7-deazapurine 2 `-deoxyribofuranosides are noncleavable competitive inhibitors of Escherichia coli purine nucleoside phosphorylase (PNP)

Autor(en): Bzowska, A
Kazimierczuk, Z
Seela, F
Stichwörter: 2'-DEOXYTUBERCIDIN; 7-deazapurine nucleosides; ANALOGS; Biochemistry & Molecular Biology; CATALYTIC MECHANISM; CLADRIBINE; DERIVATIVES; E-coli; GLYCOSYLATION; inhibitors; PHOSPHOROLYSIS; phosphorylase; PURIFICATION; SELECTIVE INHIBITORS; TUBERCIDIN
Erscheinungsdatum: 1998
Herausgeber: ACTA BIOCHIMICA POLONICA
Journal: ACTA BIOCHIMICA POLONICA
Volumen: 45
Ausgabe: 3
Startseite: 755
Seitenende: 768
Zusammenfassung: 
A series of 7-deazapurine 2'-deoxyribofuranosides were synthesized according to already known procedures and their substrate and inhibitor properties with purified E. coli purine nucleoside phosphorylase were examined. In agreement with previous findings, substrate activity was not detected for any of the compounds tested. Most of the nucleosides showed weak inhibition in the preliminary screening, i.e. at a concentration of about 100 mu M. However some combinations of 6-chloro, 6-amino or 6-methoxy substituents with bulky hydrophobic groups at position 7 of the base and/or chloro, amino, methoxy or methylthio group at position 2 markedly enhanced affinity of such modified nucleosides for the E. coli enzyme. The most potent inhibition was observed for two nucleosides: 6-chloro- and 2-amino-6-chloro-7-deazapurine 2'-deoxyribofuranosides that show inhibition constants K-i = 2.4 and 2.3 mu M, respectively. Several other compounds were also found to be good inhibitors, with inhibition constants in the range 5-50 mu M. In all instances the inhibition was competitive us. the nucleoside substrate 7-methylguanosine, Inhibition constants for 7-deazapurine nucleosides are in general several-fold lower than those observed for their purine counterparts. Therefore 7-deaza modification together with substitutions at positions 2, 6 and 7 of the base is a very promising approach to obtain competitive noncleavable inhibitors of E. coli PNP that may bind to the enzyme with inhibition constants in the mu M range.
ISSN: 0001527X
DOI: 10.18388/abp.1998_4269

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