Chair of Analytical Chemistry, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland.
Chair of Medical Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland.
J Inorg Biochem. 2019 Sep;198:110714. doi: 10.1016/j.jinorgbio.2019.110714. Epub 2019 May 28.
A micro-electrochemical reaction cell was coupled to an electrospray mass spectrometer in order to track redox transformations for two representative medicinal gold compounds - i.e. [(2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranosato-S)(triethylphosphine)gold(I)] and [Au(bipy-H)(OH)][PF] (where bipy-H is deprotonated 6-(1,1-dimethylbenzyl)-2,2'-bipyridine), known as Auranofin and Aubipy respectively - in parallel to square wave voltammetry (SWV) measurements. Irreversible oxidation of thio-glucose tetraacetate was the dominant reaction for the gold(I) compound Auranofin; oxidation was accompanied by hydrolysis leading to progressive deacetylation. Two main active forms were identified for this prodrug: the triethylphosphinegold(I) cation and a gold(I) thioglucose species, with a variable number of acetyl groups. For the gold(III) complex Aubipy irreversible reduction of the gold(III) center was highlighted, accompanied by a ligand exchange process. The free gold(I) ion is proposed to be the final species that subsequently binds transport proteins in the bloodstream. Molecule specific mass spectrometry determinations provide complementary data to square wave voltammetry helping to understand the nature of the electrochemical conversions of complex or unstable compounds. Finally, it was possible to establish that oxidizing conditions during drug preparation and administration should be avoided in the case of Auranofin; conversely, reduction conditions typical for the blood or the cytosol environment are suitable to obtain the active gold(I) species from the gold(III) complex Aubipy.
为了追踪两种代表性的药用金化合物——即[(2,3,4,6-四-O-乙酰基-1-硫代-β-D-吡喃葡萄糖基-S)(三乙基膦)金(I)]和[Au(bipy-H)(OH)][PF](其中 bipy-H 是去质子化的 6-(1,1-二甲基苄基)-2,2'-联吡啶)——的氧化还原转化，将一个微电化学反应池与电喷雾质谱仪耦合，同时进行方波伏安法(SWV)测量。硫代葡萄糖四乙酸的不可逆氧化是金(I)化合物金诺芬的主要反应；氧化伴随着水解，导致逐步去乙酰化。这种前药有两种主要的活性形式：三乙基膦金(I)阳离子和具有可变乙酰基数目的金(I)硫代葡萄糖物种。对于金(III)配合物 Aubipy，强调了金(III)中心的不可逆还原，同时伴随着配体交换过程。游离金(I)离子被认为是随后与血液中的转运蛋白结合的最终物质。分子特异性质谱测定提供了与方波伏安法互补的数据，有助于理解复杂或不稳定化合物电化学转化的性质。最后，有可能确定在金诺芬的药物制备和给药过程中应避免氧化条件；相反，血液或细胞质环境中典型的还原条件适合从金(III)配合物 Aubipy 中获得活性金(I)物种。
