Photoelectron transfer processes leading to photoadduct formation

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Surprisingly, direct DNA strand break is not the major process observed after the illumination of [RuII(TAP)3]2+ or complexes containing at least two TAP ligands in the presence of CT-DNA (calf thymus-DNA) or oligonucleotides. As demonstrated by gel electrophoresis in denaturing conditions, absorption spec-troscopy, dialysis experiments and ElectroSpray Mass Spectrometry (ESMS), the illumination of photo-oxidizing Run complexes in the presence of CT-DNA and oligonucleotides leads to the formation of a covalent adduct between the complex and the nucleic acid.63,67 The production of this photoadduct is initiated by a photoelectron transfer process from a guanine base to the excited state of the complex as described in Figure 19.9, probably accompanied by a proton transfer.68 The proposed mechanism implies, after the electron and proton transfer, the recombination of the two radicals (protonated radical anion of one TAP ligand and deprotonated radical cation of the guanine base), which gives rise to a covalent bond between both species. The TAP ligand which behaved as the electron acceptor in the complex is then rearomatized in a last step.

[RuII(TAP)3]2+* + GMP [RuII(TAP)2(TAP*!)]1+ + GMP*+ [Run(TAP)2(TAP*!)]1 + + GMP*+ [RuII(TAP)2(TAPH*)]2+ + GMP(-H)*

[RuII(TAP)2(TAPH*)]2+ + GMP(-H)* —> photoadduct

The photoadduct formed by visible light absorption of different Ru TAP complexes in the presence of CT-DNA or GMP has been isolated and characterized by ESMS and NMR spectroscopy.67,69 These analyses revealed that a covalent bond has been formed between the C2 position of one TAP ligand and the N2 position of the guanine (Figure 19.10a).

As in the cases of the other metal complexes forming adduct with DNA (such as the Pt compounds), this new type of photo-adduct could be exploited to design new anti-tumor agents that are able to perturb DNA function or

Figure 19.10 Photoadduct obtained after continuous illumination of [RuII(TAP)3]2+ (a) [RuII(HAT)2phen]2+ (b) in the presence of GMP or DNA. R = H after acid hydrolysis

enzymes involved in gene transcription and replication. Pauly and coworkers studied the influence of the photoadduct formed with [RuII(TAP)2(phen)]2+ on the activity of a RNA-polymerase.59 The results show that the illumination of 10~5M of the complex in the presence of plasmid DNA induces a 50% reduction of the in vitro transcription of a bacteriophage RNA-polymerase. The inhibition is almost complete for a complex concentration of 5 x 10~5M.

The [RuII(BPZ)3]2+ (Figure 19.8c) and other complexes with at least two BPZ ligands are also able to react via photo-induced electron transfer with GMP and DNA.64,70 This reaction leads to plasmid DNA cleavages and photoaddition of the complex probably at the level of DNA guanines. However, although the covalent nature of this adduct has been proven by dialysis and electrophoresis experiments, its structure has yet to be reported.

Photo-oxidizing RuII complexes with HAT ligands are less studied than their TAP analogues. Nevertheless, the occurrence of photo-induced electron transfer has also been proven with [RuII(HAT)3]2+ (Figure 19.8b), [RuII(HAT)2(phen)]2+ and [RuII(HAT)2(bpy)]2+.63 Very recently, photoadduct formation between [RuII(HAT)2(phen)]2+ and GMP, CT-DNA or oligonucleotides has been evidenced by absorption spectroscopy, ESMS and NMR.71 In this case, the cova-lent bond seems to be formed between the C2 or C7 position of a HAT ligand and the exocyclic O6 position of the guanine (Figure 19.10b). Interestingly, the [RuII(HAT)2(phen)]2+ is able to form a second adduct, corresponding to the addition of two GMP molecules on the complex.71 The formation of such a biadduct is very promising for a possible use of this complex as anti-cancer agent since this photoreaction could result in DNA cross-links at the level of guanine units in close proximity, as in the case of cisplatin.

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