Structures of Fe(II) Complexes with N,N,N‘-Tris(2-pyridylmethyl)ethane-1,2-diamine Type Ligands. Bleomycin-like DNA Cleavage and Enhancement by an Alkylammonium Substituent on the N‘ Atom of the Ligand

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Abstract
The complexes [L5FeIICl]BPh4 and [L5FeII(H2O)](BPh4)2 (L5 = N,N,N‘-tris(2-pyridylmethyl)-N‘-methyl-ethane-1,2-diamine) have been isolated. Bernal et al. (Bernal, J.; et al. J. Chem. Soc., Dalton Trans.1995, 3667−3675) have prepared this ligand and the corresponding complex [L5FeIICl]PF6. We obtained the structural data of [L5FeIICl]BPh4 by X-ray diffraction. It crystallizes in the orthorhombic space group P212121 with a = 17.645(7) Å, b = 16.077(6) Å, c = 13.934(5) Å, V = 3953(3) Å3, and Z = 4. It presents Fe(II)−N bond lengths close to 2.2 Å, typical of high-spin Fe(II). In solution the [L5FeII(H2O)](BPh4)2 complex showed a dependence of spin state upon the nature of the solvent. It was high spin in acetone and changed to low spin in acetonitrile. This was detected by UV−vis spectroscopy and by 1H NMR. Bernal et al. (ibidem) showed that these complexes in the presence of an excess of H2O2 give a purple species, very likely the [L5FeIII(OOH)]2+ derivative, with spectroscopic signatures analogous to those of “activated bleomycin”. The formation of [L5FeIII(OOH)]2+ is confirmed here by electrospray ionization mass spectrometry. We found that a L5/Fe system gave single-strand breaks on plasmid DNA in the presence of either a reducing agent (ascorbate) and air or oxidants (H2O2, KHSO5, MMPP) at 0.1 μM concentration. The methyl group in L5 was substituted by a (CH2)5N(CH3)3+ group in order to get higher affinity with DNA. The corresponding ligand L5+ was used to prepare the complexes [L5+FeIICl]Y2 (Y = BPh4-, PF6-, ClO4-) and [L5+FeIIBr](PF6)2. The crystal structure of [L5+FeIICl](ClO4)2 was solved. It crystallizes in the monoclinic space group P21/a with a = 14.691(2) Å, b = 13.545(2) Å, c = 17.430(2) Å, β = 93.43(1)°, V = 3462(1) Å3, and Z = 4. The Fe(II)−ligand distances are similar to those of [L5FeIICl]BPh4. At the relatively low concentration of 0.01 μM, [L5+FeIIBr]2+ promoted DNA breaks. The reaction was not inhibited by hydroxyl radical scavengers. The reaction might involve a nondiffusible oxygen reactive species, either a coordinated hydroperoxide or a high-valent metal−oxo entity.

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