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Title: Synthesis of polycyclic aromatic hydrocarbon adducts of adenine in nucleosides and oligonucleotides

Abstract

PAHs are activated metabolically to electrophilic intermediates such as diol epoxides, which bind to cellular macromolecules, particularly DNA. The dominant paradigm for the etiology of chemically induced cancer involves alterations in the structure of DNA which can cause replication errors. Synthesis of oligonucleotides bearing regiochemically and stereochemically defined PAH adducts is a prerequisite to any study of the relationships of adduct structure to mutagenicity. The first chapter introduces the history of PAH carcinogenesis studies. The second chapter contains the synthetic methodology for preparation of deoxyadenosine adducts of PAHs: benzo[a]pyrene, benz[a]anthracene, and benzo[c]phenanthrene. The nucleoside adducts were synthesized efficiently via the reaction of racemic aminotriol derivatives of PAHs with 6-fluoropurine deoxyriboside. The enantiopure PAH adducts of deoxyadenosine were obtained by HPLC separation of the diastereomers which were characterized by [sup 1]H and 2D NMR, CD, UV, and Mass spectroscopy. The third chapter describes syntheses of oligonucleotides bearing regiochemically and stereochemically defined PAH adducts of benzo[a]pyrene and benz[a]anthracene. A post-oligomerization strategy was used in which the condensation reaction between the aminotriol and a fluoronucleoside was carried out after assembling of the oligomer but before the final deprotection step. The fourth chapter describes an efficient synthesis of (+) and ([minus]) benzo[a]pyrene adducts ofmore » deoxyadenosine 3[prime]-phosphate which will be valuable as authentic standards in the Randerath [sup 32]P postlabeling procedure for identification of DNA adducts. In chapter five, a synthetic approach to PAH adducts of deoxyguanosine is discussed. A selective deprotection method is explored in which the oligonucleotide is assembled in the normal fashion except for the exocyclic amino group of the target nucleotide being protected with a labile protecting group.« less

Authors:
Publication Date:
Research Org.:
Vanderbilt Univ., Nashville, TN (United States)
OSTI Identifier:
7042704
Resource Type:
Miscellaneous
Resource Relation:
Other Information: Thesis (Ph.D.)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL AND ANALYTICAL CHEMISTRY; ADDUCTS; CHEMICAL PREPARATION; ADENINES; POLYCYCLIC AROMATIC HYDROCARBONS; CHEMICAL REACTIONS; BENZANTHRACENE; BENZOPYRENE; PHENANTHRENE; STEREOCHEMISTRY; AMINES; ANTIMETABOLITES; AROMATICS; AZAARENES; CONDENSED AROMATICS; DRUGS; HETEROCYCLIC COMPOUNDS; HYDROCARBONS; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; PURINES; SYNTHESIS; 550200* - Biochemistry; 400201 - Chemical & Physicochemical Properties

Citation Formats

Kim, S J. Synthesis of polycyclic aromatic hydrocarbon adducts of adenine in nucleosides and oligonucleotides. United States: N. p., 1992. Web.
Kim, S J. Synthesis of polycyclic aromatic hydrocarbon adducts of adenine in nucleosides and oligonucleotides. United States.
Kim, S J. Wed . "Synthesis of polycyclic aromatic hydrocarbon adducts of adenine in nucleosides and oligonucleotides". United States.
@article{osti_7042704,
title = {Synthesis of polycyclic aromatic hydrocarbon adducts of adenine in nucleosides and oligonucleotides},
author = {Kim, S J},
abstractNote = {PAHs are activated metabolically to electrophilic intermediates such as diol epoxides, which bind to cellular macromolecules, particularly DNA. The dominant paradigm for the etiology of chemically induced cancer involves alterations in the structure of DNA which can cause replication errors. Synthesis of oligonucleotides bearing regiochemically and stereochemically defined PAH adducts is a prerequisite to any study of the relationships of adduct structure to mutagenicity. The first chapter introduces the history of PAH carcinogenesis studies. The second chapter contains the synthetic methodology for preparation of deoxyadenosine adducts of PAHs: benzo[a]pyrene, benz[a]anthracene, and benzo[c]phenanthrene. The nucleoside adducts were synthesized efficiently via the reaction of racemic aminotriol derivatives of PAHs with 6-fluoropurine deoxyriboside. The enantiopure PAH adducts of deoxyadenosine were obtained by HPLC separation of the diastereomers which were characterized by [sup 1]H and 2D NMR, CD, UV, and Mass spectroscopy. The third chapter describes syntheses of oligonucleotides bearing regiochemically and stereochemically defined PAH adducts of benzo[a]pyrene and benz[a]anthracene. A post-oligomerization strategy was used in which the condensation reaction between the aminotriol and a fluoronucleoside was carried out after assembling of the oligomer but before the final deprotection step. The fourth chapter describes an efficient synthesis of (+) and ([minus]) benzo[a]pyrene adducts of deoxyadenosine 3[prime]-phosphate which will be valuable as authentic standards in the Randerath [sup 32]P postlabeling procedure for identification of DNA adducts. In chapter five, a synthetic approach to PAH adducts of deoxyguanosine is discussed. A selective deprotection method is explored in which the oligonucleotide is assembled in the normal fashion except for the exocyclic amino group of the target nucleotide being protected with a labile protecting group.},
doi = {},
url = {https://www.osti.gov/biblio/7042704}, journal = {},
number = ,
volume = ,
place = {United States},
year = {1992},
month = {1}
}

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