Cyclic urea nucleosides. Cytidine deaminase activity as a function of aglycon ring size.
Five beta-D-ribofuranosyl cyclic urea nucleosides (14-18), ranging in ring size from five to eight membered, were synthesized and evaluated as cytidine deaminase (CDA) inhibitors. The precursor protected nucleosides (9-13) were prepared by a condensation procedure utilizing persilylated ureas with a halo sugar under the specific catalytic activity of a HgO/HgBr2 mixture which provided exclusively the beta-anomers. Catalytic hydrogenation of known 1-(2,3,5-tri-O-benzoyl-beta-ribofuranosyl)-1,2-dihydropyrimidin-2-one (19) afforded nucleoside 10 identical with that obtained by the mercury-catalyzed condensation procedure. CDA activity varies significantly with the ring size of the urea aglycon the reaches its maximum level for the seven-membered analogues 16 and 17. The unexpected high potency of nucleoside 17 (Ki = 2.5 X 10(-8) M, human liver enzyme) is reported. This compound represents the most potent inhibitor of human liver CDA yet discovered.
D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000494:pharmacology*; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D051379:Mice; D009700:Nucleoside Deaminases / Q000037:antagonists & inhibitors*; D012263:Ribonucleosides / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D001381:Azepines; D012263:Ribonucleosides; D014508:Urea; D009700:Nucleoside Deaminases; D003564:Cytidine Deaminase