Xie Lina, Luo Zuandi, Zhao Zhennan, Chen Tianfeng
Department of Chemistry, Jinan University , Guangzhou 510632, China.
J Med Chem. 2017 Jan 12;60(1):202-214. doi: 10.1021/acs.jmedchem.6b00917. Epub 2016 Dec 21.
Thioredoxin reductase (TrxR) is a selenoenzyme that could regulate intracellular oxidative balance and found to be overexpressed in many human tumor cells. Due to its important role in cancer progression, TrxR is becoming an attractive target in chemotherapeutic drug design. In this study, a new class of Fe(II) complexes with phenanthroline derivatives as ligands were synthesized and characterized. The mechanism of cell death induced by complex 3 revealed that the growth of cancer cells was suppressed by apoptosis and specifically inhibited the activities of TrxR. Furthermore, complex 3 exhibited brilliant antiangiogenic activity against HUVEC cells and inhibited cell migration and invasion. In addition, results of hematological analysis and H&E staining demonstrated that complex 3 has negligible toxicity on function of the major organs of mice. Taken together, this study provides a strategy for drug design to exploit Fe-based phenanthroline derivative as a chemotherapeutic agent in cancer treatment.
硫氧还蛋白还原酶（TrxR）是一种可调节细胞内氧化平衡的硒酶，且在许多人类肿瘤细胞中呈过表达。由于其在癌症进展中发挥重要作用，TrxR正成为化疗药物设计中一个有吸引力的靶点。在本研究中，合成并表征了一类以菲咯啉衍生物为配体的新型Fe(II)配合物。配合物3诱导细胞死亡的机制表明，癌细胞的生长受到凋亡抑制，并特异性地抑制了TrxR的活性。此外，配合物3对人脐静脉内皮细胞（HUVEC）表现出显著的抗血管生成活性，并抑制细胞迁移和侵袭。另外，血液学分析和苏木精-伊红（H&E）染色结果表明，配合物3对小鼠主要器官功能的毒性可忽略不计。综上所述，本研究提供了一种药物设计策略，即利用基于铁的菲咯啉衍生物作为癌症治疗中的化疗药物。
