Jędrzejczyk Marta, Sulik Michał, Mielczarek-Puta Magdalena, Lim Gwan Yong, Podsiad Małgorzata, Hoser Jakub, Bednarczyk Piotr, Struga Marta, Huczyński Adam
Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61‒614, Poznań, Poland.
Chair and Department of Biochemistry, Faculty of Medicine, Medical University of Warsaw, Banacha 1, 02‒097, Warsaw, Poland.
Eur J Med Chem. 2025 Jan 15;282:117055. doi: 10.1016/j.ejmech.2024.117055. Epub 2024 Nov 14.
In recent years salinomycin has emerged as a promising anticancer drug. Many literature reports have proved its remarkable antiproliferative activity. Moreover, chemical modifications of salinomycin lead to analogues with even higher cytotoxicity against cancer cell lines and a better selectivity index for malignant cells than those of the unmodified compound or a standard anticancer drug such as doxorubicin. In this paper we report the synthesis of a series of twelve novel salinomycin conjugates and their characterization by spectroscopic and spectrometric methods. Salinomycin was conjugated with different triphenylphosphonium cations in order to find out whether the conjugation with mitochondrial targeting vectors would have a beneficial impact on biological properties. Salinomycin and its novel conjugates were tested to determine their in vitro antiproliferative and antimicrobial activity. Taking into account the presence of triphenylphosphonium moiety, the impact of the obtained analogues on mitochondria activity was evaluated by MitoTrackers dyes, furthermore their apoptosis effect and cell cycle arrest were assessed. In addition, the changes in the mitochondrial membrane potential were measured and the ability to generate reactive oxygen species was assessed. Finally, we conducted biophysical studies to investigate the impact of the obtained salinomycin analogues on mitochondrial respiration rates and their electrophysiological properties. Results of this study have proved that conjugation of salinomycin with phosphonium cations leads to promising results in the search for promising anticancer agents.
近年来，沙林霉素已成为一种有前景的抗癌药物。许多文献报道已证实其具有显著的抗增殖活性。此外，沙林霉素的化学修饰产生了一些类似物，这些类似物对癌细胞系具有更高的细胞毒性，并且与未修饰的化合物或标准抗癌药物（如阿霉素）相比，对恶性细胞具有更好的选择性指数。在本文中，我们报道了一系列十二种新型沙林霉素缀合物的合成及其通过光谱和光谱测定方法进行的表征。将沙林霉素与不同的三苯基鏻阳离子缀合，以探究与线粒体靶向载体的缀合是否会对生物学性质产生有益影响。对沙林霉素及其新型缀合物进行测试，以确定它们的体外抗增殖和抗菌活性。考虑到三苯基鏻部分的存在，通过线粒体跟踪染料评估所得类似物对线粒体活性的影响，此外还评估了它们的凋亡效应和细胞周期阻滞。另外，测量线粒体膜电位的变化并评估产生活性氧的能力。最后，我们进行了生物物理研究，以探究所得沙林霉素类似物对线粒体呼吸速率及其电生理性质的影响。本研究结果证明，沙林霉素与鏻阳离子的缀合在寻找有前景的抗癌药物方面产生了有前景的结果。
