María-José Fernández

Physiologically relevant concentrations of NaCl and KCl increase DNA photocleavage by an N-substituted 9-aminomethylanthracene dye.

This paper describes the synthesis of a new 9-aminomethylanthracene dye N-substituted with a pyridinylpolyamine side chain (4). The effects of NaCl and KCl on anthracene/DNA interactions were then studied, with the goal of simulating the conditions of high ionic strength that a DNA photosensitizer might encounter in the cell nucleus (~150 mM of NaCl and 260 mM of KCl). As exemplified by methylene blue (5), the expected effect of increasing ionic strength is to decrease DNA binding and photocleavage yields. In contrast, the addition of 150 mM of NaCl in combination with 260 mM of KCl to photocleavage reactions containing micromolar concentrations of 4 triggers the conversion of supercoiled, nicked, and linear forms of pUC19 plasmid into a highly degraded band of DNA fragments (350 nm hν, pH 7.0). Circular dichroism spectra point to a correlation between salt-induced unwinding of the DNA helix and the increase in DNA photocleavage yields. The results of circular dichroism, UV-vis absorption, fluorescence emission, thermal denaturation, and photocleavage inhibition experiments suggest that the combination of salts causes a change in the DNA binding mode of 4 from intercalation to an external interaction. This in turn leads to an increase in the anthracene-sensitized production of DNA-damaging reactive oxygen species.

Syntheses and copper(II)-dependent DNA photocleavage by acridine and anthracene 1,10-phenanthroline conjugate systems

We report the syntheses and characterization of a series of compounds based on 1,10-phenanthroline covalently tethered, at the 2 and 9 positions, to either two benzene, naphthalene, acridine or anthracene chromophores. The acridine and anthracene derivatives are shown to efficiently cleave pUC19 plasmid DNA upon irradiation with ultraviolet light (pH = 7.0, 22 degrees C, 350 nm). Furthermore, photocleavage levels are markedly increased by the addition of Cu2+ to the DNA photolysis reactions. Interestingly, when the concentrations of the anthracene compounds are lowered from 35 microM to 0.25 microM, the reverse trend is observed. DNA photocleavage is markedly reduced in the presence of copper(II).

Synthesis and DNA interaction of ethylenediamine platinum(II) complexes linked to DNA intercalants

A series of ethylenediamine platinum(II) complexes connected through semi-rigid chains of 1,2-bis(4-pyridyl)ethane to DNA intercalating subunits (naphthalene, anthracene or phenazine) has been synthesized, and their interactions with calf thymus (CT) DNA have been evaluated by viscometric titrations and equilibrium dialysis experiments. The parent ligands that contain anthracene or phenazine chromophores showed a monointercalative mode of DNA interaction (especially the anthracene derivative), with apparent association constants in the order of 10(4) M(-1). The corresponding platinum(II) complexes bind CT DNA through bisintercalation, as established by the significant increase of DNA contour length inferred from viscosity measurements, and the association constants are in the order of 10(5) M(-1). The naphthalene derivatives, however, exhibit a mixed mode of interaction, which suggests a partial contribution of both intercalation and groove binding for the ligand, and monointercalation in the case of the platinum(II) complex. Competition dialysis experiments carried out on the intercalative compounds have revealed a moderate selectivity towards GC DNA sequences for the derivatives containing the anthracene chromophore.

DNA photocleavage by dicationic bisintercalants

Abstract The synthesis of new dicationic bisintercalants containing phenazine or naphthalene as photosensitizers and 4,4′-bipyridinium as a linker is reported. Irradiation in the presence of 0.5 μM concentrations of the phenazine intercalants affords cleavage of plasmid DNA (at 22°C, pH 7.0) in good to excellent yields.

Anthracene and naphthalene (2,2-bipyridine)platinum(II) conjugates: synthesis and DNA photocleavage

Abstract A series of (2,2′-bipyridine)platinum(II) complexes covalently tethered to one or two anthracene or naphthalene chromophores was synthesized in high yields. The compounds were equilibrated with pUC19 plasmid and then irradiated at 350 nm. DNA cleaving reactions showed that the complex attached to two anthracene units exhibited the highest photocleavage efficiency, leading to complete conversion of supercoiled to linear DNA at 0.25 μM concentrations of the complex (37°C, pH 7.4).

An easy synthesis of lepidopterene from 9-chloromethyl anthracene. Evidence for a free radical mechanism

Abstract This communication reports a novel and efficient synthesis of lepidopterene from 9-(chloromethyl)anthracene. Furthermore, the radical nature of the process is unambiguously established through the obtention of several 9-anthracenemethyl derivatives, which are formed via a common 9-anthracenemethyl radical intermediate, derived from 9-(iodomethyl)anthracene.

Synthesis and DNA photocleavage by a pyridine-linked bis-acridine chromophore in the presence of copper(II): Ionic strength effects

We report the synthesis of photonuclease 3 consisting of two acridine rings joined by a 2,6-bis(aminomethyl)pyridine copper-binding linker. In reactions containing micromolar concentrations of 3, irradiation at 419 nm produces efficient, copper(II)-dependent cleavage of plasmid DNA in the presence of the high concentrations of salt that exist in the cell nucleus (150 mM NaCl and 260 mM KCl). The DNA interactions of 3 are compared to an analogous bis-acridine (4) containing a more flexible 2,6-bis{[(methoxycarbonylamino)-ethyl]methylaminomethyl}pyridine unit.

Synthesis and structural and conformational study of 3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one oxime and its tautomer imine N-oxide

Abstract In an attempt to synthesize the 3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one oxime hydrochloride, the corresponding tautomer imine N -oxide hydrochloride ( I ·HCl) was obtained, as deduced from X-ray and IR data. By neutralization of I ·HCl, the corresponding oxime ( II ) was obtained and characterized by IR data. From the 1 H and 13 C NMR spectra of I ·HCl and II , a twin-chair conformation for the bicyclic system, more flattened in II , was deduced. This conformation has also been shown by X-ray data for I ·HCl.

Synthesis and structural, conformational and pharmacological study of new esters derived from 3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-ol

Abstract A series of esters derived from 3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-ol has been synthesized and studied using 1 H and 13 C NMR spectroscopy and the crystal structure of 9-(3-indolycarbonyloxy)-3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane hydrochloride (V·HCl) has been determined by X-ray diffraction. In CDCl 3 solution, these compounds adopt an almost perfect chair-chair conformation with the N-substituents in equatorial positions. By comparing the NMR parameters of these compounds with those of the corresponding alcohol and some azatricyclane derivatives, several stereoelectronic effects have been deduced.

An unlikely DNA cleaving agent: A photo-active trinuclear Cu(II) complex based on hexaazatriphenylene

This paper describes the synthesis of a trinuclear Cu(II) complex (4) containing a central 1,4,5,8,9,12-hexaazatriphenylene-hexacarboxylate (hat) core (3). Low, micromolar concentrations of the negatively charged parent ligand 3 and the neutral trinuclear complex 4 were found to photocleave negatively charged pUC19 plasmid DNA with high efficiency at neutral pH (350nm, 50min, 22°C). The interactions of complex 4 with double-helical DNA were studied in detail. Scavenger and colorimetric assays pointed to the formation of Cu(I), superoxide anion radicals, hydrogen peroxide, and hydroxyl radicals during photocleavage reactions. UV-visible absorption, circular dichroism, DNA thermal denaturation, and fluorescence data suggested that the Cu(II) complex contacts double-stranded DNA in an external fashion. The persistent association of ligand 3 and complex 4 with Na(I) and/or other cations in aqueous solution might facilitate electrostatic DNA interactions.