A study concerning the substrate conformational preferences displayed by cytidine deaminase (CDA) versus the mechanistically similar enzyme, adenosine deaminase (ADA), revealed important differences between the enzymes that were explained on the basis of sugar puckering and the role of the ribose oxygen in binding and catalysis (Nucleosides Nucleotides &Nucleic Acids 2009, 28, 614-632). In a study using the most potent CDA inhibitor that our lab developed in the decade of the 80s, a diazepinone riboside, the ribose ring was replaced with conformationally locked pseudosugars built with a bicyclo[3.1.0]hexane template. Taking advantage of the stability of the carbocyclic moiety a very stable CDA inhibitor that almost equal in potency the parent diazepinone riboside was disovered (J. Org. Chem. 2009 in press).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010962-02
Application #
7965882
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2009
Total Cost
$171,342
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Ludek, Olaf R; Schroeder, Gottfried K; Liao, Chenzhong et al. (2009) Synthesis and conformational analysis of locked carbocyclic analogues of 1,3-diazepinone riboside, a high-affinity cytidine deaminase inhibitor. J Org Chem 74:6212-23
Ludek, Olaf R; Schroeder, Gottfried K; Wolfenden, Richard et al. (2008) Synthesis of conformationally locked carbocyclic 1,3-diazepinone nucleosides as inhibitors of cytidine deaminase. Nucleic Acids Symp Ser (Oxf) :659-60