ABSTRACT
The specific recognition of AT-rich DNA sequences opens up the door to promising diagnostic and/or therapeutic strategies against gene-related diseases. Here, we demonstrate that amphiphilic PtII complexes of the type [Pt(dmba)(Nâ§N)]NO3 (dmba = N,N-dimethylbenzylamine-κN, κC; Nâ§N = dpq (3), dppz (4), and dppn (5)) recognize AT-rich oligonucleotides over other types of DNA, RNA, and model proteins. The crystal structure of 4 shows the presence of significant π-stacking interactions and a distorted coordination sphere of the d8 PtII atom. Complex 5, containing the largest π-conjugated ligand, forms supramolecular assemblies at high concentrations under aqueous environment. However, its aggregation can be promoted in the presence of DNA at concentrations as low as 10 µM in a process that "turns on" its excimer emission around 600 nm. Viscometry, gel electrophoresis, and theoretical calculations demonstrate that 5 binds to minor groove when self-assembled, while the monomers of 3 and 4 intercalate into the DNA. The complexes also inhibit cancer cell growth with low-micromolar IC50 values in 2D tissue culture and suppress tumor growth in 3D tumor spheroids with a multicellular resistance (MCR) index comparable to that of cisplatin.
Subject(s)
Coordination Complexes/chemistry , DNA/chemistry , Organoplatinum Compounds/chemistry , A549 Cells , Crystallography, X-Ray , Electrophoretic Mobility Shift Assay , Humans , Intercalating Agents/chemistry , Ligands , Molecular Structure , Spectrum Analysis/methods , StereoisomerismABSTRACT
Cytochrome P450s are key players in drug metabolism, and overexpression in tumors is associated with significant resistance to many medicinal agents. Consequently, inhibition of P450s could serve as a strategy to restore drug efficacy. However, the widespread expression of P450s throughout the human body and the critical roles they play in various biosynthetic pathways motivates the development of P450 inhibitors capable of controlled local administration. Ruthenium complexes containing P450 inhibitors as ligands were synthesized in order to develop pro-drugs that can be triggered to release the inhibitors in a spatially and temporally controlled fashion. Upon light activation the compounds release ligands that directly bind and inhibit P450 enzymes, while the ruthenium center is able to directly damage DNA.
Subject(s)
Cytochrome P-450 Enzyme Inhibitors/chemistry , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Cytochrome P-450 Enzyme System/metabolism , DNA Damage , Ruthenium/chemistry , Ruthenium/pharmacology , Benzene/chemistry , Cytochrome P-450 Enzyme System/chemistry , Imidazoles/chemistry , Models, Molecular , Protein ConformationABSTRACT
A chemically reactive Ru(II) "building block", able to undergo condensation reactions with substituted diamines, was utilized to create a small library of luminescent "light switch" dipyrido-[3,2-a:2',3'-c] phenazine (dppz) complexes. The impact of substituent identity, position, and the number of substituents on the light switch effect was investigated. An unbiased, parallel screening approach was used to evaluate the selectivity of the compounds for a variety of different biomolecules, including protein, nucleosides, single stranded DNA, duplex DNA, triplex DNA, and G-quadruplex DNA. Combining these two approaches allowed for the identification of hit molecules that showed different selectivities for biologically relevant DNA structures, particularly triplex and quadruplex DNA.
Subject(s)
Coordination Complexes/chemistry , DNA/chemistry , Luminescent Agents/chemistry , Phenazines/chemistry , Ruthenium/chemistry , Coordination Complexes/chemical synthesis , DNA, Single-Stranded/chemistry , G-Quadruplexes , Luminescence , Luminescent Agents/chemical synthesis , Luminescent Measurements , Nucleic Acid Conformation , Phenazines/chemical synthesisABSTRACT
Two thermally activated ruthenium(ii) polypyridyl complexes, cis-Ru(bpy)2Cl2 and trans-Ru(qpy)Cl2 were investigated to determine the impact of the geometric arrangement of the exchangable ligands on the potential of the compounds to act as chemotherapeutics. In contrast to the geometry requirements for cisplatin, trans-Ru(qpy)Cl2 was 7.1-9.5× more cytotoxic than cis-Ru(bpy)2Cl2. This discovery could open up a new area of metal-based chemotherapeutic research.
