Rearranging the bicyclo[3.1.0]hexane template of carbocyclic nucleosides to improve binding recognition by kinases.
A novel bicyclo[3.1.0]hexane carbocyclic nucleoside (4) with a south-like conformation amenable to interact with the herpes thymidine kinase (HSV-tk) was synthesized with an endo-hydroxyl group positioned at the tip of the bicyclo[3.1.0]hexane ring system opposite to the tip of the fused cyclopropane ring. The introduction of the hydroxymethyl chain through a Baylis-Hillman type reaction and the regioselective opening of a cyclic sulfite intermediate to introduce the nitrogen functionality at the correct position are highlighted.
Marquez
Victor E
VE
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA. marquezv@dc37a.nci.nih.gov
Comin
Maria J
MJ
D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D013937:Thymidine Kinase / Q000378:metabolism*
D001643:Bridged Bicyclo Compounds; D009705:Nucleosides; C046059:bicyclo(3.1.0)hexane; D013937:Thymidine Kinase