Gátszegi Gerda T, Petrasheuskaya Tatsiana V, May Nóra V, Hajdu Bálint, Spengler Gabriella, Bacher Felix, Shova Sergiu, Arion Vladimir B, Enyedy Éva A
Department of Molecular and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7-8, H-6720 Szeged, Hungary.
Centre for Structural Science, Research Centre for Natural Sciences, Hungarian Research Network (HUN-REN), Magyar tudósok körútja 2, H-1117 Budapest, Hungary.
J Inorg Biochem. 2025 Mar;264:112812. doi: 10.1016/j.jinorgbio.2024.112812. Epub 2024 Dec 10.
Schiff bases derived from aminoguanidine are extensively investigated for their structural versatility. The tridentate 2-formylpyridine guanylhydrazones act as analogues of 2-formyl or 2-acetylpyridine thiosemicarbazones, where the thioamide unit is replaced by the guanidyl group. Six derivatives of 2-formylpyridine guanylhydrazone were synthesized and their proton dissociation and complex formation processes with Cu(II), Fe(II) and Fe(III) ions were studied using pH-potentiometry, UV-visible, NMR and electron paramagnetic resonance spectroscopic methods. The ligands have substituents such as amine, morpholine, N-methyl-piperazine at different positions of the pyridine ring. The influence of the different structural elements on the solution chemical properties and cytotoxicity has been disclosed. The solid state structure of four ligands was determined by X-ray crystallography. The ligands bind to Cu(II) in a tridentate fashion via an (N,N,N) donor set, forming mono-ligand complexes. However, for ligands with heterocyclic morpholine and piperazine nitrogen atoms in coordination position a tetradentate binding was observed. Despite the additional coordinating donor atom, the stability of these Cu(II) complexes showed little or no increase. The Cu(II), Fe(II) and Fe(III) complexes of the studied 2-formylpyridine guanylhydrazones exhibited significantly lower stability compared to their corresponding 2-formyl or 2-acetylpyridine thiosemicarbazone analogues. The ligands underwent slow partial hydrolysis (and oxidation) in the presence of Cu(II) ions, leading to the formation of new ligands through the reorganization of structural components around the metal ion. Additionally, the studied Cu(II) complexes demonstrated a great propensity for reduction by glutathione. All these features contributed to the finding that these 2-formylpyridine guanylhydrazones and their Cu(II) complexes did not display measurable cytotoxic activity.
源自氨基胍的席夫碱因其结构多样性而受到广泛研究。三齿的2-甲酰基吡啶胍腙充当2-甲酰基或2-乙酰基吡啶硫代半卡巴腙的类似物，其中硫代酰胺单元被胍基取代。合成了六种2-甲酰基吡啶胍腙衍生物，并使用pH电位滴定法、紫外可见光谱法、核磁共振光谱法和电子顺磁共振光谱法研究了它们与铜（II）、铁（II）和铁（III）离子的质子解离和络合物形成过程。这些配体在吡啶环的不同位置具有胺、吗啉、N-甲基哌嗪等取代基。已揭示了不同结构元素对溶液化学性质和细胞毒性的影响。通过X射线晶体学确定了四种配体的固态结构。配体通过（N，N，N）供体集以三齿方式与铜（II）结合，形成单配体络合物。然而，对于在配位位置具有杂环吗啉和哌嗪氮原子的配体，观察到四齿结合。尽管有额外的配位供体原子，但这些铜（II）络合物的稳定性几乎没有增加或没有增加。所研究的2-甲酰基吡啶胍腙的铜（II）、铁（II）和铁（III）络合物与其相应的2-甲酰基或2-乙酰基吡啶硫代半卡巴腙类似物相比，稳定性显著降低。在铜（II）离子存在下，配体发生缓慢的部分水解（和氧化），通过金属离子周围结构成分的重组导致形成新的配体。此外，所研究的铜（II）络合物表现出被谷胱甘肽还原的强烈倾向。所有这些特征促成了这样的发现，即这些2-甲酰基吡啶胍腙及其铜（II）络合物没有显示出可测量的细胞毒性活性。
