Highly diastereoselective synthesis of nucleoside adducts from the carcinogenic benzo[a]pyrene diol epoxide and a computational analysis.

Highly diastereoselective synthesis of nucleoside adducts from the carcinogenic benzo[a]pyrene diol epoxide and a computational analysis. Research Abstract Details 

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Highly diastereoselective synthesis of nucleoside adducts from the carcinogenic benzo[a]pyrene diol epoxide and a computational analysis. Abstract Text:

Mahesh K Lakshman,John C Keeler,Felix N Ngassa,John H Hilmer,Padmanava Pradhan,Barbara Zajc,Kathryn A Thomasson,

A diastereoselective synthesis of the nucleoside adducts corresponding to a cis ring-opening of the carcinogen (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaP DE-2) by 2'-deoxyadenosine and 2'-deoxyguanosine is described. The key intermediate (+/-)-10alpha-amino-7beta,8alpha,9alpha-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene was synthesized by a highly diastereoselective dihydroxylation wherein phenylboronic acid was a water surrogate. The resulting boronate ester was converted to a tetraol derivative in which two of the four hydroxyl groups (trans 7, 8) were protected as benzoate esters while the remaining two (cis 9, 10) were free. The cis glycol entity was then subjected to a reaction with 1-chlorocarbonyl-1-methylethylacetate to yield an intermediate chloro monoacetoxy dibenzoate. Displacement of the halide with azide, complete cleavage of the esters, and catalytic reduction of the azide yielded the requisite amino triol. Fluoride displacement from appropriately protected nucleoside derivatives, 6-fluoropurine 2'-deoxyribonucleoside and 2-fluoro-2'-deoxyinosine, by the amino triol then yielded diastereomeric pairs of diol epoxide-adducted 2'-deoxyadenosine (dA) and 2'-deoxyguanosine (dG) nucleosides. Small aliquots of these adducts were separated for characterization purposes. The present approach provides the first diastereoselective synthesis of the cis adducts of BaP DE-2 with 2'-deoxyguanosine as well as the first synthesis of both dA and dG adducts from a common intermediate. An informative analysis of the 1H NMR spectra of the cis adducts synthesized and comparisons to the trans adducts are reported. To gain insight into the diastereoselectivity in the key dihydroxylation step, a computational analysis, including molecular mechanics (MMFF94) and semiempirical AM1 geometry optimizations, yielded results that are in fairly good agreement with the experimental observations.

Highly diastereoselective synthesis of nucleoside adducts from the carcinogenic benzo[a]pyrene diol epoxide and a computational analysis. Publishing Authors By Initials

MK Lakshman,JC Keeler,FN Ngassa,JH Hilmer,P Pradhan,B Zajc,KA Thomasson,

For similar natural sciences: chemistry: chemistry, organic: isomerism: stereoisomerism research abstracts see: natural sciences: chemistry: chemistry, organic: isomerism: stereoisomerism research

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Highly diastereoselective synthesis of nucleoside adducts from the carcinogenic benzo[a]pyrene diol epoxide and a computational analysis. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Journal of the American Chemical Society

VOLUME: 129

Page Numbers: 68-76

Journal Abbreviation: J. Am. Chem. Soc.

ISSN: 0002-7863

DAY: 10

MONTH: Jan

YEAR: 2007

Highly diastereoselective synthesis of nucleoside adducts from the carcinogenic benzo[a]pyrene diol epoxide and a computational analysis. Information

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LANGUAGE: eng

NlmUniqueID: 7503056

Highly diastereoselective synthesis of nucleoside adducts from the carcinogenic benzo[a]pyrene diol epoxide and a computational analysis. Keywords Mesh Terms:

KEYWORDS: Stereoisomerism

MESH TERMS: chemical synthesis

Chemical & Substance for Abstract: Highly diastereoselective synthesis of nucleoside adducts from the carcinogenic benzo[a]pyrene diol epoxide and a computational analysis. Information

Substance Name: Deoxyguanosine

Registry Number: 961-07-9

Grant and Affiliation Information for Highly diastereoselective synthesis of nucleoside adducts from the carcinogenic benzo[a]pyrene diol epoxide and a computational analysis.

AFFILIATION: Department of Chemistry, The City College and The City University of New York, 138th Street at Convent Avenue, New York, New York 10031-9198, USA. lakshman@sci.ccny.cuny.edu

Country: United States

AGENCY: United States NIGMS

GRANT: S06 GM008168-24S1

ACRONYM: GM

MEDLINETA: J Am Chem Soc

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