Abstract

The inhibition constants (K_i) of a series of 5-(2-halogenovinyl)-2'-deoxyuridines, including E-5-(2-chlorovinyl)-dUrd, E-5-(2-bromovinyl)-dUrd, E-5-(2-iodovinyl)-dUrd, and Z-5-(2-bromovinyl)-dUrd, have been determined for the dThd kinases of human cytosol or mitochondria, herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2), or varicella-zoster virus (VZV). The E-5-(2-halogenovinyl)-2'-deoxyuridines had a much higher affinity for HSV-1 (or VZV) dThd kinase than for HSV-2 dThd kinase, and the affinity of E-5-(2-bromovinyl)-dUrd for HSV-1 dThd kinase was also much higher than that of its stereo-isomer, Z-5-(2-bromovinyl)-dUrd. The relative affinities of these compounds for the virus-induced dThd kinase correlated closely with their inhibitory effects on these viruses, suggesting that the selectivity of E-5-(2-bromovinyl)-dUrd and its congeners toward herpes viruses (HSV and VZV) is to a large extent dependent on their phosphorylation by the virus-induced dThd kinase.