Inhibitors of purine nucleoside phosphorylase: effects of 9-deazapurine ribonucleosides and synthesis of 5'-deoxy-5'-iodo-9-deazainosine.
9-Deazapurine ribonucleosides constitute a new class of noncleavable purine nucleoside phosphorylase inhibitors that have at least 30-fold greater affinity for the enzyme than the corresponding C-nucleosides of the formycin B series. 9-Deazaguanosine, 9-deazainosine, and 5'-deoxy-5'-iodo-9-deazainosine competitively inhibited human erythrocytic purine nucleoside phosphorylase with Ki values of 29, 20, and 1.8 X 10(-7) M. The last compound is the most potent nucleoside inhibitor of the enzyme presently available and its synthesis is described. In contrast, 7,9-dideaza-7-thiainosine is a very weak inhibitor of the enzyme. When tested as an inhibitor of 2'-deoxyguanosine phosphorolysis in intact human erythrocytes and MOLT-3 human T-cell lymphoblastic leukemia cells, 5'-deoxy-5'-iodo-9-deazainosine was equipotent with 8-aminoguanosine (which is a precursor for 8-aminoguanine, Ki = 2 X 10(-7) M). Similarly, 5'-deoxy-5'-iodo-9-deazainosine and 8-aminoguanosine both potentiated the growth inhibition of human T-lymphocytic MOLT-3 cells by 2'-deoxyguanosine, reducing the 50% inhibitory concentration from approximately 2 X 10(-5) to approximately 2 X 10(-6) M.
Stoeckler
J D
JD
Ryden
J B
JB
Parks
R E
RE
Chu
M Y
MY
Lim
M I
MI
Ren
W Y
WY
Klein
R S
RS
D002460:Cell Line; D003849:Deoxyguanosine / Q000378:metabolism / Q000494:pharmacology; D004912:Erythrocytes / Q000201:enzymology; D005573:Formycins / Q000494:pharmacology; D006147:Guanine / Q000378:metabolism; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007288:Inosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007945:Leukemia, Lymphoid / Q000201:enzymology; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors*; D011684:Purine Nucleosides / Q000494:pharmacology*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D005573:Formycins; D011684:Purine Nucleosides; C048246:5'-deoxy-5'-iodo-9-deazainosine; D006151:Guanosine; C034561:formycin B; C032533:8-aminoguanosine; D007288:Inosine; D006147:Guanine; D010430:Pentosyltransferases; D011683:Purine-Nucleoside Phosphorylase; D003849:Deoxyguanosine