Kinetics of the reaction of a potential chemopreventive agent, 2,6-dithiopurine, and its major metabolite, 2,6-dithiouric acid, with multiple classes of electrophilic toxicants

Chemical Research in Toxicology
W G QingMichael C MacLeod

Abstract

Purinethiols are a class of potential cancer chemopreventive agents that exhibit nucleophilic scavenging activity against the carcinogenic electrophile benzo[a]pyrene diol epoxide (BPDE). Of the purinethiols tested previously, 2,6-dithiopurine (DTP), exhibited the highest scavenging activity for BPDE when tested either in vitro or in vivo. Sulfur-based nucleophiles are typically classified as "soft" nucleophiles, showing selectivity in nucleophilic substitution reactions for "soft", easily polarizable electrophiles. It was of interest to determine whether electrophilic toxicants other than BPDE react facilely with DTP, and whether 2,6-dithiouric acid (DUA), the major in vivo metabolite of DTP, also has scavenging activity. Four diverse toxicants tested in the present work, acrolein, melphalan, dimethyl sulfate, and cisplatin, all react facilely with DTP in vitro near neutral pH. These toxicants are expected to react as "soft" electrophiles. Furthermore, each of these compounds, as well as BPDE, reacts with DUA with rate constants comparable to the analogous rate constants for reaction with DTP. In contrast, several toxicants classified as "hard" electrophiles (ethyl methanesulfonate, methylnitrosourea, ethylnitrosourea, 1-methy...Continue Reading

Citations

Jan 7, 2010·Chemical Research in Toxicology·Jinyun LiuMichael C MacLeod
Aug 19, 2010·Oxidative Medicine and Cellular Longevity·Abdulaziz A Al-YahyaAdel R A Abd-Allah
Jun 30, 2011·Molecular Nutrition & Food Research·Qin ZhuMingfu Wang
Mar 1, 2012·The Biochemical Journal·Ashlee HigdonVictor M Darley-Usmar
Mar 4, 2019·Toxicology·Richard M LoPachinLars U Nordstroem

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