Qing W G, Powell K L, MacLeod M C
Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Smithville 78957, USA.
Chem Res Toxicol. 1996 Dec;9(8):1298-304. doi: 10.1021/tx960088n.
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-methyl-3-nitro-1-nitrosoguanidine) show no appreciable reaction with DTP. These results suggest that both DTP and its major metabolite act as "soft" nucleophiles in nucleophilic substitution reactions and may be effective in scavenging a wide range of toxicants that react as "soft" electrophiles.
嘌呤硫醇是一类潜在的癌症化学预防剂，对致癌亲电试剂苯并[a]芘二醇环氧化物（BPDE）具有亲核清除活性。在先前测试的嘌呤硫醇中，2,6 - 二硫代嘌呤（DTP）在体外或体内测试时，对BPDE表现出最高的清除活性。基于硫的亲核试剂通常被归类为“软”亲核试剂，在亲核取代反应中对“软”的、易于极化的亲电试剂具有选择性。确定除BPDE之外的亲电毒物是否能与DTP轻松反应，以及DTP的主要体内代谢物2,6 - 二硫代尿酸（DUA）是否也具有清除活性，这很有意思。在本研究中测试的四种不同毒物，丙烯醛、美法仑、硫酸二甲酯和顺铂，在接近中性pH的体外环境中都能与DTP轻松反应。预计这些毒物会作为“软”亲电试剂发生反应。此外，这些化合物以及BPDE与DUA反应的速率常数与它们与DTP反应的类似速率常数相当。相比之下，几种被归类为“硬”亲电试剂的毒物（甲磺酸乙酯、甲基亚硝基脲、乙基亚硝基脲、1 - 甲基 - 3 - 硝基 - 1 - 亚硝基胍）与DTP没有明显反应。这些结果表明，DTP及其主要代谢物在亲核取代反应中都作为“软”亲核试剂起作用，并且可能有效地清除作为“软”亲电试剂反应的多种毒物。
