Structure−Activity Relationships of l-Dioxolane Uracil Nucleosides as Anti-Epstein Barr Virus Agents

A series of 1,3-dioxolanyluracil analogues was prepared from the dioxolane intermediates 2, and their anti-Epstein Barr virus (anti-EBV) activities were detemined. The potency of l-dioxolane uracil nucleosides against EBV replication is dependent on the substituents at the 5-position in the following decreasing order:  I > Br > Cl > CH3 > CF3 > F. The most active and selective analogue was the iodo derivative (l-I-OddU) with an EC50 value of 0.03 μΜ and an EC90 value of 0.16 μΜ. There was no cytotoxicity or depletion of mitochondrial DNA in cells after exposure to l-I-OddU at 50 μΜ. The action against EBV replication in H1 cells is time-dependent, and EBV DNA in cells treated with l-I-OddU could rebound to pretreatment levels once the drug was removed. In view of the potent antiviral activity plus favorable toxicity profiles, l-I-OddU may be potentially useful for the treatment of EBV-related infectious diseases as well as for delaying the onset or decreasing the incidence of EBV-associated cancers.