Defense Date


Document Type


Degree Name

Doctor of Philosophy


Pharmaceutical Sciences

First Advisor

Richard A. Glennon


During the past few decades, analogs of purine nucleosides have been described that are modified either in the heterocyclic base, sugar moiety or both, and many of these modified nucleosides display antiviral and/or antineoplastic activity. The Class II mesoionic purinones are isosteric with their non~mesoionic purinone counterparts. It is conceivable that the mesoionic purinone nucleosides might constitute an entirely novel class of modified nucleosides with potential chemotherapeutic activity. That the mesoionic heterobases are bioisosteric as well as isosteric with non-mesoionic purinones was realized by demonstrating that certain mesoionic xanthine derivatives, such as Anhydro-8-ethylw-5-hydroxy-7-oxo-l,3,4-thiadiazolo[3,2-a]pyrimidinium hydroxide and Anhydro-6-p-chlorobenzyl-8-ethyl-5-hydroxy-7-oxo—l,3,4—thiadiazolo [3,2-a]pyrimidinium hydroxide were comparable in potency to test compound, theophylline as inhibitors of adenosine binding at the A1 site.

Three different types of mesoionic nucleosides were subsequently designed and synthesized as potential antineoplastic agents. Mesoionic thiadiazolopyrimidine nucleosides, i.e. Anhydro-6-ethyl-8-(2’,3',5'-tri-O-acetyl-D-ribofuranosyl)MS-hydroxy-7-oxo-l,3,4~thiadiazolo{3,2-a]pyrimidinium hydroxide and Anhydro-8-(2',3'.5’-tri-O-acetyl-D-ribofuranosyl) -5-hydroxy-7-oxo-l,3,4-thiadiazolo[3,2-a]pyrimidinium hydroxide were designed to serve as potential pro-drugs of 2-amino-l,3,4~thiadiazole mononucleotide which has been reported to be a potent inhibitor of inosine monophosphate dehydrogenase. The O~acylated derivatives of the target compounds were prepared by the acid catalyzed condensation of D-ribose with 2-ATD followed by protection of the hydroxyl groups and subsequent cyclization to the mesoionic products; anomeric separation was achieved by column chromatography; All attempts to deprotect the hydroxyl groups of the mesoionic nucleosides resulted in hydrolytic ring-opening of the mesoionic heterobase. The 0-acetyl derivatives of the mesoionic thiadiazolopyrimidine nucleosides were evaluated for antineoplastic activity but were found to be inactive. The mesoionic thia-zolinopyrimidine nucleoside, i.e. Anhydro-6-ethyl-8-(D-2‘-deoxyribo-furanosyl-5-hydroxy-7-oxo-2,3-dihydrothiazolo[3,2-a]pyrimidinium hydrox- ide, prepared in a similar fashion to the mesoionic thiadiazolopyrimie- dine nucleosides, was designed as a potential inhibitor of the enzyme thymidylate synthetase. The mesoionic thiazolinopyrimidine nucleoside, was obtained as the a anomer and was not evaluated for antineoplastic activity. The mesoionic imidazothiazine nucleoside, i.e. Anhydro-l- (2',3',5'-tri-O-acetyl-D-ribofuranosyl)-5-hydroxy-7-oxoimidazo[2,l-b] thiazinium hydroxide was prepared as a potentially useful agent, due to its structural and isosteric similarity with purine nucleosides. The mesoionic imidazothiazine nucleoside was prepared by a cyclization reaction between the tri-0-acetyl-D-ribofuranosyl imidazole-2-thione and carbon suboxide. The mesoionic imidazothiazine nucleoside was not stable at room temperature or in aqueous Solution. While the results of this study on the chemotherapeutic utility of mesoionic nucleosides was rather discouraging, knowledge has been.gained that might be of value for the future design and synthesis of useful mesoionic nucleosides.


Scanned, with permission from the author, from the original print version, which resides in University Archives.


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