Vere Hodge R A, Darlison S J, Earnshaw D L, Readshaw S A
SmithKline Beecham Pharmaceuticals, Epsom, Surrey, England.
Chirality. 1993;5(8):583-8. doi: 10.1002/chir.530050804.
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'-13C]PCV precursors and 13C 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 fo 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.
喷昔洛韦是一种强效抗疱疹病毒药物，因其仅在病毒感染细胞中磷酸化而具有高度选择性。喷昔洛韦（PCV）的一个羟甲基磷酸化会产生一个手性中心，导致可能形成（R）-和（S）-对映体。使用同位素手性[4'-13C]PCV前体和分离代谢物的13C NMR光谱，确定了在感染1型和2型单纯疱疹病毒（HSV-1和HSV-2）的细胞中以及由HSV-1编码的胸苷激酶产生的PCV-磷酸盐的绝对构型和立体特异性。在HSV-1感染细胞中产生的喷昔洛韦三磷酸酯（PCV-TP）的绝对构型显示为S，对映体纯度大于95%。然而，与未检测到（R）对映体的HSV-1感染细胞相反，在HSV-2感染细胞中产生了约10%的（R）-PCV-TP。发现HSV-1编码的胸苷激酶对PCV的磷酸化产生75%的（S）-和25%的（R）-PCV-单磷酸酯。在随后导致三磷酸酯的磷酸化过程中，（S）-异构体的比例似乎被放大。
