The cellular uptake of a series of dipyridophenazine (dppz) complexes of Ru(II) was examined by flow cytometry. The complexes, owing to their facile synthesis, stability, and luminescence, provide a route to compare and contrast systematically factors governing cellular entry. Substituting the ancillary ligands in the dppz complexes of Ru(II) permits variation in the overall complex charge, size, and hydrophobicity. In HeLa cells, cellular uptake appears to be facilitated by the lipophilic 4,7-diphenyl-1,10-phenanthroline (DIP) ligand. Despite the large size of Ru(DIP)_2dppz^(2+) (20 A diameter), this complex is readily transported inside the cell compared to smaller and more hydrophilic complexes, such as Ru(bpy)_2dppz^(2+). Accumulation in the cellular interior is confirmed by confocal microscopy.

Methods to Explore Cellular Uptake of Ruthenium Complexes

Recent developments in the d-block metallo-supramolecular chemistry of polypyridyls

Four ruthenium(II) asymmetric complexes, [Ru(bpy)2(PAIDH)]2+ (bpy = 2,2′-bipyridine, PAIDH = 2-pyridyl-1H-anthra[1,2-d]imidazole-6,11-dione, 1), [Ru(phen)2(PAIDH)]2+ (phen = 1,10-phenanthroline, 2), [Ru(dmp)2(PAIDH)]2+ (dmp = 4,7-dimethyl-1,10-phenanthroline, 3) and [Ru(dip)2(PAIDH)]2+ (dip = 4,7-diphenyl-1,10-phenanthroline, 4), have been synthesized and characterized. These complexes displayed potent anti-proliferation activity against various cancer cell lines and had high selectivity between tumor cells and normal cells. HeLa cells exhibited the highest sensitivity to complex 4, accounting for the greatest cellular uptake. Complex 4 was shown to accumulate preferentially in the mitochondria of HeLa cells and induced apoptosis via the mitochondrial pathway, which involved ROS generation, mitochondrial membrane potential depolarisation, and Bcl-2 and caspase family members activation. These results demonstrated that complex 4 induced cancer cell apoptosis by acting on mitochondrial pathways.

The induction of mitochondria-mediated apoptosis in cancer cells by ruthenium(II) asymmetric complexes

Coordination polymers with nucleobases: From structural aspects to potential applications

A brief overview of mechanistic studies on the reactions of different Pt(II) complexes with nitrogen- and sulfur-donor biomolecules is presented. The first part describes the results obtained for substitution reactions of mono-functional Pt(II) complexes with different biomolecules, under various experimental conditions (temperature, pH and ionic strength). In addition, an overview of the results obtained for the substitution reactions of bi-functional Pt(II) complexes, analogous to cisplatin, with biomolecules is given. The last part of this report deals with different polynuclear Pt(II) complexes and their substitution behaviour with different biomolecules. The purpose of this perspective is to improve the understanding of the mechanism of action of Pt(II) complexes as potential anti-tumour drugs in the human body.

Mechanistic studies on the reactions of platinum(II) complexes with nitrogen- and sulfur-donor biomolecules

Cisplatin analogues with 2,2?-dipyridylamine ligands and their reactions with DNA model nucleobases

