9-(DIFLUOROPHOSPHONOALKYL)GUANINES AS A NEW CLASS OF MULTISUBSTRATE ANALOG INHIBITORS OF PURINE NUCLEOSIDE PHOSPHORYLASE

9-(5,5-Difluoro-5-phosphonopentyl)guanine (3) was synthesized as a potential multisubstrate analogue inhibitor of purine nucleoside phosphorylase (EC 2.4.2.1, PNP). At pH 7.4, 3 has a K(i) value 18-, 26-, 25-, and 5.5-fold lower than that of the nonfluorinated analogue 9-(5-phosphonopentyl)guanine (2) regarding PNP from human erythrocyte, rat erythrocyte, calf spleen, and Escherichia coli, respectively. Further studies with human erythrocytic PNP show that at pH 6.2 the difference in K(i) is more pronounced (K(i)2/K(i)3 is 96), and at pH 8.8, where 2 and 3 are both essentially present in the unprotonated form, the ratio is 8. The superiority of the difluorophosphonate 3 over the phosphonate 2 is explained by electronic as well as by steric effects.