Synthesis of conformationally locked carbocyclic 1,3-diazepinone nucleosides as inhibitors of cytidine deaminase.
We synthesized a series of carbocyclic nucleoside inhibitors of cytidine deaminase (CDA) based on a seven-membered 1,3-diazepin-2-one moiety. In the key step, the seven-membered ring was formed by a ring-closing-metathesis reaction. Therefore, the bis-allyl-urea moiety had to be protected by benzoylation in order to obtain an orientation suitable for ring closure. To our surprise, the analogue built on a flexible sugar template (4) showed a 100-fold stronger inhibition of CDA than the derivative with the preferred south-conformation.
Ludek
Olaf R
OR
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA.
Schroeder
Gottfried K
GK
Wolfenden
Richard
R
Marquez
Victor E
VE
D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002236:Carbohydrate Conformation; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D001381:Azepines; D004791:Enzyme Inhibitors; D009705:Nucleosides; D003564:Cytidine Deaminase
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