9-[(PHOSPHONOALKYL)BENZYL]GUANINES - MULTISUBSTRATE ANALOG INHIBITORS OF HUMAN ERYTHROCYTE PURINE NUCLEOSIDE PHOSPHORYLASE

被引:27
作者
KELLEY, JL [1 ]
LINN, JA [1 ]
MCLEAN, EW [1 ]
TUTTLE, JV [1 ]
机构
[1] BURROUGHS WELLCOME CO,DIV EXPTL THERAPY,RES TRIANGLE PK,NC 27709
关键词
D O I
10.1021/jm00074a029
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of 9-[(phosphonoalkyl)benzyl]guanines was synthesized and tested for inhibition of human erythrocyte purine nucleoside phosphorylase (PNPase). Inhibitors of PNPase should be T-cell selective, immunosuppressive agents with potential clinical utility in the treatment of a wide variety of disorders in which T-lymphocytes are pathogenic. An initial set of six analogues of the weak PNPase inhibitor 9-benzylguanine (2) contained a phosphonic acid group linked to the ortho, meta, or para position of the aryl moiety via two-or three-atoms pacers. These compounds allowed us to probe for a favorable interaction with the phosphate-binding domain. Several additional meta phosphonoalkyl substituents were examined in an effort to optimize the spacer. The two most potent compounds, [[3-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methyl]benzyl]oxy]-methylphosphonic acid (3f) and [[3-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methyl]benzyl]-thio]methylphosphonic acid (3j), were inhibitors of PNPase with K(i)'s of 5.8 and 1.1 n M, respectively. These inhibitors displayed competitive kinetics with respect to inosine and inorganic phosphate, which showed that these compounds possess binding determinants for both the purine- and phosphate-binding domains of the enzyme, characteristics that are consistent with 3f and 3j being multisubstrate analogue inhibitors of PNPase. The potency of 9-benzylguanine (2) was enhanced more than 6000-fold by linking a phosphonic acid residue with a (methylthio)methyl spacer to the meta position of 2 to give 3j, which illustrates the potent enzyme inhibitory properties available to multisubstrate analogue inhibitors.
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页码:3455 / 3463
页数:9
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