In modern cancer therapy the clinical application of platinum-based drugs is more and more limited by the occurrence of intrinsic or acquired resistances. In this context the potential use of dinuclear platinum complexes in chemotherapy is increasingly relevant. The novel complexes Pd(Bzdpa)Cl2, Pd2(C4H8(dpa)2)Cl4, and Pt2(C4H8(dpa)2)Cl4 allow a direct comparison of mono- and dinuclear palladium and platinum complexes respectively deriving from a 2,2′-dipyridylamine (Hdpa) ligand system. They were characterized by single crystal X-ray analysis as well as infrared spectroscopy and elemental analysis. The cisplatin analogous mononuclear palladium complex Pd(Bzdpa)Cl2 (1) (Bzdpa: (2,2′-dipyridylbenzyl)amine) belongs to a range of 2,2′-dipyridylamine-based compounds which were extensively studied in our laboratories. 1 crystallizes in the orthorhombic space group Pna21 with a = 13.722(3), b = 13.457(3), c = 9.483(2), V = 1751.1(6) A3, and Z = 4. The metal binding motif of 1 was expanded by a flexible butyl-linker to form the tetradentate C4H8(dpa)2 ligand. The resulting isotypic dinuclear complexes Pd2(C4H8(dpa)2)Cl4·2CH3CN (2) and Pt2(C4H8(dpa)2)Cl4·2CH3CN (3) crystallize in the triclinic space group with a = 7.8427(2), b = 8.7940(2), c = 11.7645 (3), α = 79.219(2)°, β = 84.033(2)°, γ = 87.744(2)°, V = 792.58(3) A3 (2) and a = 7.831(5), b = 8.814(5), c = 11.817(5), α = 79.271(5)°, β = 83.571(5)°, γ = 88.063(5)°, V = 796.3(8) A3 (3), both with one centrosymmetrical molecule in the unit cell.

Dinuclear and Mononuclear Platinum(II) and Palladium(II) Complexes with Modified 2,2′‐Dipyridylamine Ligands Featuring a Cisplatin Analogous Structure Motif

Structure–toxicity relationships for different types of dinuclear platinum complexes

The electrical resistance breakdown assay provides a novel approach for the quantification of cytotoxic activity of platinum based anticancer drugs. It is a functional assay system for cancer cell invasion that detects nanoscale alterations of an epithelial test barrier prior to microscopic morphometric changes. We measured changes in transepithelial electrical resistance (TEER) of a tight epithelial MDCK-C7 monolayer in response to highly invasive amelanotic melanoma cells (A7-clone) in combination with different platinum complexes (cis-, oxali- and carboplatin). The efficiency of the electrical resistance breakdown assay was compared a standard method for measurement of cytostatic activity, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The MTT-assay utilizes mitochondrial enzymatic activity to draw conclusions from a functional cell metabolism to the number of living cells in a sample. When human melanoma cells were seeded on top of an electrically tight MDCK-C7 monolayer, electrical leakage occurred within 48 h of co-culture. Electrical resistance breakdown was effectively prevented by cisplatin and its analogs (no significant difference between 100 microM cisplatin and corresponding controls with non-invasive cells). The results of the electrical resistance breakdown and MTT-assay were linearly dependent. Significance of both tests was equivalent, but the electrical resistance breakdown assay gave additional functional information. Compared to oxali- and carboplatin, cisplatin was more effective in preventing TEER-breakdown than reducing the number of tumor cells, giving rise to the assumption that cisplatin can reduce tumor cell number as well as invasiveness. In conclusion the electrical resistance breakdown assay provides a sensitive, continuous and cell-based assay system for the quantification of cancer cell invasiveness and evaluation of chemotherapeutics under physiological conditions.

Platinum Complex Cytotoxicity Tested by the Electrical Resistance Breakdown Assay

Erratum to “Cisplatin analogues with 2,2’-dipyridylamine ligands and their reactions with DNA model nucleobases” [Inorg. Chim. Acta 350 (2003) 355–365]

Sarah Fakih

Papers

Cisplatin analogues with 2,2?-dipyridylamine ligands and their reactions with DNA model nucleobases

Dinuclear and Mononuclear Platinum(II) and Palladium(II) Complexes with Modified 2,2′‐Dipyridylamine Ligands Featuring a Cisplatin Analogous Structure Motif

Structure–toxicity relationships for different types of dinuclear platinum complexes

Platinum Complex Cytotoxicity Tested by the Electrical Resistance Breakdown Assay

Erratum to “Cisplatin analogues with 2,2’-dipyridylamine ligands and their reactions with DNA model nucleobases” [Inorg. Chim. Acta 350 (2003) 355–365]