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 determined. 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 microM and an EC90 value of 0.16 microM. There was no cytotoxicity or depletion of mitochondrial DNA in cells after exposure to L-I-OddU at 50 microM. 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.
Lin
J S
JS
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Kira
T
T
Gullen
E
E
Choi
Y
Y
Qu
F
F
Chu
C K
CK
Cheng
Y C
YC
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004148:Dioxolanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004854:Herpesvirus 4, Human / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004148:Dioxolanes; D009705:Nucleosides; D014498:Uracil