8-Aza-immucillins as Transition-State Analogue Inhibitors of Purine Nucleoside Phosphorylase and Nucleoside Hydrolases

• Published in: Journal of medicinal chemistry Vol. 46; no. 1; pp. 155 - 160
• Main Authors: Evans, Gary B, Furneaux, Richard H, Gainsford, Graeme J, Hanson, John C, Kicska, Gregory A, Sauve, Antony A, Schramm, Vern L, Tyler, Peter C
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 02.01.2003; Amer Chemical Soc
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - chemistry; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Aza Compounds - chemical synthesis; Aza Compounds - chemistry; Biological and medical sciences; Cattle; Chemistry, Medicinal; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Humans; Immunomodulators; Inosine - analogs & derivatives; Inosine - chemical synthesis; Inosine - chemistry; Life Sciences & Biomedicine; Medical sciences; N-Glycosyl Hydrolases - antagonists & inhibitors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Purine Nucleosides - chemical synthesis; Purine Nucleosides - chemistry; Purine-Nucleoside Phosphorylase - antagonists & inhibitors; Science & Technology; Structure-Activity Relationship; MYCOBACTERIUM-TUBERCULOSIS; FORMYCIN; 1,4-DINITROPYRAZOLES; CINE-SUBSTITUTION; C-NUCLEOSIDE; IMMUCILLIN-H; AMP NUCLEOSIDASE; Nitrogen heterocycle; Glycosyltransferases; Structure activity relation; Bicyclic compound; Chemical synthesis; Trypanosoma brucei; Ungulata; Kinetoplastida; Human; Protozoa; C-Nucleoside; Bovine; Enzyme; Transferases; Enzyme inhibitor; Crithidia fasciculata; In vitro; Purine-nucleoside phosphorylase; Vertebrata; Mammalia; Animal; Transition state; Hydrolases; Artiodactyla; Pentosyltransferases
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0203332

The 8-aza-immucillins (8-aza-9-deazapurines linked from C9 to C1 of 1,4-dideoxy-1,4-iminoribitol) have been designed as transition-state analogues of the reactions catalyzed by purine nucleoside phosphorylase and nucleoside hydrolases. Syntheses of the 8-aza-immucillin analogues of inosine and adenosine are described. They are powerful inhibitors of the target enzymes with equilibrium dissociation constants as low as 42 pM.