The design and synthesis of analogues of adenosine deaminase inhibitors

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.