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https://hdl.handle.net/2142/67289
Description
Title
Chemical Studies on Nucleic Acid Analogues
Author(s)
Czarnik, Anthony William, Jr.
Issue Date
1981
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Chemistry, Organic
Language
eng
Abstract
Dicarbonyl aldehydes are known to react preferentially with guanine residues in both DNA and RNA; however, the exact structure of the modification product has never been assigned unequivocally as either the "linear" or the "bent" isomer. Accordingly, we have synthesized the products of guanine modification with both glyoxal (an (alpha)-dialdehyde) and methylmalondialdehyde (a (beta)-dialdehyde) from a common precursor in four and eight steps, respectively, using a sequence which allows us to distinguish between the two potential structural isomers. For each product, open-ring precursors were prepared which could be differentiated unambiguously from their isomeric counterparts by NMR, owing to the magnetic equivalence of the imidazole or pyrimidine protons. Ring-closure of each precursor affords in one or two steps the corresponding guanine modification products which can for the first time be assigned unequivocally as the "linear" isomers.
Syntheses of foreshortened nucleotide analogues of uridine have been carried out to test the possibility of base pairing with the linearly-extended nucleoside, lin-benzoadenosine. Phosphorylation of N-((beta)-D-ribofuranosyl)formamide (F) provided the 5-monophosphate, which could be dephosphorylated by the action of either alkaline phosphatase or, surprisingly, 5'-nucleotidase. Additional phosphorylations by the method of Hoard and Ott afforded the 5-di- and triphosphates. The diphosphate, 5-FDP, was found not to undergo polymerization using polynucleotide phosphorylase. Syntheses of the self-complementary dinucleoside monophosphates FpA and Fp(lin-benzo-A) are described. The foreshortened analogue was protected as its 2-methoxytetrahydropyranyl-5-t-butyldiphenylsilyl derivative, while 5'-AMP and lin-benzo-AMP were protected using a new and easy method as the corresponding 2',3'-di-O-(t-butyldimethylsilyl) nucleotides. Condensation of the fully-protected F and 5'-monophosphate moieties using DCC provided the desired (3 (--->) 5')-linked nucleotides which, on treatment with phosphodiesterase I, were hydrolyzed back to F and the corresponding 5'-monophosphate.
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