RESUMO
With the long-term aim of enhancing the binding properties of dinuclear RuII -based DNA light-switch complexes, a series of eight structurally related mono- and dinuclear systems are reported in which the linker of the bridging ligand has been modulated. These tethered systems have been designed to explore issues of steric demand at the binding site and the thermodynamic cost of entropy loss upon binding. Detailed spectroscopic and isothermal titration calorimetry (ITC) studies on the new complexes reveal that one of the linkers produces a dinuclear system that binds to duplex DNA with an affinity (Kb >107 m-1 ) that is higher than its corresponding monometallic complex and is the highest affinity for a non-threading bis-intercalating metal complex. These studies confirm that the tether has a major effect on the binding properties of dinuclear complexes containing intercalating units and establishes key design rules for the construction of dinuclear complexes with enhanced DNA binding characteristics.
Assuntos
Complexos de Coordenação/química , DNA/química , Substâncias Intercalantes/química , Rutênio/química , Sítios de Ligação , Ligantes , Espectroscopia de Ressonância MagnéticaRESUMO
Using a new mononuclear "building block," for the first time, a dinuclear RuII (dppn) complex and a heteroleptic system containing both RuII (dppz) and RuII (dppn) moieties are reported. The complexes, including the mixed dppz/dppn system, are 1 O2 sensitizers. However, unlike the homoleptic dppn systems, the mixed dppz/dppn complex also displays a luminescence "switch on" DNA light-switch effect. In both cisplatin sensitive and resistant human ovarian carcinoma lines the dinuclear complexes show enhanced uptake compared to their mononuclear analogue. Thanks to a favorable combination of singlet oxygen generation and cellular uptake properties all three of the new complexes are phototoxic and display potent activity against chemotherapeutically resistant cells.
Assuntos
Complexos de Coordenação/farmacologia , Substâncias Intercalantes/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Rutênio/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacocinética , DNA/metabolismo , Feminino , Humanos , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacocinética , Neoplasias Ovarianas/metabolismo , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Rutênio/química , Rutênio/farmacocinética , Oxigênio Singlete/metabolismoRESUMO
I2CITC allows the analysis of isothermal titration calorimetry (ITC) data for complex coupled equilibria. Here we describe how, using I2CITC, ITC data for systems involving a self-aggregating ligand and a host offering one or two binding sites can be analyzed, how interaction models can be tested, and how confidence intervals for the optimized parameters can be determined.