Diazepinone Nucleosides as Inhibitors of Cytidine Deaminase.

The synthesis of 2'-deoxy and 2',3'-dideoxy derivatives of 1-beta-D-ribofuranosyl-1,3,4,7-tetrahydro-2H-1,3- diazepin-(2)-one (2) was undertaken in order to find new cytidine deaminase (CDA) inhibitors and potential adjuvants in anticancer chemotherapy. Replacement of ribose by a 2-deoxyribose moiety led to compound 9 that appeared slightly more potent than 2 (Ki=2.5x10(-8) M). Remarkably, the corresponding alpha-2'-deoxynucleoside 10 acted as a very potent inhibitor of human placenta CDA, with a Ki=7.5x10(-8) M. Attempt to synthesize the 2',3'-dideoxy derivative of 2 led to N-[4,5-dihydroxy-1-(2-oxo-2,3,4,7-tetrahydro[1,3]diazepin-1-yl)-pentyl] -2,2,2-trifluoroacetamide (13), which is devoid of CDA inhibitory activity.