Hošek Jan, Petrželová Kamila, Héžová Renata, Straková Nicol, Kajabová Simona, Nemec Ivan, Šimečková Pavlína, Pěnčíková Kateřina, Mašek Josef, Moncoľ Ján, Štarha Pavel
Department of Pharmacology and Toxicology, Veterinary Research Institute, Hudcova 296/70, Brno, 62100, Czech Republic.
Department of Inorganic Chemistry, Faculty of Science, Palacky University Olomouc, 17. listopadu 12, 77146, Olomouc, Czech Republic.
Eur J Med Chem. 2025 Nov 5;297:117970. doi: 10.1016/j.ejmech.2025.117970. Epub 2025 Jul 11.
A series of ruthenium(II) and osmium(II) half-sandwich complexes was synthesized and characterized for its potential as a new class of anticancer agents. The complexes feature polycyclic aromatic hydrocarbon (PAH)-substituted Schiff bases and were rationally designed to combine the redox-modulating MoA of half-sandwich Ru, Rh, Os and Ir complexes, connected with their ability to induce the formation of various reactive oxygen species (ROS), with the ability of PAH-substituents to target and disrupt DNA. The complexes [Ru(η-pcym)Cl(L)]PF (1-4) and [Os(η-pcym)Cl(L)]PF (5-8) were stable in aqueous environments, in contrast to the rapid degradation observed for the co-studied rhodium(III) (9-12) and iridium(III) (13-16) [M(η-Cp∗)Cl(L)]PF complexes; L = ethane-1,2-diamine-based Schiff bases (L1-L4) bearing two terminal PAH substituents 2-naphtyl (for L1), 9-anthracenyl (for L2), 9-phenanthrenyl (L3) or 1-pyrenyl (L4); pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene), Cp∗ = pentamethylcyclopentadienyl. Biological testing demonstrated that 1-8 possess significant antiproliferative activity against various lung cancer cell lines, including those resistant to cisplatin, with Os(II) complex 5 showing the highest cytotoxicity. Treatment with these complexes led to the activation of stress-related gene pathways, including unconventional endoplasmic reticulum stress, apoptotic signalling, and mitochondrial membrane depolarization. Activation of p21/GADD45A pathway indicates DNA-damage response, as well. Notably, these complexes did not induce significant inflammatory responses, a notable advantage over cisplatin. The results highlight the potential of Ru and Os half-sandwich complexes as alternative metallodrugs, capable of overcoming platinum resistance and minimizing inflammatory side effects. This study suggests that these compounds could serve as a promising class of anticancer agents for future clinical development.
合成了一系列钌（II）和锇（II）半夹心配合物，并对其作为一类新型抗癌剂的潜力进行了表征。这些配合物具有多环芳烃（PAH）取代的席夫碱，经过合理设计，将半夹心钌、铑、锇和铱配合物的氧化还原调节作用机制（与它们诱导形成各种活性氧（ROS）的能力相关）与PAH取代基靶向和破坏DNA的能力相结合。配合物[Ru(η-pcym)Cl(L)]PF（1-4）和[Os(η-pcym)Cl(L)]PF（5-8）在水性环境中稳定，这与共同研究的铑（III）（9-12）和铱（III）（13-16）[M(η-Cp∗)Cl(L)]PF配合物观察到的快速降解形成对比；L = 基于乙二胺的席夫碱（L1-L4），带有两个末端PAH取代基2-萘基（对于L1）、9-蒽基（对于L2）、9-菲基（L3）或1-芘基（L4）；pcym = 1-甲基-4-（丙烷-2-基）苯（对异丙基苯），Cp∗ = 五甲基环戊二烯基。生物学测试表明，1-8对各种肺癌细胞系具有显著的抗增殖活性，包括对顺铂耐药的细胞系，其中锇（II）配合物5显示出最高的细胞毒性。用这些配合物处理导致应激相关基因途径的激活，包括非常规内质网应激、凋亡信号传导和线粒体膜去极化。p21/GADD45A途径的激活也表明了DNA损伤反应。值得注意的是，这些配合物没有诱导显著的炎症反应，这是相对于顺铂的一个显著优势。结果突出了钌和锇半夹心配合物作为替代金属药物的潜力，能够克服铂耐药性并将炎症副作用降至最低。这项研究表明，这些化合物有望成为未来临床开发中有前景的一类抗癌剂。
