Weintraub Sagiv, Moskovitz Yoni, Fleker Ohad, Levy Ariel R, Meir Aviv, Ruthstein Sharon, Benisvy Laurent, Gruzman Arie
Department of Chemistry, Bar-Ilan University, 5290002, Ramat Gan, Israel.
J Biol Inorg Chem. 2015 Dec;20(8):1287-98. doi: 10.1007/s00775-015-1307-x. Epub 2015 Nov 7.
The search for novel anticancer therapeutic agents is an urgent and important issue in medicinal chemistry. Here, we report on the biological activity of the copper-based bioinorganic complex Cu4 (2,4-di-tert-butyl-6-(1H-imidazo- [1, 10] phenanthrolin-2-yl)phenol)4]·10 CH3CN (2), which was tested in rat L6 myotubes, mouse NSC-34 motor neurone-like cells, and HepG-2 human liver carcinoma. Upon 96 h incubation, 2 exhibited a significant cytotoxic effect on all three types of cells via activation of two cell death mechanisms (apoptosis and necrosis). Complex 2 exhibited better potency and efficacy than the canonical cytotoxic drug cisplatin. Moreover, during shorter incubations, complex 2 demonstrated a significant SOD mimetic activity, and it was more effective and more potent than the well-known SOD mimetic TEMPOL. In addition, complex 2 was able to interact with DNA and, cleave DNA in the presence of sodium ascorbate. This study shows the potential of using polynuclear redox active compounds for developing novel anticancer drugs through SOD-mimetic redox pathways.
寻找新型抗癌治疗药物是药物化学中一个紧迫且重要的问题。在此，我们报道了铜基生物无机配合物Cu4(2,4 - 二叔丁基 - 6 - (1H - 咪唑并[1,10]菲咯啉 - 2 - 基)苯酚)4]·10 CH3CN(2)的生物活性，该配合物在大鼠L6肌管、小鼠NSC - 34运动神经元样细胞和HepG - 2人肝癌细胞中进行了测试。在孵育96小时后，2通过激活两种细胞死亡机制（凋亡和坏死）对所有三种类型的细胞均表现出显著的细胞毒性作用。配合物2比经典细胞毒性药物顺铂表现出更好的效力和效果。此外，在较短的孵育时间内，配合物2表现出显著的超氧化物歧化酶（SOD）模拟活性，并且它比著名的SOD模拟物TEMPOL更有效且更具效力。另外，配合物2能够与DNA相互作用，并在抗坏血酸钠存在下切割DNA。这项研究表明了利用多核氧化还原活性化合物通过SOD模拟氧化还原途径开发新型抗癌药物的潜力。
