Structure-Activity Relationship Investigation on Reaction Mechanism between Chlorinated Quinoid Carcinogens and...

Pyridinium aldoximes are best-known therapeutic antidotes used for clinical treatment of poisonings by organophosphorus nerve-agents and pesticides. Recently, we found that pralidoxime (2-PAM, a currently clinically used nerve-agent antidote) could also detoxify tetrachloro-1,4-benzoquinone (TCBQ), which is a carcinogenic quinoid metabolite of the widely used wood preservative pentachlorophenol under normal physiological conditions, via an unusually mild and facile Beckmann fragmentation mechanism accompanied by radical homolysis. However, it is not clear whether the less-chlorinated benzoquinones (CBQs, n ≤ 3) act similarly; if so, what is the structure-activity relationship? In this study, we found that (1) The stability of reaction intermediates produced by different CBQs and 2-PAM was dependent not only on the position but also the degree of Cl-substitution on CBQs, which can be divided into TCBQ- and DCBQ (dichloro-1,4-benzoquinone)-subgroup; (2) The pK_a value of hydroxlated quinones (CBQ-OHs, the hydrolysis products of CBQs), determined the stability of corresponding intermediates, that is, the decomposition rate of the intermediates depended on the acidity of CBQ-OHs; (3) The pK_a value of the corresponding CBQ-OHs could also determine the reaction ratio of Beckmann fragmentation to radical homolysis in CBQs/2-PAM. These new findings on the structure-activity relationship of the halogenated quinoid carcinogens detoxified by pyridinium aldoxime therapeutic agents via Beckmann fragmentation and radical homolysis reaction may have broad implications on future biomedical and environmental research.