ABSTRACT
The similarities between adenosine deaminase (ADA) and cytidine deaminase (CDA) and the discovery of coformycin as a potent transition-state inhibitor of ADA inspired the construction of ring-expanded uridine (1,3-diazepin-2-one) nucleosides. The most potent 5-hydroxyperhydro-1,3-diazepin-2-one has a tertiary alcohol that interacts with CDA via a zinc-mediated coordinated complex. The increase in potency correlates with the distorted non-planar conformation of the seven-membered ring that provides an additional element of mimicry to the transition-state intermediate of the CDA reaction. New methods of syntheses were developed for the syntheses of these nucleosides as conventional methods do not work for non-aromatic nucleobases. A new potent 1,3,4,7-tetrahydro-2H-1,3-diazepin-2-one nucleoside, which displays a symmetric double bond unable to interact with zinc, matched the potency of the 5-hydroxyperhydro-1,3-diazepin-2–1,3-diazepin-2-one nucleoside. The X-ray structure of the complex trapped at the active site of CDA revealed a new mode of interaction with the enzyme that compensates for the loss of metal coordination. 1,3-Diazepin-2-one nucleosides protect the rapid deamination of important antitumor agents that are substrates of CDA.
