The role of the iminium bond in the inhibition of reverse transcriptase by quaternary benzophenanthridines

• Published in: Journal of pharmacy and pharmacology 1998-11, Vol.50 (11), p.1307-1315
• Main Authors: Kerry, M A, Duval, O, Waigh, R D, Mackay, S P
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Alkaloids - pharmacology; Benzophenanthridines; DNA - metabolism; DNA Polymerase I - physiology; Escherichia coli - genetics; HIV Reverse Transcriptase - antagonists & inhibitors; Models, Molecular; Phenanthridines - pharmacology; Reverse Transcriptase Inhibitors - pharmacology; Spectrophotometry, Ultraviolet
• ISSN: 0022-3573; 2042-7158
• DOI: 10.1111/j.2042-7158.1998.tb03350.x

The quaternary benzo[c]phenanthridines fagaronine, nitidine and O-methylfagaronine have been reviewed as potential antitumour and antiviral agents. Their 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 synthesized, methoxidine and ethoxidine are active against HIV-1 reverse transcriptase (IC50 values 2.8 microM and 2.4 microM 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 known that a positive charge on a polyaromatic nucleus facilitates intercalative binding with DNA. Through UV spectrophotometric and modelling studies, we have shown that the iminium bond plays a more fundamental role in enzyme inhibition through its susceptibility to nucleophilic attack--the inactive analogue 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 reverse transcriptase.