Efficient hydrolytic cleavage of plasmid DNA by chloro-cobalt(ii) complexes based on sterically hindered pyridyl tripod tetraamine ligands: synthesis, crystal structure and DNA cleavage

Abstract

Four new cobalt(II) complexes [Co(6-MeTPA)Cl]ClO₄/PF₆ (2/2a), [Co(6-Me₂TPA)Cl]ClO₄/PF₆ (3/3a), [Co(BPQA)Cl]ClO₄/PF₆ (4/4a) and [Co(BQPA)Cl]ClO₄/PF₆ (5/5a) as well as [Co(TPA)Cl]ClO₄ (1) where TPA = tris(2-pyridylmethyl)amine, 6-MeTPA = ((6-methyl-2-pyridyl)methyl)bis(2-pyridylmethyl)amine, 6-Me₂TPA = bis(6-methyl-2-pyridyl)methyl)-(2-pyridylmethyl)amine, BPQA = bis(2-pyridylmethyl)-(2-quinolylmethyl)-amine and BQPA = bis(2-quinolylmethyl)-(2-pyridylmethyl)amine were synthesized and structurally characterized. Single crystal X-ray crystallography confirmed the distorted trigonal bipyramidal geometries of complexes 2a–5a. Spectrophotometric titrations and conductivity measurements of the complexes in the CH₃CN–H₂O mixture showed that the chloro complexes exist in equilibrium with the corresponding hydrolyzed aqua species, [Co(L)(H₂O)]²⁺. The pK_a values of the coordinated H₂O in aqua complexes vary from 8.4 to 8.7 (37 °C). The interactions of the complexes (1–5) with DNA have been investigated at pH = 7.0 and 9.0 (10 mM Tris-HCl buffer) and 37 °C where very high catalytic cleavage was observed. Under pseudo Michaelis–Menten kinetic conditions, the catalytic rate constants, k_cat, decrease in the order 4>2>5>1>3. At pH 7.0 (10 mM Tris-HCl buffer) and 37 °C, the k_cat value for complex 4 (6.02 h⁻¹), where [Co(BPQA)(H₂O)]²⁺ is the major species, corresponds to 170 million rate enhancement over the non-catalyzed DNA. Electrophoretic experiments conducted in the presence and absence of radical scavengers (DMSO, KI, NaN₃) ruled out the oxidative mechanistic pathway of the reaction and suggested that the hydrolytic mechanism is the preferred one. This finding was in agreement with the observed increase in the k_cat values at pH 9.0 compared to the corresponding values at pH 7.0 as a result of the increased concentration of the reactive hydroxo species, [Co(L)(OH)]⁺. The reactivity of the synthesized complexes in catalyzing the DNA cleavage is discussed in relation to the steric effect imposed by the coordinated pyridyl ligand around the central cobalt(II) center.