title: Sculpting the bicyclo[3.1.0]hexane template of carbocyclic nucleosides to improve recognition by herpes thymidine kinase.
abstract: The replacement of the furanose ring by a cyclopentane in nucleosides generates a group of analogues known generically as carbocyclic nucleosides. These compounds have increased chemical and enzymatic stability due to the absence of a true glycosyl bond that characterizes conventional nucleosides. The additional fusion of a cyclopropane ring to the cyclopentane produces a bicyclo[3.1.0]hexane system that depending on its location relative to the nucleobase is able to lock the embedded cyclopentane ring into conformations that mimic the typical north and south conformations of the furanose ring in conventional nucleosides. These bicyclo[3.1.0]hexane templates have already provided important clues to differentiate the contrasting conformational preferences between kinases and polymerases. Herein, we describe the design, synthesis, and phosphorylation pattern of a new bicyclo[3.1.0]hexane thymidine analogue that seems to possess an ideal spatial distribution of pharmacophores for an optimal interaction with herpes simplex 1 thymidine kinase. The bicyclo[3.1.0]hexane template represents a privileged rigid template for sculpting other carbocyclic nucleosides to meet the demands of specific receptors.
authors: Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, 376 Boyles Street, Frederick, Maryland 21702, USA.
authors: Maria J
authors: MJ
authors: Comin
authors: Riad
authors: R
authors: Agbaria
authors: Tsipi
authors: T
authors: Ben-Kasus
authors: Mahmoud
authors: M
authors: Huleihel
authors: Chenzhong
authors: C
authors: Liao
authors: Guangyu
authors: G
authors: Sun
authors: Marc C
authors: MC
authors: Nicklaus
authors: Jeffrey R
authors: JR
authors: Deschamps
authors: Damon A
authors: DA
authors: Parrish
authors: Victor E
authors: VE
authors: Marquez
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D003500:Cyclization; D004355:Drug Stability; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D008958:Models, Molecular; D008968:Molecular Conformation; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry; D013936:Thymidine / Q000737:chemistry; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors*
chemical_list: D000998:Antiviral Agents; D001643:Bridged Bicyclo Compounds; D009705:Nucleosides; C046059:bicyclo(3.1.0)hexane; D013937:Thymidine Kinase; D013936:Thymidine