Structure-activity study of paracetamol analogs: inhibition of replicative DNA synthesis in V79 Chinese hamster cells

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.