DIAZEPINONE NUCLEOSIDES AS INHIBITORS OF CYTIDINE DEAMINASE

The synthesis of 2'-deoxy and 2',3'-dideoxy derivatives of 1-beta-D-ri bofuranosyl-1,3,4,7-tetrahydro-2H-1,3- diazepin-(2)-one (2) was undert aken in order to find new cytidine deaminase (CDA) inhibitors and pote ntial adjuvants in anticancer chemotherapy. Replacement of ribose by a 2-deoxyribose moiety led to compound 9 that appeared slightly more po tent 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 d erivative of 2 led to -oxo-2,3,4,7-tetrahydro[1,3]diazepin-1-yl)-penty l] -2,2,2-trifluoroacetamide (13), which is devoid of CDA inhibitory a ctivity.