Inhibitors of purine nucleoside phosphorylase: effects of 9-deazapurine ribonucleosides and synthesis of 5'-deoxy-5'-iodo-9-deazainosine.

Abstract

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.

• Authors: J D Stoeckler, J B Ryden, R E Parks Jr, M Y Chu, M I Lim, W Y Ren, R S Klein
• Journal: Cancer research (Cancer Res) Vol. 46 Issue 4 Pt 1 Pg. 1774-8 (Apr 1986) ISSN: 0008-5472 [Print] United States
• PMID: 3081256 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Formycins
• Purine Nucleosides
• 5'-deoxy-5'-iodo-9-deazainosine
• Guanosine
• formycin B
• 8-aminoguanosine
• Inosine
• Guanine
• Pentosyltransferases
• Purine-Nucleoside Phosphorylase
• Deoxyguanosine

Topics

• Cell Line
• Deoxyguanosine (metabolism, pharmacology)
• Erythrocytes (enzymology)
• Formycins (pharmacology)
• Guanine (metabolism)
• Guanosine (analogs & derivatives, pharmacology)
• Humans
• Inosine (analogs & derivatives, chemical synthesis, pharmacology)
• Leukemia, Lymphoid (enzymology)
• Pentosyltransferases (antagonists & inhibitors)
• Purine Nucleosides (pharmacology)
• Purine-Nucleoside Phosphorylase (antagonists & inhibitors)
• Structure-Activity Relationship