title: Synthesis of conformationally locked carbocyclic 1,3-diazepinone nucleosides as inhibitors of cytidine deaminase.
abstract: 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.
authors.affiliation: Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Olaf R
authors.initials: OR
authors.lastname: Ludek
authors.forename: Gottfried K
authors.initials: GK
authors.lastname: Schroeder
authors.forename: Richard
authors.initials: R
authors.lastname: Wolfenden
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
mesh_terms: 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
chemical_list: D001381:Azepines; D004791:Enzyme Inhibitors; D009705:Nucleosides; D003564:Cytidine Deaminase
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