Sculpting the bicyclo[3.1.0]hexane template of carbocyclic nucleosides to improve recognition by herpes thymidine kinase.
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.
Comin
Maria J
MJ
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, 376 Boyles Street, Frederick, Maryland 21702, USA.
Agbaria
Riad
R
Ben-Kasus
Tsipi
T
Huleihel
Mahmoud
M
Liao
Chenzhong
C
Sun
Guangyu
G
Nicklaus
Marc C
MC
Deschamps
Jeffrey R
JR
Parrish
Damon A
DA
Marquez
Victor E
VE
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*
D000998:Antiviral Agents; D001643:Bridged Bicyclo Compounds; D009705:Nucleosides; C046059:bicyclo(3.1.0)hexane; D013937:Thymidine Kinase; D013936:Thymidine