RELATIONSHIP BETWEEN THE STRUCTURE OF SANGIVAMYCIN-DERIVED NUCLEOSIDES AND THEIR EFFECT ON LEUKEMIC-CELL GROWTH AND ON PROTEIN-KINASE-A AND PROTEIN-KINASE-C ACTIVITY

The nucleoside antibiotic sangivamycin (4-amino-7-(beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine-5-carboxamide, (1) is an effective inhibitor of protein kinase A (PKA) and protein kinase C (PKC) but, upon its phosphorylation in intact cells, it gains the ability to affect other targets as well. To retain its selectivity for the protein kinases, a series of nonphosphorylatable sangivamycin derivatives was prepared by replacing the 5'-hydroxyl group with other functions including N-3, F, SO2NH2, NO2, and NH2, These derivatives were more potent inhibitors of PKA and PKC than were the phosphorylatable compounds, although the fatter were more potent inhibitors of leukemic cell growth.