Chemistry and Chemical Biology ETDs

Publication Date

9-26-1973

Abstract

Various N2-alkyl- and dialkylsubstituted 2’-deoxyguanosines have been synthesized. After future conversion into nucleotides, these compounds are to be used for incorporation into DNA. The modified DNA is expected to be useful in complexing studies with actinomycin. The presence of the 2-amino group in a purine has earlier been shown to be required for binding of actinomycin. Possible reasons for this requirement are an electronic effect or a precise steric fit involving hydrogen bonding. By comparing the relative stability of the complex formed between actinomycin and modified DNA versus actinomycin and normal DNA a better understanding of the mechanism by which actinomycin acts as an antibiotic might be gained. The synthesis of these derivatives was first attempted by altering the natural nucleoside 2’-deoxyguanosine. This pathway involved preparing 3, 5'-di-0-acetyl-2'-deoxyguanosine, which was accomplished in good yield. The second step was to chlorinate the nucleoside at the 6-position using phosphorus oxychloride. However, 2-amino-6-chloro-9-(3, 5'-di-0-acetyl-2'-deoxy-β-D-ribofuranosyl)purine could not be prepared. The second approach used in the synthesis of the N2-alkyl and dialkyl derivatives involved acid catalyzed fusion of 2-fluoro-6-benzyloxypurine with 1, 3, 5-tri-0-acetyl-2-deoxyribose. The purine was synthesized from guanine by first chlorinating with phosphorus oxychloride to give 2-amino-6-chloropurine which could be readily converted into 2-amino-6-benzyloxypurine with sodium in benzyl alcohol. Treatment of the benzyloxy derivative with sodium nitrite in aqueous fluoboric acid provided 2-fluoro-6-benzyloxypurine. 1, 3, 5-tri-0-acetyl-2-deoxyribose was obtained from 2’-deoxyadenosine by acetylation with acetic anhydride and pyridine followed by hydrolysis and further acetylation with acetic anhydride and acetic acid. 2-Fluoro-6-benzyloxy-9-{3, 5'-di-0-acetyl-2’-deoxy-α-and-β-D-ribofuranosyl)purine produced from the acid-catalyzed fusion reaction was treated with the appropriate amine (i.e., diethyl-, n-propyl-, di-n­propyl-, n-butyl-, di-n-butyl-, iso-butyl-, and di-iso-butylamine) to give the N2-alkyl-and dialkyl-substituted benzyloxy derivatives. After anomeric resolution and catalytic hydrogenation, the desired N2-alkyl-and dialkyl-substituted 2’-deoxyguanosines were isolated, with the exception of the iso-butyl derivative which was not hydro­genated. The di-iso-propyl and tert-butyl derivatives could not be synthesized by this procedure. This lack of reactivity has been tentatively attributed to steric hindrance.

Language

English

Document Type

Dissertation

Degree Name

Chemistry

Level of Degree

Doctoral

Department Name

Department of Chemistry and Chemical Biology

First Committee Member (Chair)

Ulrich Hollstein

Second Committee Member

Guido Herman Daub

Third Committee Member

Edward A. Walters

Fourth Committee Member

Robert Edwin Tapscott

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