Copper(II) Complexes with 2,2′:6′,2″-Terpyridine Derivatives Displaying Dimeric Dichloro−μ–Bridged Crystal Structure: Biological Activities from 2D and 3D Tumor Spheroids to In Vivo Models

Eight 2,2′:6′,2″-terpyridines, substituted
at the 4′-position with aromatic groups featuring variations
in π-conjugation, ring size, heteroatoms, and methoxy groups,
were employed to enhance the antiproliferative potential of [Cu2Cl2(R-terpy)2](PF6)2. Assessing the cytotoxicity in A2780 (ovarian carcinoma), HCT116
(colorectal carcinoma), and HCT116DoxR (colorectal carcinoma resistant
to doxorubicin) and normal primary fibroblasts revealed that Cu(II)
complexes with 4-quinolinyl, 4-methoxy-1-naphthyl, 2-furanyl, and
2-pyridynyl substituents showed superior therapeutic potential in
HCT116DoxR cells with significantly reduced cytotoxicity in normal
fibroblasts (42–129× lower). Besides their cytotoxicity,
the Cu(II) complexes are able to increase intracellular ROS and interfere
with cell cycle progression, leading to cell death by apoptosis and
autophagy. Importantly, they demonstrated antimetastatic and antiangiogenic
properties without in vivo toxicity. In accordance with their nuclear
accumulation, the Cu(II) complexes are able to cleave pDNA and interact
with bovine serum albumin, which is a good indication of their ability
for internalization and transport toward tumor cells.

8种2,2′:6′,2″-三联吡啶（2,2′:6′,2″-terpyridines）在其4′位引入具有不同π共轭体系、环尺寸、杂原子及甲氧基的芳香取代基，用以提升配合物[Cu₂Cl₂(R-三联吡啶)₂](PF₆)₂的抗增殖活性。通过在A2780（卵巢癌细胞）、HCT116（结肠癌细胞）、阿霉素耐药结肠癌细胞HCT116DoxR以及正常原代成纤维细胞中评估细胞毒性，结果显示：带有4-喹啉基、4-甲氧基-1-萘基、2-呋喃基及2-吡啶基取代基的铜(II)配合物在HCT116DoxR细胞中展现出更优异的治疗潜力，且对正常成纤维细胞的细胞毒性显著降低（仅为对照的1/42至1/129）。除细胞毒性外，该类铜(II)配合物还可提升细胞内活性氧（ROS）水平、干扰细胞周期进程，进而通过凋亡与自噬途径诱导细胞死亡。尤为重要的是，这类配合物展现出抗转移与抗血管生成活性，且无体内毒性。鉴于其可在细胞核中富集，该类铜(II)配合物能够切割质粒DNA（pDNA）并与牛血清白蛋白结合，这一特性充分表明其具备进入肿瘤细胞并实现胞内转运的能力。