Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005, Paris, France.
Department of Chemical and Pharmaceutical Sciences, University of Trieste, 34127, Trieste, Italy.
Chembiochem. 2022 Oct 6;23(19):e202200398. doi: 10.1002/cbic.202200398. Epub 2022 Aug 26.
Cancer is one of the main causes of death worldwide. Platinum complexes (i. e., cisplatin, carboplatin, and others) are currently heavily used for the treatment of different types of cancer, but unwanted effects occur. Ruthenium complexes have been shown to be potential promising alternatives to these metal-based drugs. In this work, we performed a structure-activity relationship (SAR) study on two small series of Ru(II) polypyridyl complexes of the type [Ru(L1) (O^O)]Cl (3-8), where L1 is 4,7-diphenyl-1,10-phenantroline (DIP) or 1,10-phenantroline (phen), and O^O is a symmetrical anionic dioxo ligand: oxalate (ox, n=0), malonate (mal, n=0), or acetylacetonate (acac, n=1). These two self-consistent series of compounds allowed us to perform a systematic investigation for establishing how the nature of the ligands and the charge affect the anticancer properties of the complexes. Cytotoxicity tests on different cell lines demonstrated that some of the six compounds 3-8 have a promising anticancer activity. More specifically, the cationic complex [Ru(DIP) (η -acac)]Cl (4) has IC values in the mid-nanomolar concentration range, lower than those of cisplatin on the same cell lines. Interestingly, [Ru(DIP) (η -acac)]Cl was found to localize mainly in the mitochondria, whereas a smaller fraction was detected in the nucleus. Overall, our SAR investigation demonstrates the importance of combining the positive charge of the complex with the highly lipophilic diimine ligand DIP.
癌症是全球主要死亡原因之一。铂配合物（例如顺铂、卡铂等）目前被广泛用于治疗不同类型的癌症，但会产生不良反应。钌配合物已被证明是这些基于金属的药物的潜在有前途的替代品。在这项工作中，我们对两种类型的 Ru(II) 聚吡啶配合物[Ru(L1)(O^O)]Cl（3-8）进行了构效关系（SAR）研究，其中 L1 是 4,7-二苯基-1,10-菲咯啉（DIP）或 1,10-菲咯啉（phen），O^O 是对称的阴离子二氧配体：草酸盐（ox，n=0）、丙二酸盐（mal，n=0）或乙酰丙酮酸盐（acac，n=1）。这两个自洽的化合物系列使我们能够进行系统的研究，以确定配体的性质和电荷如何影响配合物的抗癌特性。对不同细胞系的细胞毒性测试表明，六种化合物 3-8 中的一些具有有前途的抗癌活性。具体而言，阳离子配合物[Ru(DIP)(η -acac)]Cl（4）的 IC 值在中纳摩尔浓度范围内，低于相同细胞系中顺铂的 IC 值。有趣的是，[Ru(DIP)(η -acac)]Cl 被发现主要定位于线粒体，而在核内检测到的比例较小。总体而言，我们的 SAR 研究表明，将配合物的正电荷与高度亲脂性二亚胺配体 DIP 结合起来非常重要。
