[[(GUANINYLALKYL)PHOSPHINICO]METHYL]PHOSPHONIC ACIDS - MULTISUBSTRATEANALOG INHIBITORS OF HUMAN ERYTHROCYTE PURINE NUCLEOSIDE PHOSPHORYLASE

A series of [[(guaninylalkyl)phosphinico]methyl]phosphonic acids, 2, w as synthesized and tested as inhibitors of human erythrocyte purine nu cleoside phosphorylase (PNPase). The target (phosphinicomethyl)phospho nic acids 2 were synthesized in six or seven steps from alkenylphospho nates 4. The latter were converted to the intermediate alkylmesylates 9 in a series of steps that included (1) conversion of the diethyl pho sphonates 4 to the (phosphinoylmethyl)pho sphonates 7 and (2) conversi on of the terminal double bond of [(alkenylphosphinoyl)methyl]-phospho nates 7 to the alkylmesylates 9. The pure 9-isomers 2 were obtained by alkylation of 2-amino-6-(2-methoxyethoxy)-9H-purine with alkylmesylat es 9 followed by hydrolysis of the protecting groups with concentrated hydrochloric acid and ion exchange chromatography to give 2 as hydrat ed ammonium salts. The most potent inhibitor of human erythrocyte PNPa se, 9H-purin-9-yl)pentyl]phosphinico]methyl]phosphonic acid(2b), was a multisubstrate analogue inhibitor with a K-i' of 3.1 nM. Optimum PNPa se inhibitory activity required the presence of zinc ions in the assay medium. These potent inhibitors of PNPase exhibited only weak activit y against human leukemic T-cells in vitro.