Doctoral Dissertations

Date of Award

12-1994

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Chemistry

Major Professor

David C. Baker

Committee Members

G. Kabalka, B. Xue, S. Georghiou

Abstract

In the continued search for inhibitors of adenosine deaminase, the synthesis of seven- and eight-membered fused-ring imidazole compounds were carried out to probe the effect of ring size and replacement of N in the ring system on enzyme inhibition. This research has accomplished the synthesis of analogs of 2'-deoxycoformycin, namely 1,4,5,6,7,8-hexahydroimidazo[4,5-α]cycloheptane (1), 4,5,6,7,8,9-hexahydro-1Himidazo[4,5-a]cyclooctanone (2) and 4,5,8,9-tetrahydro-1H-imidazo[4,5-α]cycloocta-6-ene (3). The imidazole ring system being a π-electron rich system led to the formation of the unstable nucleosides. The sugar moiety upon being fixed to the N-1 of the imidazole ring was found to cleaved off almost immediately upon isolation of the compound. This research has also accomplished the synthesis of the heterocyclic moiety of the nebularine analog, namely 3H-imidazo[4,5-b]pyridin-7-ol (5). Attempts to synthesize the eight-membered imidazole compound, namely 6,7,8,9-tetrahydro-1H-imidazo[4,5-b]cyclooctene-9-ol (6) along similar lines proved to futile. The synthesis of 9-(2,3-dideoxy-β-D-erythro-pentofuranosyl)-6-methoxy-9H-purine was accomplished in excellent overall yields. The main aim of this research was to conduct a comparative study on the rate of deamination of dideoxyadenosine (ddA), as well as the dechlorination and demethoxylation, respectively, of 6-chloro- and 6-methoxypurine dideoxynucleosides with respect to adenosine. This research has also successfully accomplished the synthesis of 1,2,3,4,6,7,8,9- octahydro-1,3-dimethylpyrimido[2,1-f]purine-2,4,8-trione and methyl hexahydro-2- (hydroxymethyl)-2-methyl pyrrolo[l ,2-b]isoxazole-3-carboxylate.

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