No abstract

No abstract

No abstract

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, 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¡ value is more pronounced { / 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.

Structural analogues of decarboxylated S-adenosyl-L-methionine (dc-SAM), product of the reaction catalyzed by S-adenosyl-L-methionine decarboxylase (SAM-DC), with modifications in the side-chain portion of the molecule have been synthesized, and their ability to inhibit SAM-DC has been investigated. Mainly, compounds with a nitrogen atom in place of the sulfur were investigated. The data from these inhibition studies have resulted in a delineation of the structural features required for binding on SAM-DC. It was concluded that a terminal primary amino group, a terminal carboxyl group, and the sulfonium functionality are not required for binding on SAM-DC. It was also found that analogues of dc-SAM in which replacement of the sulfur by nitrogen was the only modification were still able to form an azomethine with the enzyme. As found for SAM and dc-SAM, these compounds also caused a time-dependent inactivation of SAM-DC.