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Use of isotopically chiral [4′‐ 13 C]penciclovir and 13 C NMR to determine the specificity and absolute configuration of penciclovir phosphate esters formed in HSV‐1‐ and HSV‐2‐infected cells and by HSV‐1‐encoded thymidine kinase
Author(s) -
Hodge R. Anthony Vere,
Darlison Sarah J.,
Earnshaw David L.,
Readshaw Simon A.
Publication year - 1993
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530050804
Subject(s) - penciclovir , thymidine kinase , chemistry , absolute configuration , famciclovir , enantiomer , herpes simplex virus , stereochemistry , hydroxymethyl , thymidine , phosphorylation , guanosine , virus , virology , biochemistry , in vitro , biology
Penciclovir is a potent antiherpesvirus agent which is highly selective due to its phosphorylation only in virus infected cells. Phosphorylation of one of the hydroxymethyl groups of penciclovir (PCV) creates a chiral centre leading to the possible formation of ( R )‐ and ( S )‐enantiomers. The absolute configuration and stereospecificity of the PCV‐phosphates produced in cells infected with herpes simplex viruses types 1 and 2 (HSV‐1 and HSV‐2), as well as by HSV‐1‐encoded thymidine kinase, were determined using isotopically chiral [4′‐ 13 C]PCV precursors and 13 C NMR spectroscopy of the isolated metabolites. The absolute configuration of penciclovir‐triphosphate (PCV‐TP) produced in HSV‐1‐infected cells was shown to be S with an enantiomeric purity of greater than 95%. However, in contrast to HSV‐1‐infected cells in which none of the ( R ) enantiomer was detected, about 10% of ( R )‐PCV‐TP was produced in HSV‐2‐infected cells. Phosphorylation of PCV by HSV‐1‐encoded thymidine kinase was found to give 75% ( S )‐ and 25% ( R )‐PCV‐monophosphate. The proportion of the ( S )‐isomer appears to be amplified in the subsequent phosphorylations leading to the triphosphate. © 1993 Wiley‐Liss, Inc.