title: Antiviral activity of 5'-PAA and 5'-PFA phosphate esters of 2'-deoxyuridines.
abstract: The 5'-PAA and 5'-PFA phosphate esters of 5-bromo-2'-deoxyuridine (BUdR) were synthesized and their antiherpes virus activity was evaluated in vitro. Both compounds showed activity of the same order as the parent nucleoside, BUdR, against HSV-2 but were 4 to 12 times less potent against HSV-1. The 5'-PAA phosphate ester of BUdR (Ro 21-9875) was also active against varicella-zoster virus (VZV) and human cytomegalovirus (HCMV). The 5'-PAA phosphate ester of 5-bromovinyl-2'-deoxyuridine (BVdU) was also synthesized and showed good antiviral activity against HSV-1 only (ID50 = 1.3 mg/l). Further evaluation against selected mutants (TK- or PAAr) indicated a requirement for the expression of the virus-coded thymidine kinase (TK) for the antiviral activity of Ro 21-9875. Kinetic studies revealed non-competitive mixed inhibition of the viral enzyme by this compound. This suggests that it may have some intrinsic TK mediated activity though breakdown to its component parts is undoubtedly a significant contributing factor.
mesh_terms: D000818:Animals; D000998:Antiviral Agents; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D017245:Foscarnet; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors; D014709:Vero Cells / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C020235:brivudine; D017245:Foscarnet; D013937:Thymidine Kinase; D001973:Bromodeoxyuridine; D010746:Phosphonoacetic Acid