Abstract
Experimental and theoretical evidence pertaining to cytotoxic and genotoxic activity of paracetamol in biological systems was used to formulate a simple mechanistic hypothesis to explain the relative inhibition of replicative DNA synthesis by a series of 19 structurally similar paracetamol analogues, 5 of which were specifically analyzed for the current study. It was hypothesized that the observed activity variation of the paracetamol analogues was based on the relative abilities of these compounds to undergo H atom loss at the phenolic oxygen, and on the relative stabilities of the resulting free-radical species. Three calculated parameters were found to be relevant--the partial atomic charge on the ring carbon attached to the phenolic oxygen, the partial charge on the phenoxy radical oxygen, and the energy difference between the parent phenolic paracetamol analogue and the corresponding radical dissociation products. The variation in parameter values was significantly correlated with the relative inhibition of DNA synthesis and was easily rationalized in terms of the mechanistic hypothesis proposed. More specifically, competitive reaction with a tyrosyl radical species involving the transfer of a hydrogen atom at the active site of ribonucleotide reductase was suggested as the underlying mechanistic basis for the observed activity variation of the paracetamol analogues. Comparison of calculated parameters for a model tyrosyl species and the paracetamol analogues was entirely consistent with this view.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.