D-(+)-iso-methanocarbathymidine: a high-affinity substrate for herpes simplex virus 1 thymidine kinase.
The stereoselective syntheses of the (+)-D and (-)-L enantiomers of iso-methanocarbathymidine (iso-MCT) was achieved through two independent linear approaches that converged on two antipodal enantiomers, common to a key precursor used in the synthesis of racemic iso-MCT. In the study reported herein we identified (+)-3 [D-(+)-iso-MCT] as the active enantiomer that was exclusively recognized by the herpes simplex virus 1 thymidine kinase (HSV1-tk), as was predicted by molecular modeling. For this purpose, a human osteosarcoma (HOS) cell line modified to contain and express HSV1-tk from herpes simplex virus 1 (HSV1) was used to determine the cytotoxicity of the compounds by an assay that measures the level of ATP in the cells. The work demonstrates that changes in the substitution pattern of rigid bicyclo[3.1.0]hexane nucleosides, which, relative to normal nucleosides, appear unconventional, can lead to the spatial optimization of pharmacophores and vastly improved substrate recognition.
Comin
Maria J
MJ
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, P.O. Box B, Building 376, Frederick, MD 21702, USA.
Vu
B Christie
BC
Boyer
Paul L
PL
Liao
Chenzhong
C
Hughes
Stephen H
SH
Marquez
Victor E
VE
D000255:Adenosine Triphosphate / Q000378:metabolism; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D009705:Nucleosides / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D013379:Substrate Specificity; D013936:Thymidine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors*
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009705:Nucleosides; D000255:Adenosine Triphosphate; D013937:Thymidine Kinase; C469995:(north)-methanocarbathymidine; D013936:Thymidine