Dinuclear Organoruthenium Complex for Mitochondria-Targeted Near-Infrared Imaging and Anticancer Therapy to Overcome Platinum Resistance

Abstract

New mononuclear and dinuclear Ru­(II) coordination compounds with the 2,7-bisbenzoimidazolyl-naphthyridine ligand have been synthesized and characterized by UV–vis, NMR, and MALDI-TOF. The molecular structures for Ru­(II) compounds were determined by single-crystal X-ray diffraction. With the expansion of ligand π-conjugation and the increase in the complexed Ru number, the maximum emission wavelength red-shifted from 696 to 786 nm. The binding mode between complexes and DNA was predicted by molecular docking, which is intercalations and π–π stacking interactions with the surrounding bases. The intercalation mode of DNA binding was then determined by DNA titration and ethidium bromide (EB) displacement experiments. The antigrowth effects of complexes RuY, RuY1, and RuY2 were tested in HaCat (normal cells), HeLa (cervical cancer), A549 (lung cancer), and A549/DDP (cisplatin-resistant lung cancer) through the MTT assay. The dinuclear complex RuY2 was superior to mononuclear complexes and cisplatin in the cisplatin-resistant cell line. Confocal imaging proved that the subcellular localization of Ru­(II) complexes was mitochondria; moreover, apoptosis was detected by flow cytometry. All three complexes showed a dose-dependent manner in all four cell lines. All Ru­(II) complexes were found to have reactive oxygen species (ROS). The finding indicated that these Ru­(II) complexes caused cell death by both DNA disruption and ROS. This study helps to explore the potential of the polynuclear Ru­(II) complexes for the combination of NIR imaging and Pt-resistant cancer therapy.

Anticancer Potential of Diruthenium Complexes with Bridging Hydrocarbyl Ligands from Bioactive Alkynols

“…Extensive research has been dedicated to the exploration of ruthenium compounds as potential candidates for anticancer drugs, − and a few ruthenium complexes entered clinical trials for chemotherapy or photodynamic therapy (Figure A). − Organometallic piano-stool complexes based on the [Ru II (η 6 -arene)] core have emerged as possible alternatives to platinum-based chemotherapeutics, ,− and in particular complexes belonging to the RAPTA family have shown great promise (Figure B). − In addition, various ruthenium­(II) compounds bearing a η 5 -coordinated cyclopentadienyl ligand (Cp), or its substituted derivatives, have attracted increasing attention in the medicinal field (Figure C). − Since the Cp ligand is formally anionic, the bond with the ruthenium is strengthened by an electrostatic contribution, supplying robustness to the overall structure. In the pursuit of novel and potent metallodrugs, dinuclear metal complexes could offer significant advantages compared to their corresponding monometallic counterparts. , In this regard, several complexes containing two ruthenium­(II) arene fragments connected by variable linkers − and a diversity of other diruthenium species − have been evaluated, showing an interesting activity in several cases. We note that the “diruthenium approach” is not always favorable; for instance, the assembly of two {RuCp­(CO) 2 } units with diamine linkers resulted in the absence of cytotoxicity on human cancer cell lines. , …”

Adding Diversity to a Diruthenium Biscyclopentadienyl Scaffold via Alkyne Incorporation: Synthesis and Biological Studies

“…Since a bimetallic scaffold may provide significant advantages with respect to related monometallic species, a diversity of dinuclear ruthenium complexes have also been considered in the anticancer field. − In general, the bimetallic assembly consists of two monoruthenium units connected via a suitable bidentate ligand acting as a linker, , while diruthenium (or polyruthenium) structures containing metal–metal bond(s) have been almost unexplored . Our attention turned to the dinuclear commercial compound [Ru 2 Cp 2 (CO) 4 ], which has been employed as a convenient starting material for classical organodiruthenium chemistry. − Biological studies on [Ru 2 Cp 2 (CO) 4 ] and its dinuclear derivatives are still missing in the literature, and we considered this research worthy of development for several reasons.…”

Recent Advances in Mitochondria‐Localized Luminescent Ruthenium(II) Metallodrugs as Anticancer Agents

“…[9] In the imaging aspect, a d6 transitional metal, Ru(II) has gathered much attention due to its rich and tunable photophysical and photochemical properties based upon its coordination environments and associated ligands. [16] Because of the heavy atom effect, Ru-complexes exhibit phosphorescence and are also popular due to their large shifts, better water solubility, chemical-and photostability, excellent nonlinear optical properties, intense polarized luminescence, and comparatively longer lifetimes. Moreover, in therapeutic aspects such as anticancer agents, Ru(II) complex has been widely studied due to their outstanding DNA binding mechanism of action for anticancer therapy.…”