STRUCTURE-ACTIVITY RELATIONSHIP BETWEEN (E)-5-(2-BROMOVINYL)-ARABINOFURANOSYLURACIL AND 5-VINYL-1-BETA-D-ARABINOFURANOSYLURACIL (BV-ARAU, V-ARAU) IN INHIBITION OF EPSTEIN-BARR-VIRUS REPLICATION

The structure-activity relationship between (E)-5-(2-bromovinyl)- and 5-vinyl-l-beta-D-arabinofuranosyluracil (BV-araU and V-araU) in inhibition of Epstein-Barr virus (EBV) was evaluated. Both V-araU and BV-araU effectively inhibited EBV replication in virus-producer P3HR-l(LS) cells, as determined by DNA-DNA hybridization. The 50% effective doses (ED50) for viral DNA replication were 0.005 and 0.3-mu-M for V-araU and BV-araU, respectively. The in vitro therapeutic index was 4000 for V-araU and 1300 for BV-araU. Synthesis of EBV-induced polypeptides with molecular weights of 145 000 (145, 140, 130, and 110 kDa) was significantly inhibited by both drugs. Only V-araU inhibited the synthesis of 85-, 55-, and 32-kDa polypeptides by approx. 50%. Kinetic analysis of inhibition and reversibility of EBV DNA replication after removal of the drugs indicated that BV-araU has a more prolonged inhibitory effect than V-araU. These results indicate that the substitution of H by Br in the 5-vinyl group results in marked reduction in anti-EBV activity while prolonging the drug effect and diminishing cytotoxicity.