Abbehausen C, Manzano C M, Corbi P P, Farrell N P
Institute of Chemistry, University of Campinas - UNICAMP, PO Box 6154, CEP 13083-970 Campinas, SP, Brazil.
Institute of Chemistry, University of Campinas - UNICAMP, PO Box 6154, CEP 13083-970 Campinas, SP, Brazil.
J Inorg Biochem. 2016 Dec;165:136-145. doi: 10.1016/j.jinorgbio.2016.05.011. Epub 2016 May 30.
Gold(I) based drugs are interesting for their potential medical use. The relatively facile ligand substitution in linear gold(I) compounds makes the identification of active species complicated. Ligands such as PR and CN are likely to be carrier ligands due to their strong trans-directing properties and will dictate the nature of substitution reactions. The 2-mercaptothiazoline (mtz) ligand is an N,S-heterocyclic compound which presents an exocyclic thiol sulfur as well as a heterocyclic nitrogen. The coordination of mtz to transition metals can be modulated by the trans ligand and complexes with metal bound through the nitrogen and/or the exocyclic sulfur are known. Therefore, the complexes [NCAu(N-mtz)] (N-coordinated) and [(PhP)Au(S-mtz)] (S-coordinated) were investigated to compare the influence of CN and PR as well as the coordination mode of the mtz ligand on reactivity with thiols and sulfur-containing proteins. As a further comparison the compound [(PhP)AuCN] was also studied. Human serum albumin, egg white lysozyme and, principally, the C-terminal zinc finger (ZF2) of the nucleocapsid NCp7protein of HIV-1 were studied. Results from zinc finger studies show that the coordination structure can determine the reactivity toward biomolecules. Due to ligand scrambling, the complex [NCAu(N-mtz)] forms very reactive species in solution generating [NCAu-biomolecule] adducts, where x,y≤3. The observation by mass spectrometry of [(CN)Au]-ZF confirms the ability of Au(I) compounds to form [(Ligand)Au] adducts on zinc fingers, in contrast to Au(III), where all ligands are lost upon reaction with the zinc finger. On the other hand, [(PhP)Au(S-mtz)] also generates the [(PhP)Au] species due to ligand scrambling, that showed lower reactivity, probably due to steric hindrance. For this complex [(PhP)Au-biomolecule] and [Au-biomolecule] adducts are dominant. The results corroborate the hypothesis of modulation through coordination as the reactivity clearly depends on not only the ligand, but also the coordination mode.
基于金（I）的药物因其潜在的医学用途而备受关注。线性金（I）化合物中相对容易发生的配体取代使得活性物种的鉴定变得复杂。诸如PR和CN之类的配体由于其强烈的反位导向性质而可能是载体配体，并将决定取代反应的性质。2-巯基噻唑啉（mtz）配体是一种N，S-杂环化合物，它具有环外硫醇硫以及杂环氮。mtz与过渡金属的配位可以通过反位配体进行调节，并且已知通过氮和/或环外硫与金属结合的配合物。因此，研究了配合物[NCAu（N-mtz）]（N配位）和[（PhP）Au（S-mtz）]（S配位），以比较CN和PR的影响以及mtz配体的配位模式对与硫醇和含硫蛋白质反应性的影响。作为进一步的比较，还研究了化合物[（PhP）AuCN]。研究了人血清白蛋白、蛋清溶菌酶，主要是HIV-1核衣壳NCp7蛋白的C端锌指（ZF2）。锌指研究结果表明，配位结构可以决定对生物分子的反应性。由于配体重排，配合物[NCAu（N-mtz）]在溶液中形成非常活泼的物种，生成[x,y≤3的][NCAu-生物分子]加合物。通过质谱观察[（CN）Au]-ZF证实了金（I）化合物在锌指上形成[（配体）Au]加合物的能力，这与金（III）相反，金（III）与锌指反应时所有配体都会失去。另一方面，[（PhP）Au（S-mtz）]由于配体重排也会生成[（PhP）Au]物种，其反应性较低，可能是由于空间位阻。对于这种配合物，[（PhP）Au-生物分子]和[Au-生物分子]加合物占主导地位。结果证实了通过配位进行调节的假设，因为反应性显然不仅取决于配体，还取决于配位模式。
