ABSTRACT
The water-soluble and visible luminescent complexes cis-[Ru(L-L)2(L)2](2+) where L-L = 2,2-bipyridine and 1,10-phenanthroline and L= imidazole, 1-methylimidazole, and histamine have been synthesized and characterized by spectroscopic techniques. Spectroscopic (circular dichroism, saturation transfer difference NMR, and diffusion ordered spectroscopy NMR) and isothermal titration calorimetry studies indicate binding of cis-[Ru(phen)2(ImH)2](2+) and human serum albumin occurs via noncovalent interactions with K(b) = 9.8 × 10(4) mol(-1) L, ΔH = -11.5 ± 0.1 kcal mol(-1), and TΔS = -4.46 ± 0.3 kcal mol(-1). High uptake of the complex into HCT116 cells was detected by luminescent confocal microscopy. Cytotoxicity of cis-[Ru(phen)2(ImH)2](2+) against proliferation of HCT116p53(+/+) and HCT116p53(-/-) shows IC50 values of 0.1 and 0.7 µmol L(-1). Flow cytometry and western blot indicate RuphenImH mediates cell cycle arrest in the G1 phase in both cells and is more prominent in p53(+/+). The complex activates proapoptotic PARP in p53(-/-), but not in p53(+/+). A cytostatic mechanism based on quantification of the number of cells during the time period of incubation is suggested.
Subject(s)
Antineoplastic Agents/chemical synthesis , Coordination Complexes/chemical synthesis , Luminescent Agents/chemical synthesis , Ruthenium , 2,2'-Dipyridyl/analogs & derivatives , 2,2'-Dipyridyl/chemical synthesis , 2,2'-Dipyridyl/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Caspase 3/metabolism , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Coordination Complexes/pharmacology , Drug Screening Assays, Antitumor , Histamine/analogs & derivatives , Histamine/chemical synthesis , Histamine/pharmacology , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Luminescent Agents/pharmacology , Phenanthrolines/chemical synthesis , Phenanthrolines/pharmacology , Poly(ADP-ribose) Polymerases/metabolism , Protein Binding , Serum Albumin/metabolism , Structure-Activity Relationship , Tumor Suppressor Protein p53/metabolismABSTRACT
The photochemical and photophysical properties of the cis-[Ru(II)(α-diimine)2(4-APy)2](2+) complexes, where α-diimine = 1,10-phenanthroline (phen) and 4-APy = 4-aminopyridine I, 4,7-diphenyl-1,10-phenanthroline (Ph2phen) II, 2,2'-bipyridine (bpy) III, and 4,4'-dimethyl-2,2'-bipyridine (Me2bpy) IV, are reported. The four complexes were characterized using high-performance liquid chromatography, (1)H NMR, UV-visible, emission, and transient absorption spectroscopy. Upon photolysis in acetonitrile solution these complexes undergo 4-APy dissociation to give the monoacetonitrile complex (for II, III, and IV) or the bis(acetonitrile) complex (for I). A fairly wide range of excitation wavelengths (from 420 to 580 nm) were employed to explore the photophysics of these systems. Quantum yields and transient spectra are provided. Density functional theory (DFT) and time-dependent DFT analysis of singlet and triplet excited states facilitated our understanding of the photochemical behavior. A detailed assessment of the geometric and electronic structures of the lowest energy spin triplet charge transfer state ((3)MLCT) and spin triplet metal centered state ((3)MC) (dπ â σ* transitions) for species I-IV is presented. A second, previously unobserved, and nondissociative, (3)MC state is identified and is likely involved in the primary step of photodissociation. This new (3)MC state may indeed play a major role in many other photodissociation processes.
ABSTRACT
The monodentate cis-[Ru(phen)(2)(hist)(2)](2+)1R and the bidentate cis-[Ru(phen)(2)(hist)](2+)2A complexes were prepared and characterized using spectroscopic ((1)H, ((1)H-(1)H)COSY and ((1)H-(13)C)HSQC NMR, UV-vis, luminescence) techniques. The complexes presented absorption and emission in the visible region, as well as a tri-exponential emission decay. The complexes are soluble in aqueous and non-aqueous solution with solubility in a buffer solution of pH 7.4 of 1.14 × 10(-3) mol L(-1) for (1R + 2A) and 6.43 × 10(-4) mol L(-1) for 2A and lipophilicity measured in an aqueous-octanol solution of -1.14 and -0.96, respectively. Photolysis in the visible region in CH(3)CN converted the starting complexes into cis-[Ru(phen)(2)(CH(3)CN)(2)](2+). Histamine photorelease was also observed in pure water and in the presence of BSA (1.0 × 10(-6) mol L(-1)). The bidentate coordination of the histamine to the ruthenium center in relation to the monodentate coordination increased the photosubstitution quantum yield by a factor of 3. Pharmacological studies showed that the complexes present a moderate inhibition of AChE with an IC(50) of 21 µmol L(-1) (referred to risvagtini, IC(50) 181 µmol L(-1) and galantamine IC(50) 0.006 µmol L(-1)) with no appreciable cytotoxicity toward to the HeLa cells (50% cell viability at 925 µmol L(-1)). Cell uptake of the complexes into HeLa cells was detected by fluorescence confocal microscopy. Overall, the observation of a luminescent complex that penetrates the cell wall and has low cytotoxicity, but is reactive photochemically, releasing histamine when irradiated with visible light, are interesting features for application of these complexes as phototherapeutic agents.
