Kelley J L, McLean E W, Crouch R C, Averett D R, Tuttle J V
Division of Organic Chemistry, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.
J Med Chem. 1995 Mar 17;38(6):1005-14. doi: 10.1021/jm00006a020.
A series of [[(guaninylalkyl)phosphinico]methyl]phosphonic acids, 2, was synthesized and tested as inhibitors of human erythrocyte purine nucleoside phosphorylase (PNPase). The target (phosphinicomethyl)phosphonic acids 2 were synthesized in six or seven steps from alkenylphosphonates 4. The latter were converted to the intermediate alkylmesylates 9 in a series of steps that included (1) conversion of the diethyl phosphonates 4 to the (phosphinoylmethyl)-phosphonates 7 and (2) conversion of the terminal double bond of [(alkenylphosphinoyl)methyl]-phosphonates 7 to the alkylmesylates 9. The pure 9-isomers 2 were obtained by alkylation of 2-amino-6-(2-methoxyethoxy)-9H-purine with alkylmesylates 9 followed by hydrolysis of the protecting groups with concentrated hydrochloric acid and ion exchange chromatography to give 2 as hydrated ammonium salts. The most potent inhibitor of human erythrocyte PNPase, [[[5-(2-amino-1,6-dihydro-6-oxo-9H-purin-9- yl)pentyl]phosphinico]methyl]phosphonic acid (2b), was a multisubstrate analogue inhibitor with a Ki' of 3.1 nM. Optimum PNPase inhibitory activity required the presence of zinc ions in the assay medium. These potent inhibitors of PNPase exhibited only weak activity against human leukemic T-cells in vitro.
合成了一系列[[(鸟嘌呤基烷基)膦酰基]甲基]膦酸（2），并将其作为人红细胞嘌呤核苷磷酸化酶（PNPase）的抑制剂进行测试。目标（膦酰基甲基）膦酸2由链烯基膦酸酯4经六步或七步合成。后者通过一系列步骤转化为中间体烷基甲磺酸酯9，这些步骤包括：（1）将二乙基膦酸酯4转化为（膦酰基甲基）膦酸酯7；（2）将[(链烯基膦酰基)甲基]膦酸酯7的末端双键转化为烷基甲磺酸酯9。通过用烷基甲磺酸酯9烷基化2-氨基-6-(2-甲氧基乙氧基)-9H-嘌呤，然后用浓盐酸水解保护基团并通过离子交换色谱法得到水合铵盐形式的2，从而获得纯的9-异构体2。人红细胞PNPase最有效的抑制剂[[[5-(2-氨基-1,6-二氢-6-氧代-9H-嘌呤-9-基)戊基]膦酰基]甲基]膦酸（2b）是一种多底物类似物抑制剂，其Ki'为3.1 nM。PNPase的最佳抑制活性需要在测定介质中存在锌离子。这些PNPase的有效抑制剂在体外对人白血病T细胞仅表现出微弱的活性。
