ACYCLONUCLEOSIDE ANALOG INHIBITORS OF MAMMALIAN PURINE NUCLEOSIDE PHOSPHORYLASE

被引:29
作者
BZOWSKA, A
KULIKOWSKA, E
SHUGAR, D
CHEN, BY
LINDBORG, B
JOHANSSON, NG
机构
[1] UNIV WARSAW,INST EXPTL PHYS,DEPT BIOPHYS,93 ZWIRKI WIGURY,PL-02089 WARSAW,POLAND
[2] MEDIVIR AB,RES LABS,S-14144 HUDDINGE,SWEDEN
关键词
D O I
10.1016/0006-2952(91)90117-N
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
A series of about 60 purine acyclonucleosides, most with guanine as the aglycone and a 4-carbon chain as the acyclic moiety, was examined for ability to inhibit purine nucleoside phosphorylase from human erythrocytes and calf spleen. Compounds with shorter and longer acyclic chains were less effective inhibitors. Synthetic procedures are described. About 25 of the analogues were competitive inhibitors (relative to inosine or 7-methylguanosine as substrates) with K(i) values in the range of 2 to 100-mu-M. The more potent ones (K(i) 2-5-mu-M) included guanine as the aglycone, with various substituents at C(2') of the acyclic chain and hydroxyls at C(3') and C(4'). In one instance, 9-(2-fluoro-3,4-dihydroxybutyl)guanine, the (+)erythro enantiomer was 10-fold more effective than its (-) counterpart (2.5-mu-M vs 27-mu-M). Replacement of guanine by 8-bromo- or 8-aminoguanine enhanced affinity for the enzyme by an order of magnitude or more; 7-deazaacyclovir was also 10-fold more effective than acyclovir. With some of the inhibitors, K(i) (human)/K(i) (calf) varied over the range 0.4 to 4, reflecting differences between the two enzymes; nonetheless, the much more stable, and commercially available, calf spleen enzyme is recommended for preliminary screening of potential inhibitors of the human or other unstable enzymes. The overall results provide useful indications for the synthesis of potentially more potent inhibitors of the enzyme, by simultaneous modifications of the aglycone and the acyclic chains.
引用
收藏
页码:1791 / 1803
页数:13
相关论文
共 55 条
[1]  
AGARWAL KC, 1975, BIOCHEMISTRY-US, V14, P79, DOI 10.1021/bi00672a013
[2]  
AGARWAL RP, 1969, J BIOL CHEM, V244, P644
[3]  
AMMANN AJ, 1978, CIBA F S, V68, P55
[4]  
BZOWSKA A, 1988, J BIOL CHEM, V263, P9212
[5]   COMPARISON OF ACID-CATALYZED AND ENZYME-CATALYZED CLEAVAGE OF THE GLYCOSIDIC BOND OF N(7)-SUBSTITUTED GUANOSINES [J].
BZOWSKA, A ;
KULIKOWSKA, E ;
SHUGAR, D .
NUCLEOSIDES & NUCLEOTIDES, 1990, 9 (03) :439-440
[6]  
BZOWSKA A, 1990, Z NATURFORSCH C, V45, P59
[7]   CHARACTERIZATION OF THE ACTIVE-SITE OF HOMOGENEOUS THYROID PURINE NUCLEOSIDE PHOSPHORYLASE [J].
CARLSON, JD ;
FISCHER, AG .
BIOCHIMICA ET BIOPHYSICA ACTA, 1979, 571 (01) :21-34
[8]   THYROID PURINE NUCLEOSIDE PHOSPHORYLASE .2. KINETIC-MODEL BY ALTERNATE SUBSTRATE AND INHIBITION STUDIES [J].
CARLSON, JD ;
FISCHER, AG .
BIOCHIMICA ET BIOPHYSICA ACTA, 1979, 566 (02) :259-265
[9]   FLUOROCARBOHYRATES .5. METHYL ( +/- )2-DEOXY-2-FLUOROERYTHRONATE AND RELATED COMPOUNDS [J].
CHERRY, R ;
KENT, PW .
JOURNAL OF THE CHEMICAL SOCIETY, 1962, (JUN) :2507-&
[10]   ELECTROCHEMICAL ANALYSIS OF 3'-AZIDOTHYMIDINE (AZT) [J].
CZOCHRALSKA, B ;
SAPOK, B ;
SHUGAR, D .
NUCLEOSIDES & NUCLEOTIDES, 1990, 9 (03) :443-444