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目的合成制备芥子气(SM)的重要氧化代谢产物二乙烯砜(DVS)的谷胱甘肽(GSH)加合物,并研究其体外与DNA的加合反应活性。方法以SM为起始原料,通过两步氧化反应制备芥子亚砜(SMO)和芥子砜(SMO_2),在碱性条件下通过“脱氯”反应合成并纯化获得DVS,进而采用制备液相色谱纯化获得了DVS-GSH单加合物及其与鸟嘌呤或腺嘌呤形成的2种DVS双加合物,并通过超高效液相色谱串联质谱(UPLC-MS/MS)技术研究DVS-GSH与体外DNA的加合反应活性。核磁共振谱和高分辨质谱鉴定DVS加合物表征和结构。结果在水溶液中DVS与GSH的反应活性显著高于SM,且生成的DVS-GSH单加合物也具有较强的反应活性,可与DNA的腺嘌呤和鸟嘌呤生成系列新的加合物,且与腺嘌呤加合物的丰度高于与鸟嘌呤加合物。结论 SM的氧化代谢产物DVS的二相代谢产物(DVS-GSH)与DNA体外仍具有较强的加合反应活性,其对DNA的损伤效应值得关注。
Objective To synthesize the glutathione (GSH) adduct of divinylsulfone (DVS), an important oxidative metabolite of mustard gas (SM), and to study its in vitro reactivity with DNA. Methods SMS and SMO_2 were prepared by two-step oxidation reaction with SM as the starting material. The DVS was synthesized and purified by the “dechlorination” reaction under alkaline conditions, and then the preparation solution DVS-GSH monoadducts and their two DVS double adducts with guanine or adenine were obtained by phase-HPLC purification. The effects of DVS-GSH on DVS-GSH were studied by UPLC-MS / MS. Addition of GSH to in vitro DNA. Identification and Structure of DVS Adducts by Nuclear Magnetic Resonance Spectroscopy and High Resolution Mass Spectrometry. Results The reactivity of DVS and GSH in aqueous solution was significantly higher than that of SM, and the resulting DVS-GSH monoadduct also had strong reactivity and could form a series of new adducts with adenine and guanine of DNA, And the abundance of adenine adducts is higher than that of guanine adducts. Conclusions The two-phase metabolite of DVS (DVS-GSH), an oxidative metabolite of SM, still has strong adduct reactivity with DNA in vitro and its DNA damage effect deserves attention.