Tuning the mechanism of DNA cleavage photosensitized by ruthenium dipyridophenazine complexes by varying the structure of the two non intercalating ligands.

The influence of the nature of ligands on the efficiency of ruthenium complexes for photosensitizing DNA cleavage was investigated. Ru(bipy)2dppz2+ and Ru(bpz)2dppz2+ were selected as DNA breakers on the basis of their high affinity for DNA due to the presence of a dppz ligand which can partially intercalate in the major groove of DNA. Their photosensitizing properties were compared to those of Ru(bipy)3(2+), a complex which binds to DNA with a far lower constant. Upon irradiation, these complexes promoted the formation of single strand breaks in supercoiled phi X 174 DNA. Unexpectedly, Ru(bipy)2dppz2+ was found to be less efficient than Ru(bipy)3(2+) whatever the dye concentration or the [base pair]/[Ru] molar ratio r. Scavenging experiments have shown that the oxidative DNA cleavage induced by Ru(bipy)2dppz2+ mainly results from a Type II mechanism. The behavior of Ru(bipy)2dppz2+ was different: this compound was clearly more efficient than Ru(bipy)3(2+) as DNA breaker and its efficiency was not modified by the presence of oxygen or by addition of scavengers of reactive oxygen species. In this case, a mechanism involving electron transfer between the excited state of the ruthenium complex and the guanine residue was proposed in agreement emission lifetime measurements. The change in mechanism observed between Ru(bipy)2dppz2+ and Ru (bipy)2dppz2+ results from an increase of the reduction potential of the ruthenium complexes in the excited state, which appears to be the main factor controlling the efficiency.

DNA cleavage photoinduced by new water-soluble zinc porphyrins linked to 9-methoxyellipticine.

Two hybrid molecules based on a water-soluble zinc porphyrin covalently linked to 9-methoxyellipticine, 1 and 2, were studied as photoactivable DNA cleavers. The behaviour and efficiency of these photosensitizers were compared with the constitutive units of the hybrid molecules: meso-tetrakis(4-N-methylpyridiniumyl)porphyrinato-zinc(II) tetraacetate (ZnTMPyP, 3) and 9-methoxy-N2methylellipticinium acetate (9-OMe-NME, 4). On irradiation at 436 nm, the efficiency of these hybrids is similar to that of ZnTMPyP and 50-fold greater than that of haematoporphyrin derivative (HPD). This photoinduced DNA cleavage is markedly reduced in the absence of oxygen and also depends on the DNA base pair to porphyrin ratio. It is inhibited by N-acetylhistidine and sodium azide, unaffected by mannitol and superoxide dismutase (SOD) and enhanced when changing H2O for D2O. The same scavenger effects are observed on irradiation at 514 nm. At 313 nm, the efficiency of hybrids 1 and 2 is intermediate between those of ZnTMPyP and 9-OMe-NME. In these conditions, a slight inhibitory effect of mannitol is observed, suggesting the participation of radicals probably derived from partial decomposition of the porphyrins. At these three wavelengths, singlet oxygen seems to be the main species responsible for DNA cleavage. In contrast with expectation, the great affinity of these molecules for DNA does not enhance their efficiency as DNA cleavers. This effect is discussed taking into account the long lifetime of singlet oxygen which may be generated far from the target. These molecules which are only photoactivable in the presence of DNA appear to be an efficient "molecular light switch".