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DNA binding, prominent DNA cleavage and efficient anticancer activities of Tris(diimine)iron(ii) complexes?

Dalton Transactions Pub Date: 2011-03-02 DOI: 10.1039/C0DT00466A

Abstract

The complexes rac-[Fe(diimine)₃](ClO₄)₂1–4, where diimine = 2,2′-bipyridine (bpy) 1, 1,10-phenanthroline (phen) 2, 5,6-dimethyl-1,10-phenanthroline (5,6-dmp) 3 and dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq) 4, have been isolated, characterized and their interaction with calf thymus DNA studied by using a host of physical methods. The X-ray crystal structure of rac-[Fe(5,6-dmp)₃](ClO₄)₂3 has been determined and the packing diagram shows the presence of two enantiomeric forms of the complex cations in the same unit cell. The structures of 1–4 in solution have also been studied using UV-Visible, Cyclic Voltammetry and ESI–MS data and all data available suggests that they retain their solid state structures even in solution. The absorption spectral titrations of the iron(II) complexes with CT DNA reveal that the DNA binding affinities of the complexes vary in the order, 4 (K_b: 9.0 × 10³) > 2 (6.8 × 10³) > 3 (4. 8 × 10³) > 1 (2.9 × 10³ M^?1). The DNA interaction of dpq complex (4) involves partial insertion of the extended phen ring in between the DNA base pairs, which is deeper than that of phen (2). The 5,6-dmp (3) complex is involved in groove binding in the major groove of DNA. The lower DNA binding affinity of 1 is due to electrostatic interaction of the cationic complexes with exterior phosphates of DNA. The EthBr displacement assay and DNA viscosity study support these DNA binding modes and the above trend in DNA binding affinities. The complexes of 1 and 2 show induced CD (ICD) upon interaction with CT DNA while 3 and 4 bound to DNA exhibit inversion in the positive band with the helicity band showing very small changes, which implies that 3 and 4 bind enantiopreferentially to DNA. The DNA cleavage abilities of 1–4 have been observed at 10 μM concentration of complexes in the presence of 100 μM H₂O₂ and the DNA cleavage efficiency (> 90%) follows the order 3 > 1 > 2 > 4. The anticancer activity of 1–4 against human breast cancer cell line (MCF-7) has also been studied. The IC₅₀ values of the complexes at different incubation time intervals of 24 and 48 h follow the order, 3 (0.8, 0.6) < 4 (20.0, 17.0) < 2 (28.0, 22.0) < 1 (32.0, 29.0 μM). Interestingly, 3 exhibits anticancer activity more potent than 1, 2 and 4 and cisplatin for both 24 and 48 h. It induces cell death both through apoptosis and necrosis mechanisms, as revealed by morphological assessment data obtained by using AO/EB and Hoechst 33258 fluorescence staining methods.