Stocchetti Sara, Vančo Ján, Bresciani Giulio, Biancalana Lorenzo, Belza Jan, Zacchini Stefano, Dvořák Zdeněk, Benetti Sara, Biver Tarita, Bortoluzzi Marco, Trávníček Zdeněk, Marchetti Fabio
University of Pisa, Department of Chemistry and Industrial Chemistry, Via G. Moruzzi 13, I-56124, Pisa, Italy.
Regional Centre of Advanced Technologies and Materials, Czech Advanced Technology and Research Institute, Palacký University, Šlechtitelů 27, CZ-779 00, Olomouc, Czech Republic.
Eur J Med Chem. 2025 Mar 15;286:117304. doi: 10.1016/j.ejmech.2025.117304. Epub 2025 Jan 21.
The novel diiron amine complexes [FeCp(CO)(NHR')(μ-CO){μ-CN(Me)(Cy)}]CFSO [R' = H, 3; Cy, 4; CHCHNH, 5; CHCHNMe, 6; CHCH(4-CHOMe), 7; CHCH(4-CHOH), 8; Cp = η-CH, Cy = CH = cyclohexyl] were synthesized in 49-92 % yields from [FeCp(CO)(μ-CO){μ-CN(Me)(Cy)}]CFSO, 1a, using a straightforward two-step procedure. They were characterized by IR and multinuclear NMR spectroscopy, and the structure of 7 was confirmed through X-ray diffraction analysis. Complexes 3-8 and the acetonitrile adducts [FeCp(CO)(NCMe)(μ-CO){μ-CN(Me)(R)}]CFSO (R = Cy, 2a; Me, 2b; Xyl = 2,6-CHMe, 2c) were assessed for their water solubility, octanol-water partition coefficient and stability in physiological-like solutions. The in vitro antiproliferative activity of 2a-c and 3-8 was tested on seven human cancer cell lines (A2780, A2780R, PC3, A549, MCF7, HOS and HT-29), while the selectivity was evaluated using normal MRC-5 cells. Overall, the complexes exhibited variable cytotoxicity, with IC values reaching the low micromolar range for 3, 7 and 8 in A2780 and A2780R cells, along with significant selectivity. Targeted experiments covered cell cycle modification, induction of cell death, mitochondrial membrane potential, ROS production and interaction with DNA and bovine serum albumin (BSA) as a model protein. The interaction of 3 with BSA was further investigated through computational studies. Results showed a negligible increase in intracellular ROS levels (except for 2b) and insignificant changes in mitochondrial membrane potential.
新型二铁胺配合物[FeCp(CO)(NHR')(μ-CO){μ-CN(Me)(Cy)}]CFSO [R' = H, 3；Cy, 4；CHCHNH, 5；CHCHNMe, 6；CHCH(4-CHOMe), 7；CHCH(4-CHOH), 8；Cp = η-CH, Cy = CH = 环己基] 通过一个简单的两步程序由[FeCp(CO)(μ-CO){μ-CN(Me)(Cy)}]CFSO（1a）合成，产率为49 - 92%。它们通过红外光谱和多核核磁共振光谱进行表征，并且通过X射线衍射分析确定了7的结构。评估了配合物3 - 8以及乙腈加合物[FeCp(CO)(NCMe)(μ-CO){μ-CN(Me)(R)}]CFSO（R = Cy, 2a；Me, 2b；Xyl = 2,6-CHMe, 2c）的水溶性、辛醇 - 水分配系数以及在类生理溶液中的稳定性。在七种人类癌细胞系（A2780、A2780R、PC3、A549、MCF7、HOS和HT - 29）上测试了2a - c和3 - 8的体外抗增殖活性，同时使用正常的MRC - 5细胞评估其选择性。总体而言，这些配合物表现出不同的细胞毒性，在A2780和A2780R细胞中，3、7和8的IC值达到低微摩尔范围，并且具有显著的选择性。有针对性的实验涵盖细胞周期改变、细胞死亡诱导、线粒体膜电位、活性氧生成以及与DNA和作为模型蛋白的牛血清白蛋白（BSA）的相互作用。通过计算研究进一步研究了3与BSA的相互作用。结果显示细胞内活性氧水平增加可忽略不计（2b除外），线粒体膜电位变化不显著。