ABSTRACT
The only crystals that could be grown from racemic solutions of the PF6(-) salt of the resolvable cation [Ru(2,9-dimethyl-1,10-phenanthroline)2(dipyrido[3,2-d:2',3'-f]quinoxaline)](2+) have translational symmetry only (space group P1), contain nine independent sets of ions, and include numerous independent solvent molecules (11 acetone, one diethyl ether and possibly several water molecules). Layers of hydrophobic cations alternate with layers containing most of the anions and solvent molecules. All nine cations have the same basic conformation, which is distorted by the presence of the methyl substituents on the two 1,10-phenanthroline ligands. Four pairs of enantiomeric cations within a layer are related by approximate inversion centers; the ninth cation, which shows no sign of disorder, makes the layer chiral. Within the cation layers stripes parallel to [110] of six cations alternate with stripes of three; the local symmetry and the cation orientations are different in the two stripes. These stripes are reflected in the organization of the anion/solvent layer. The ca 80:20 inversion twinning found indicates that enantiomeric preference is transmitted less perfectly across the anion/solvent layer than within the cation layer. The structure is exceptional in having nine independent formula units and an unbalanced set (ratio 4:5) of resolvable enantiomers. The difficulty in growing crystals of this material is consistent with its structural complexity.
ABSTRACT
Recognition and regulation of G-quadruplex nucleic acid structures is an important goal for the development of chemical tools and medicinal agents. The addition of a bromo-substituent to the dipyridylphenazine (dppz) ligands in the photophysical "light switch", [Ru(bpy)2 dppz](2+) , and the photochemical "light switch", [Ru(bpy)2 dmdppz](2+) , creates compounds with increased selectivity for an intermolecular parallel G-quadruplex and the mixed-hybrid G-quadruplex, respectively. When [Ru(bpy)2 dppz-Br](2+) and [Ru(bpy)2 dmdppz-Br](2+) are incubated with the G-quadruplexes, they have a stabilizing effect on the DNA structures. Activation of [Ru(bpy)2 dmdppz-Br](2+) with light results in covalent adduct formation with the DNA. These complexes demonstrate that subtle chemical modifications of Ru(II) complexes can alter G-quadruplex selectivity, and could be useful for the rational design of in vivo G-quadruplex probes.
Subject(s)
Coordination Complexes/chemistry , DNA/chemistry , Nucleic Acids/chemistry , Phenazines/chemistry , Circular Dichroism , G-Quadruplexes , Ruthenium/chemistryABSTRACT
Two novel strained ruthenium(II) polypyridyl complexes containing a 2,3-dihydro-1,4-dioxino[2,3-f]-1,10-phenanthroline (dop) ligand selectively ejected a methylated ligand when irradiated with >400 nm light. The best compound exhibited a 1880-fold increase in cytotoxicity in human cancer cells upon light-activation and was 19-fold more potent than the well-known chemotherapeutic, cisplatin.
Subject(s)
Coordination Complexes/chemistry , Organometallic Compounds/pharmacology , Phenanthrolines/chemistry , Ruthenium/chemistry , Cell Survival/drug effects , Dose-Response Relationship, Drug , HL-60 Cells , Humans , Ligands , Models, Molecular , Molecular Structure , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Photochemical Processes , Structure-Activity RelationshipABSTRACT
[Ru(bpy)2dmdppz](2+) (bpy = 2,2'-bipyridine and dmdppz = 3,6-dimethyl dipyridylphenazine), a strained Ru(II) polypyridyl complex, is a derivative of the well-known luminescent "light switch", [Ru(bpy)2dppz](2+) (dppz = dipyridylphenazine). [Ru(bpy)2dmdppz](2+) is of interest because it acts as a photochemical sensor and metalating agent for DNA. Here we report a detailed study to elucidate the mechanism of ligand substitution by investigating the photochemical reaction in a variety of solvents and by determining the effects of different incoming ligands, the incoming ligand concentration, and the temperature dependence. Results from these studies indicate that the mechanism of substitution is associative or interchange associative, in contrast with the dissociative mechanism of other photolabile Ru(II) polypyridyl complexes.
Subject(s)
2,2'-Dipyridyl/chemistry , Phenazines/chemistry , Ruthenium Compounds/chemistry , Acetonitriles/chemistry , Dimethyl Sulfoxide/chemistry , Hydrogen Bonding , Ions/chemistry , Nitriles/chemistry , Photochemical Processes , Solvents/chemistry , Temperature , Viscosity , Water/chemistryABSTRACT
Ru(bpy)2dppz, a well studied "light-switch" metal complex, transforms into a photochemical "light-switch" and DNA damaging agent by incorporating structural strain. This distorted compound is photoreactive and ejects a ligand upon binding duplex and G-quadruplex DNA, producing a reactive metal center that metalates the DNA.
Subject(s)
DNA/chemistry , G-Quadruplexes , Organometallic Compounds/chemistry , Phenazines/chemistry , Crystallography, X-Ray , DNA Damage , Light , Spectrophotometry, Ultraviolet , StereoisomerismABSTRACT
Incorporation of biquinoline ligands into Ru(II) polypyridyl complexes produces light-activated systems that eject a ligand and photobind DNA after irradiation with visible and near-IR light. Structural analysis shows that distortion facilitates the photochemistry, and gel shift and cytotoxicity studies prove the compounds act as anti-cancer photodynamic therapy (PDT) agents in the tissue penetrant region.
