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D ‐(+)‐ iso ‐Methanocarbathymidine: a High‐Affinity Substrate for Herpes Simplex Virus 1 Thymidine Kinase
Author(s) -
Comin Maria J.,
Vu B. Christie,
Boyer Paul L.,
Liao Chenzhong,
Hughes Stephen H.,
Marquez Victor E.
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800027
Subject(s) - herpes simplex virus , thymidine kinase , pharmacophore , enantiomer , chemistry , stereochemistry , thymidine , kinase , substrate (aquarium) , cytotoxicity , simplex , cell culture , enzyme , biochemistry , virus , biology , virology , dna , in vitro , genetics , geometry , mathematics , ecology
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.