutyl adducts and/or second alkylation to yield 2,3-butanediol cross-links. In the present work, synthetic DNA 16-mers containing structurally defined racemic N6-(2-hydroxy-3,4-epoxybut-1-yl)-2'-deoxyadenosine (N6-HEB-dA) adducts (5'-AATTATGTXACGGTAG-3', where X = N6-HEB-dA) were prepared by coupling 6-chloropurine-containing oligodeoxynucleotides with 1-amino-2-hydroxy-3,4-epoxybutane. The latter was generated in situ from the corresponding Fmoc-protected amino epoxide. The N6-HEB-dA-containing DNA oligomer was isolated by reverse-phase HPLC, and the presence of N6-HEB-dA in its structure was confirmed by molecular weight determination and by HPLC-UV-ESI+-MS/MS analyses of enzymatic digests. An independently prepared N6-HEB-dA nucleoside served as an authentic standard. The fate of N6-HEB-dA within DNA at physiological conditions in the presence of various nucleophiles (e.g., cysteine, dG, and the complementary DNA strand) was investigated. Under all conditions tested, N6-HEB-dA rapidly cyclized to produce previously unidentified exocyclic dA lesions (t1/2 < 2 h at physiological conditions). Only trace amounts of hydrolyzed and cross-linked products were detected, suggesting that the rate of cyclization was much greater than the rates of other reactions at the epoxide ring. These results indicate that DEB-induced alkylation of N6-adenine in DNA is unlikely to lead to DNA-DNA cross-linking but instead can result in the formation of exocyclic dA adducts.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">17355152</PMID><DateCompleted><Year>2007</Year><Month>08</Month><Day>09</Day></DateCompleted><DateRevised><Year>2018</Year><Month>10</Month><Day>16</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Print">0893-228X</ISSN><JournalIssue CitedMedium="Print"><Volume>20</Volume><Issue>4</Issue><PubDate><Year>2007</Year><Month>Apr</Month></PubDate></JournalIssue><Title>Chemical research in toxicology</Title><ISOAbbreviation>Chem. Res. Toxicol.</ISOAbbreviation></Journal><ArticleTitle>Site specific N6-(2-hydroxy-3,4-epoxybut-1-yl)adenine oligodeoxynucleotide adducts of 1,2,3,4-diepoxybutane: synthesis and stability at physiological pH.</ArticleTitle><Pagination><MedlinePgn>641-9</MedlinePgn></Pagination><Abstract><AbstractText>1,2,3,4-Diepoxybutane (DEB) is an important metabolite of 1,3-butadiene, a high volume industrial chemical classified as a human and animal carcinogen. DEB is a bifunctional alkylating agent that exhibits both mutagenic and cytotoxic activity, presumably a result of its ability to form bifunctional DNA adducts. Initial reactions of DEB with DNA produce 2-hydroxy-3,4-epoxybut-1-yl (HEB) lesions at guanine and adenine nucleobases. The epoxy group of the monoadduct is inherently reactive and can then undergo further reactions, for example, hydrolysis to the corresponding 2,3,4-trihydroxybutyl adducts and/or second alkylation to yield 2,3-butanediol cross-links. In the present work, synthetic DNA 16-mers containing structurally defined racemic N6-(2-hydroxy-3,4-epoxybut-1-yl)-2'-deoxyadenosine (N6-HEB-dA) adducts (5'-AATTATGTXACGGTAG-3', where X = N6-HEB-dA) were prepared by coupling 6-chloropurine-containing oligodeoxynucleotides with 1-amino-2-hydroxy-3,4-epoxybutane. The latter was generated in situ from the corresponding Fmoc-protected amino epoxide. The N6-HEB-dA-containing DNA oligomer was isolated by reverse-phase HPLC, and the presence of N6-HEB-dA in its structure was confirmed by molecular weight determination and by HPLC-UV-ESI+-MS/MS analyses of enzymatic digests. An independently prepared N6-HEB-dA nucleoside served as an authentic standard. The fate of N6-HEB-dA within DNA at physiological conditions in the presence of various nucleophiles (e.g., cysteine, dG, and the complementary DNA strand) was investigated. Under all conditions tested, N6-HEB-dA rapidly cyclized to produce previously unidentified exocyclic dA lesions (t1/2 < 2 h at physiological conditions). Only trace amounts of hydrolyzed and cross-linked products were detected, suggesting that the rate of cyclization was much greater than the rates of other reactions at the epoxide ring. These results indicate that DEB-induced alkylation of N6-adenine in DNA is unlikely to lead to DNA-DNA cross-linking but instead can result in the formation of exocyclic dA adducts.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Antsypovich</LastName><ForeName>Sergey</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Medicinal Chemistry and The Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Quirk-Dorr</LastName><ForeName>Danaè</ForeName><Initials>D</Initials></Author><Author ValidYN="Y"><LastName>Pitts</LastName><ForeName>Crystal</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Tretyakova</LastName><ForeName>Natalia</ForeName><Initials>N</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 9CA095039</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType><PublicationType UI="D013486">Research Support, U.S. Gov't, Non-P.H.S.</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2007</Year><Month>03</Month><Day>14</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Chem Res Toxicol</MedlineTA><NlmUniqueID>8807448</NlmUniqueID><ISSNLinking>0893-228X</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D018736">DNA Adducts</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D003839">Deoxyadenosines</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004852">Epoxy Compounds</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C521702">N6-(2-hydroxy-3,4-epoxybut-1-yl)-2'-deoxyadenosine</NameOfSubstance></Chemical><Chemical><RegistryNumber>60OB65YNAB</RegistryNumber><NameOfSubstance UI="C007366">diepoxybutane</NameOfSubstance></Chemical><Chemical><RegistryNumber>K72T3FS567</RegistryNumber><NameOfSubstance UI="D000241">Adenosine</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000241" MajorTopicYN="N">Adenosine</DescriptorName><QualifierName UI="Q000031" MajorTopicYN="Y">analogs & derivatives</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002851" MajorTopicYN="N">Chromatography, High Pressure Liquid</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018736" MajorTopicYN="N">DNA Adducts</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003839" MajorTopicYN="N">Deoxyadenosines</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004852" MajorTopicYN="N">Epoxy Compounds</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006863" MajorTopicYN="N">Hydrogen-Ion Concentration</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009682" MajorTopicYN="N">Magnetic Resonance Spectroscopy</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015394" MajorTopicYN="N">Molecular Structure</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D021241" MajorTopicYN="N">Spectrometry, Mass, Electrospray Ionization</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2007</Year><Month>3</Month><Day>16</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2007</Year><Month>8</Month><Day>10</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2007</Year><Month>3</Month><Day>16</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">17355152</ArticleId><ArticleId IdType="doi">10.1021/tx060178k</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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