1,4,7,10-Tetraazacyclododecane Metal Complexes as Potent Promoters of Phosphodiester Hydrolysis under Physiological Conditions

Abstract

Previously reported mono- and dinuclear Zn(II), Cu(II), and Ni(II) complexes of 1,4,7,10-tetrazacyclododecane ([12]aneN 4 or cyclen) with different heterocyclic spacers (triazine, pyridine) of various lengths (bi- and tripyridine) or an azacrown-pendant have been tested for the hydrolysis of bis(4-nitrophenyl)phosphate (BNPP) under physiological conditions (pH 7−9, 25 °C). All Zn(II) complexes promote the hydrolysis of BNPP under physiological conditions, while those of Cu(II) and Ni(II) do not have a significant effect on the hydrolysis reaction. The hydrolysis kinetics in buffered solutions (0.05 M Bis/Tris, TRIS, HEPES, or CHES, I = 0.1 M, NaCl) at 25 °C were determined by the initial slope method (product conversion <5%). Comparison of the second-order pH-independent rate constants ( k BNPP, M −1 s −1 ) for the mononuclear complexes ZnL1, ZnL3, and ZnL6, which are 6.1 ×10 −5, 5.1 × 10 −5, and 5.7 × 10 −5, respectively, indicate that the heterocyclic moiety improves the rate of hydrolysis up to six times over the parent Zn([12]aneN 4 ) complex ( k BNPP = 1.1 × 10 −5 M −1 s −1 ). The reactive species is the Zn(II)−OH − complex, in which the Zn(II)-bound OH − acts as a nucleophile. For dinuclear complexes Zn 2 L2, Zn 2 L4, and Zn 2 L5, the rate of reaction is defined by the degree of cooperation between the metal centers, which is determined by the spacer length. Zn 2 L2 and Zn 2 L4 possessing shorter spacers are able to hydrolyze BNPP 1 to 2 orders of magnitudes faster than Zn 2 L5 . The second-order rate constants k of Zn 2 L4 and Zn 2 L2 at pH 7, 8, and 9 are significantly higher than those of previously reported related complexes. The high BNPP hydrolytic activity may be related to π-stacking and hydrophobic interactions between the aromatic spacer moieties and the substrate. Complexes Zn 2 L4 and Zn 2 L2 show hydrolytic activity at pH 7 and 8, which allows for the hydrolysis of activated phosphate esters under physiological conditions.