Doctoral Dissertations
Date of Award
8-1994
Degree Type
Dissertation
Degree Name
Doctor of Philosophy
Major
Chemistry
Major Professor
David C. Baker
Committee Members
S. Alexandratos, D. Dougall, G. Kabalka
Abstract
Inhibitors of adenosine deaminase, 2'-deoxycoformycin (pentostatin) and coformycin, have demonstrated chemotherapeutic activity against various forms of leukemia. The purpose of this research was to develop procedures for synthesizing analogues of 2'-deoxycoformycin with the aimed of probing the effect of nitrogen position and ring size of the imidazodiazepinol moiety on the inhibition activity of the enzyme.
This research has accomplished the synthesis of two aglycon analogues of 2'- deoxycoformycin, namely 3H-imidazo[4,5-c]azocan-9-ol and 3H-imidazo[4,5-c]azepan-8- ol dihydrochloride. Although inhibition of adenosine deaminase for these two heterocycles was not observed, the achievement of synthesizing these two heterocycles is itself notable, since it has helped in the exploration of the chemistry of imidazole heterocycles and nucleosides derived therefrom. The two heterocycles were derived from the same intermediate, 3-benzyl-5-formyl-3H-imidazole-4-carbonitrile. Extension by two or three carbons on the intermediate, and cyclizations on the intermediate were then accomplished by different procedures to form seven- or eight-membered rings fused with the imidazole ring.
In the attempt to synthesize 3,6,7,8-tetrahydroimidazo[4,5-b]azepin-8-ol, 1-benzyl-5-nitro-1H-imidazole-4-carboxaldehyde has been successfully extended by three carbons from the carbonyl group to furnish 3-benzyl-8-(tert-butyldimethylsilyloxy)- 3,6,7,8-tetrahydroimidazo-[4,5-b]azepine and 3-benzyl-8-(tert-butyldiphenylsilyloxy)- 3,6,7,8-tetrahydroimidazo[4,5-b]azepine. Because of the problems with removal of the protecting groups, the target compound could not be obtained. However, the approaches do come close to the target compound. If the correct protecting group were to be found, the synthesis of 3,6,7,8-tetrahydroimidazo[4,5-b]azepin-8-ol might be made possible, thus providing an excellent probe into the effect of N-6 of 2'-deoxycoformycin. In an attempted synthesis of 1,4,5,6,7,8-hexahydrocyclohepta[4,5]imidazol-4-ol, it was found that the chemistry of the π-excessive imidazole system was very different from other aromatic systems. Because of new findings, the attempted synthesis of 1,4,5,6,7,8- hexahydrocyclohepta[4,5]-imidazole-4-ol was abandoned.
In studies on condensation of heterocycles with a ribose derivative, a ketonucleoside,3-(2,3,5-tri-O-benzoyl-Β-D-ribosyl)-3H-imidazo[4,5-c]azepan-8-one,was synthesized. Unfortunately, conversion of the ketonucleoside into the corresponding deprotected alcohol nucleoside was unsuccessful because of instability of the alcohol nucleoside.
Recommended Citation
Chao, Qi, "The design and synthesis of analogues of adenosine deaminase inhibitors. " PhD diss., University of Tennessee, 1994.
https://trace.tennessee.edu/utk_graddiss/10326