Carbocyclic analogs of 1,3-diazepin-2-one nucleosides as transition-state inhibitors of cytidine deaminase

ORGN 148

Victor E. Marquez, marquezv@mail.nih.gov, Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, 376 Boyles St, Frederick, MD 21702 and Olaf R. Ludek, oludek@ncifcrf.gov, Laborarory of Medicinal Chemistry, National Cancer Institute at Frederick, National Institutes of Health, 376 Boyle Street, Frederick, MD 21702.
Cytidine deaminase (CDA) is a catabolic enzyme of the salvage pyrimidine pathway, catalyzing the hydrolytic deamination of cytidine/deoxycytidine into uracil nucleosides. Aside from these natural substrates, the enzyme also deaminates cytosine containing nucleoside analogues used in the clinical treatment of cancer and antiviral therapies, resulting in loss of activity. In our search for stable and potent inhibitors of CDA, we decided to construct a 1,3-diazepine aglycon on carbocyclic scaffolds, locked in the extreme north- and south-conformation of the pseudorotational cycle. Therefore, the respective carbocyclic amines (1) were alkylated and acylated to give the intermediate ureas (2). Unfortunatelly, direct ring-closing metathesis to 3 was not succesfull, since the trans-configuration of the secondary amide bond prevented the necessary cis-configuration of the allyl-groups. This obstacle was overcome by benzoylation of the amide NH, resulting in a significantly lower cis/trans-isomerization barrier. Interestingly, silylation of urea 2 gave a six-membered derivative, due to double-bond isomerization.

 

Total Synthesis, Materials, Devices and Switches, Molecular Recognition and Self-Assembly, Biologically-Related Molecules and Processes
8:00 PM-10:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Organic Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007