Synthesis and conformational analysis of locked carbocyclic analogues of 1,3-diazepinone riboside, a high-affinity cytidine deaminase inhibitor.
Cytidine deaminase (CDA) catalyzes the deamination of cytidine via a hydrated transition-state intermediate that results from the nucleophilic attack of zinc-bound water at the active site. Nucleoside analogues where the leaving NH(3) group is replaced by a proton and prevent conversion of the transition state to product are very potent inhibitors of the enzyme. However, stable carbocyclic versions of these analogues are less effective as the role of the ribose in facilitating formation of hydrated species is abolished. The discovery that a 1,3-diazepinone riboside (4) operated as a tight-binding inhibitor of CDA independent of hydration provided the opportunity to study novel inhibitors built as conformationally locked, carbocyclic 1,3-diazepinone nucleosides to determine the enzyme's conformational preference for a specific form of sugar pucker. This work describes the synthesis of two target bicyclo[3.1.0]hexane nucleosides, locked as north (5) and south (6) conformers, as well as a flexible analogue (7) built with a cyclopentane ring. The seven-membered 1,3-diazepinone ring in all the three targets was built from the corresponding benzoyl-protected carbocyclic bis-allyl ureas by ring-closing metathesis. The results demonstrate CDA's binding preference for a south sugar pucker in agreement with the high-resolution crystal structures of other CDA inhibitors bound at the active site.
Ludek
Olaf R
OR
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
Schroeder
Gottfried K
GK
Liao
Chenzhong
C
Russ
Pamela L
PL
Wolfenden
Richard
R
Marquez
Victor E
VE
D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000737:chemistry; D003517:Cyclopentanes / Q000737:chemistry; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation
D001381:Azepines; D001643:Bridged Bicyclo Compounds; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; C074608:diazepinone riboside; D003564:Cytidine Deaminase