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.