A dinuclear zinc(II) complex of a new unsymmetric ligand with an N5O2 donor set; A structural and functional model for the active site of zinc phosphoesterases

• Two dizinc complexes of a new unsymmetrical ligand have ben synthesized and characterized.
• The catalytic phosphoesterase activity of the complexes has been investigated using [bis(2,4-dinitrophenyl) phosphate] (BDNPP) as substrate.
• Speciation studies have been performed to understand the possible species involve in the catalytic reaction.
• Cumulative results from all studies indicate the formation of an organophosphate-bridged intermediate that undergoes phosphodiester bond cleavage.

The dinuclear complex [Zn2(DPCPMP)(pivalate)](ClO4), where DPCPMP is the new unsymmetrical ligand [2-(N-(3-((bis((pyridin-2-yl)methyl)amino)methyl)-2-hydroxy-5-methylbenzyl)-N-((pyridin-2-yl)methyl)amino)acetic acid], has been synthesized and characterized. The complex is a functional model for zinc phosphoesterases with dinuclear active sites. The hydrolytic efficacy of the complex has been investigated using bis-(2,4-dinitrophenyl)phosphate (BDNPP), a DNA analog, as substrate. Speciation studies using potentiometric titrations have been performed for both the ligand and the corresponding dizinc complex to elucidate the formation of the active hydrolysis catalyst; they reveals that the dinuclear zinc(II) complexes, [Zn2(DPCPMP)]2 + and [Zn2(DPCPMP)(OH)]+ predominate the solution above pH 4. The relatively high pKa of 8.38 for water deprotonation suggests that a terminal hydroxide complex is formed. Kinetic investigations of BDNPP hydrolysis over the pH range 5.5–11.0 and with varying metal to ligand ratio (metal salt:ligand = 0.5:1 to 3:1) have been performed. Variable temperature studies gave the activation parameters ΔH‡ = 95.6 kJ mol− 1, ΔS‡ = − 44.8 J mol− 1 K− 1, and ΔG‡ = 108.0 kJ mol− 1. The cumulative results indicate the hydroxido-bridged dinuclear Zn(II) complex [Zn2(DPCPMP)(μ-OH)]+ as the effective catalyst. The mechanism of hydrolysis has been probed by computational modeling using density functional theory (DFT). Calculations show that the reaction goes through one concerted step (SN2 type) in which the bridging hydroxide in the transition state becomes terminal and performs a nucleophilic attack on the BDNPP phosphorus; the leaving group dissociates simultaneously in an overall inner sphere type activation. The calculated free energy barrier is in good agreement with the experimentally determined activation parameters.

Catalytic hydrolysis of a phosphodiester bond has been investigated using dizinc complexes of a new dinucleating ligand as catalysts. Cumulative results from speciation studies, computational modeling and kinetic results indicate that the same intermediate (I) is formed in all hydrolytic reactions.Figure optionsDownload as PowerPoint slide