Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.
Dalton Trans. 2020 Dec 8;49(46):16887-16902. doi: 10.1039/d0dt03465g.
α-N-Heterocyclic thiosemicarbazones are an important class of investigational anticancer drugs. The most prominent representative is 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine), which has shown promising results in clinical trials and is currently evaluated in phase III. In this study, we investigated the influence of a chalcogen atom exchange from S (Triapine) to O (O-Triapine) and Se (Se-Triapine) and the methylation of the hydrazonic NH moiety (Me-Triapine) on their complexation with Fe(ii), Fe(iii) and Cu(ii) ions and their cytotoxicity. The main aim of this study was to characterize and compare the most feasible chemical forms in solution, their stability and redox properties, as well as to reveal the relationships of the solution speciation and kinetic data with cytotoxic activity. The complex equilibria and redox properties of the complexes were characterized by the combined use of pH-potentiometry, UV-visible spectrophotometry, electron paramagnetic resonance spectroscopy, and cyclic voltammetry. These revealed that Se-Triapine forms Cu(ii) complexes with higher, and O-Triapine with lower stability as compared with Triapine. Me-Triapine, which is not able to coordinate via the typical (N,N,S-) donor set, nevertheless coordinates to Cu(ii) with unexpected high stability. The Cu(ii) complexes of Se-Triapine and Me-Triapine can be relatively slowly reduced by glutathione at pH 7.4 (but not by ascorbate), similarly to Cu(ii)-Triapine. In contrast, the Cu(ii)-O-Triapine complex can be reduced by both reducing agents in rapid redox reactions. Se-Triapine and Triapine form high stability complexes with both Fe(ii) and Fe(iii) ions, while O-Triapine has a much stronger preference towards Fe(iii) and Me-Triapine towards Fe(ii). This difference in the iron preference of the ligands seems to have a strong impact on their cytotoxic effects, which was measured in a human uterine sarcoma cell line (MES-SA) and its multidrug-resistant subline (MES-SA/Dx5). The Cu(ii) complexes of these calcogensemicarbazones are moderately toxic, and the highest level of ROS generation was found for the Cu(ii) complex of O-Triapine, which is the most reducible.
α-N-杂环硫代缩氨基脲是一类重要的研究性抗癌药物。最突出的代表是 3-氨基吡啶-2-甲醛缩氨基硫脲（Triapine），它在临床试验中显示出了很好的效果，目前正在进行 III 期评估。在这项研究中，我们研究了从 S（Triapine）到 O（O-Triapine）和 Se（Se-Triapine）的硫原子交换以及腙 NH 部分的甲基化（Me-Triapine）对它们与 Fe(ii)、Fe(iii)和 Cu(ii)离子的络合以及细胞毒性的影响。本研究的主要目的是表征和比较溶液中最可行的化学形式、它们的稳定性和氧化还原性质，并揭示溶液形态和动力学数据与细胞毒性活性之间的关系。通过 pH 电位滴定、紫外可见分光光度法、电子顺磁共振波谱法和循环伏安法的联合使用，研究了配合物的配合平衡和氧化还原性质。结果表明，与 Triapine 相比，Se-Triapine 形成 Cu(ii)配合物的稳定性更高，O-Triapine 形成 Cu(ii)配合物的稳定性更低。Me-Triapine 不能通过典型的（N，N，S-）供体组配位，但仍能与 Cu(ii)形成出乎意料的高稳定性配合物。在 pH 7.4 下（但不能由抗坏血酸），谷胱甘肽可相对缓慢地还原 Se-Triapine 和 Me-Triapine 的 Cu(ii)配合物，类似于 Cu(ii)-Triapine。相比之下，Cu(ii)-O-Triapine 配合物可以通过两种还原剂快速进行氧化还原反应。Se-Triapine 和 Triapine 与 Fe(ii)和 Fe(iii)离子形成高稳定性的配合物，而 O-Triapine 对 Fe(iii)的偏好更强，Me-Triapine 对 Fe(ii)的偏好更强。配体对铁的这种偏好差异似乎对它们的细胞毒性作用有很大影响，这在人子宫肉瘤细胞系（MES-SA）及其多药耐药亚系（MES-SA/Dx5）中进行了测量。这些硫代缩氨基脲的 Cu(ii)配合物具有中等毒性，并且 O-Triapine 的 Cu(ii)配合物产生的 ROS 最多，这表明它最易还原。
