The role of the iminium bond in the inhibition of reverse transcriptase byquaternary benzophenanthridines

The quaternary benzo[c]phenanthridines fagaronine, nitidine and O-methylfag aronine have been reviewed as potential antitumour and antiviral agents. Th eir mode of action has not been established, but their ability to bind with DNA by intercalation is believed to be involved. Of the three synthetic analogues of O-methylfagaronine which we have synthe sized, methoxidine and ethoxidine are active against HIV-1 reverse transcri ptase (IC50 values 2.8 mu M and 2.4 mu M respectively) whereas hydroxidine is inactive. One of the prerequisites for the enzyme inhibitory activity of this class of molecule is the presence of an iminium group-it is well know n that a positive charge on a polyaromatic nucleus facilitates intercalativ e binding with DNA. Through UV spectrophotometric and modelling studies, we have shown that the iminium bond plays a more fundamental role in enzyme i nhibition through its susceptibility to nucleophilic attack-the inactive an alogue hydroxidine has a non-electrophilic iminium bond. Consequently, we have demonstrated that iminium bond electrophilicity is a parameter which needs to be considered in ternary complex formation with re verse transcriptase.