3 '-fluorine-substitution in 3 '-fluorocarbocyclic oxetanocin a augments the drug's inhibition of HHV-6B propagation in chronically infected cultures

An infection of TaY cells, which originated from an adult T-cell leukemia, with an HHV-6B OK isolate resulted in a chronically infected culture, terme d TaY(OK), Cell cloning analysis revealed that the TaY(OK) culture consiste d of a mixture of cells permissive and refractory to the infection, and tha t the permissive cells were continuously produced from the refractory cell population. Since the chronically infected culture has been maintained for over 2 years without the addition of uninfected TaY cells, we used it for a n evaluation of the antiviral potency of nucleoside analogs, especially car bocyclic oxetanocins (C.OXTs), MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphen yltetrazolium bromide) assays showed a lack of toxicity of ganciclovir (GCV ), C.OXTs, and their derivatives, to TaY(OK) cells at 1 muM. Therefore we c ompared the antiviral potencies of these drugs at 1 I-I IM by monitoring th e viral loads produced during a 1-day period during the course of the drug treatment. Among the drugs tested, 3 ' -fluorocarbocyclic oxetanocin A (3 ' F-C.OXT-A) was the most effective for inhibiting the virus production, and at concentrations ranging from 0.5 muM to 10 muM, the inhibition of the vir al production was dose-dependent. A comparison of the chemical structures o f the derivatives with that of C.OXT-A, which is the parental molecule, sug gested that the 3 ' -fluorine-modification might account for the higher ant i-HHV-6 activity and lower cytotoxicity.