Copper(II) complexes of N3O tripodal ligands appended with pyrene and polyamine groups: Anti-proliferative and nuclease activities

5 years ago

Copper(II) complexes of N3O tripodal ligands appended with pyrene and polyamine groups: Anti-proliferative and nuclease activities

A series of tripodal ligands based on the 2-tert-butyl-4-R-6-phenol was synthesized, where R=aldehyde (HL¹), R=putrescine-pyrene (HL²) and R=putrescine (HL³). A dinucleating ligand wherein a putrescine group connects two tripodal moieties was also prepared (H2L⁴). The corresponding copper complexes (1, 2, 3, and 4, respectively) were prepared and characterized. We determined the phenol's pKas in the range 2.47–3.93. The DNA binding constants were determined at 6×10⁶, 5.5×10⁵ and 2.7×10⁶ for 2, 3 and 4, respectively. The complexes display a metal-centered reduction wave at Ep ^c,red =−0.45 to −0.5V vs. saturated calomel electrode, as well as a ligand-centered oxidation wave above 0.57V at pH7. In the presence of ascorbate they promote an efficient cleavage of DNA, with for example a concentration required to cleave 50% of supercoiled DNA of 1.7μM for 2. The nuclease activity is affected by the nature of the R group: putrescine-pyrene≈bis-ligating>putrescine>aldehyde. The species responsible for strand scission is the hydroxyl radical. The cytotoxicity of the complexes was evaluated on bladder cancer cell lines sensitive or resistant to cis-platin. The IC50 of complexes 2 and 4 span over a short range (1.3–2μM) for the two cell lines. They are lower than those of the other complexes (3.1–9.7μM) and cis-platin. The most active compounds block the cell cycle at the G1 phase and promote apoptosis.

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DOI: S0162013417305950