Department of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI-Center for Molecular Biosciences Innsbruck, CCB-Center for Chemistry and Biomedicine, University of Innsbruck, Innsbruck, Austria.
Tyrolean Cancer Research Institute, Innsbruck, Austria.
Arch Pharm (Weinheim). 2023 May;356(5):e2200655. doi: 10.1002/ardp.202200655. Epub 2023 Feb 3.
Recent in vitro investigations of N,N'-bis(salicylidene)-1,2-phenylenediamine (SAP) iron(III) complexes substituted with alkyl (ethyl, propyl, butyl) carboxylates at position 4 in tumor and leukemia cells revealed strong cytotoxic activity. In continuation of this study, analogous nickel(II) and cobalt(III) complexes were synthesized and tested in HL-60 leukemia, and cisplatin-sensitive and -resistant A2780 ovarian cancer cell lines. The biological activity depended on the extent of cellular uptake and the formation of reactive oxygen species (ROS). Inactive [(Ni(II)SAP] complexes (1-3) only marginally accumulated in tumor cells and did not induce ROS. The cellular uptake of [Co(III)SAP]Cl complexes (4-6) into the cells depended on the length of the ester alkyl chain (ethyl, 4 < propyl, 5 < butyl, 6). The cytotoxicity correlated with the presence of ROS. The low cytotoxic complex 4 induced only few ROS, while 5 and 6 caused a good to outstanding antiproliferative activity, exerted high ROS generation, and induced cell death after 48 h. Necrostatin-1 prevented the biological effects, proving necroptosis as part of the mode of action. Interestingly, the effects of 5 and 6 were not reversed by Ferrostatin-1, but even enhanced upon simultaneous application to the tumor cells.
最近在肿瘤和白血病细胞中对 N,N'-双（水杨醛）-1,2-苯二胺（SAP）铁（III）配合物进行的体外研究表明，取代 4 位的烷基（乙基、丙基、丁基）羧酸酯的 SAP 铁（III）配合物具有很强的细胞毒性。在这项研究的延续中，类似的镍（II）和钴（III）配合物被合成并在 HL-60 白血病和顺铂敏感和耐药的 A2780 卵巢癌细胞系中进行了测试。生物活性取决于细胞摄取的程度和活性氧物质（ROS）的形成。无活性的 [(Ni(II)SAP)]配合物（1-3）仅在肿瘤细胞中轻微积累，并且不诱导 ROS。[Co(III)SAP]Cl 配合物（4-6）进入细胞的细胞摄取取决于酯烷基链的长度（乙基，4 < 丙基，5 < 丁基，6）。细胞毒性与 ROS 的存在相关。低细胞毒性的配合物 4 仅诱导少量 ROS，而 5 和 6 导致良好至出色的抗增殖活性，产生高 ROS 生成，并在 48 小时后诱导细胞死亡。坏死抑制剂-1 阻止了这些生物效应，证明坏死是作用模式的一部分。有趣的是，Ferrostatin-1 不能逆转 5 和 6 的作用，反而在同时应用于肿瘤细胞时增强了这些作用。
