Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.
Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudósok körútja 2, H-1117 Budapest, Hungary and Department of Physiology, Semmelweis University, Tűzoltó utca 37-47, H-1094 Budapest, Hungary.
Dalton Trans. 2021 Jun 15;50(23):8218-8231. doi: 10.1039/d1dt00808k.
A series of half-sandwich polypyridyl complexes was synthesized and compared focusing on structural, cytotoxic and aqueous solution behaviour. The formula of the synthesized complexes is [M(arene)(N,N)Cl]Cl, where M: Ru or Rh, arene: p-cymene, toluene or C5Me5-, (N,N): 2,2'-bipyridine (bpy), 4,4'-dimethyl-2,2'-bipyridine (dmb), 1,10-phenanthroline (phen) or 2,9-dimethyl-1,10-phenanthroline (neo). The structures of five half-sandwich complexes were determined by X-ray crystallography. It was found that introducing methyl groups next to the coordinating nitrogen atoms of the bidentate ligand causes steric congestion around the metal centre which changes the angle between ligand planes. The ligands and the Rh complexes showed significant cytotoxicity in A2780 and MES-SA cancer cell lines (IC50 = 0.1-56 μM) and in the cisplatin-resistant A2780cis cells. Paradoxically, phen and dmb as well as their half-sandwich Rh complexes showed increased toxicity against multidrug resistant MES-SA/Dx5 cells. In contrast, coordination to Ru caused loss of toxicity. Solution equilibrium constants showed that the studied metal complexes have high stability, and no dissociation was found for Ru and Rh complexes even at micromolar concentrations in a wide pH range. However, in the case of Ru complexes a slow and irreversible decomposition, namely arene loss, was also observed, which was more pronounced in light exposure in aqueous solution. In the case of neo, the methyl groups next to the nitrogen atoms significantly decrease the stability of complexes. For Rh complexes, the order of the stability constants corrected with ligand basicity (log K*): 9.78 (phen) > 9.01 (dmb) > 8.89 (bpy) > 3.93 (neo). The coordinated neo resulted in an enormous decrease in the chloride ion affinity of Ru compounds. Based on the results, a universal model was introduced for the prediction of chloride ion capability of half-sandwich Rh and Ru complexes. It combines the effects of the bidentate ligand and the M(arene) part using only two terms, performing multilinear regression procedure.
一系列半三明治多吡啶配合物被合成并进行了比较，重点关注结构、细胞毒性和水溶液行为。合成配合物的公式为[M(芳烃)(N，N)Cl]Cl，其中 M：Ru 或 Rh，芳烃：对异丙基甲苯、甲苯或 C5Me5-，(N，N)：2,2'-联吡啶(bpy)、4,4'-二甲基-2,2'-联吡啶(dmb)、1,10-菲咯啉(phen)或 2,9-二甲基-1,10-菲咯啉(neo)。通过 X 射线晶体学确定了五个半三明治配合物的结构。发现，在双齿配体的配位氮原子的邻位引入甲基会导致金属中心周围的空间位阻增加，从而改变配体平面之间的角度。配体和 Rh 配合物在 A2780 和 MES-SA 癌细胞系（IC50=0.1-56 μM）以及顺铂耐药的 A2780cis 细胞中表现出显著的细胞毒性。矛盾的是，phen 和 dmb 以及它们的半三明治 Rh 配合物对多药耐药 MES-SA/Dx5 细胞表现出更高的毒性。相比之下，与 Ru 配位会导致毒性丧失。溶液平衡常数表明，所研究的金属配合物具有高稳定性，即使在宽 pH 范围内的微摩尔浓度下，也未发现 Ru 和 Rh 配合物解离。然而，在 Ru 配合物的情况下，还观察到缓慢且不可逆的分解，即芳烃的损失，这在水溶液中的光照下更为明显。对于 neo，氮原子邻位的甲基显著降低了配合物的稳定性。对于 Rh 配合物，用配体碱性（log K*）校正的稳定性常数顺序为：9.78（phen）>9.01（dmb）>8.89（bpy）>3.93（neo）。配位的 neo 导致 Ru 化合物对氯离子的亲和力大大降低。基于这些结果，引入了一个通用模型来预测半三明治 Rh 和 Ru 配合物的氯离子能力。它使用两个术语结合双齿配体和 M(芳烃)部分，执行多元线性回归程序。
