Phosphate Ester Hydrolysis: Metal Complexes As Purple Acid Phosphatase and Phosphotriesterase Analogues

Abstract

This microreview describes the structures and properties of a number of bimetallic complexes designed as both structural and functional mimics of the active sites of some specific metallohydrolase enzymes. The metalloenzymes in question include the predominantly monoesterase-activity-displaying

Phosphate Diester Cleavage, DNA Interaction and Cytotoxic Activity of a Bimetallic Bis(1,4,7‐triazacyclononane) Zinc Complex

“…The high catalytic efficiency of dizinc enzymes has been attributed to the synergistic action of the two metal ions [14] and has inspired the design and study of a large number of bimetallic Zn complexes as potential cleaving agents for nucleic acids and phosphate esters as their models. [15][16][17] In particular, dinuclear zinc complexes with bis(1,4,7-triazacyclonon-1-yl) ligands [bis(tacn)] are of considerable interest due to their often remarkable reactivity towards phosphodiesters. A range of ligands with the two aza-crown rings separated by spacers of different length, rigidity and geometry have been studied to date.…”

The impact of the second coordination sphere in phosphatase model complexes

“…9,21,79,80 Moreover, the two chemically distinct coordination environments around the metal centers have been found to be essential for catalytic activity. 21,24,[81][82][83][84][85] The amino acid backbone of the active site in PAPs generate two different coordination sites, which favor the binding to a specific metal, though their individual roles remain a matter of debate.…”

“…Low molecular weight mimics of phosphoesterases simplify the study of both the environment of the metal ions and the hydrolysis of phosphoesters, and can provide insight into possible catalytic mechanisms. 81 Therefore, small metal complexes have been used extensively to model the active site of phosphoesterases. 81 Moreover, dinuclear complexes have been shown to bind phosphates more strongly and to be significantly more reactive for the cleavage of phosphate esters compared to their mononuclear counterparts.…”

“…81 Therefore, small metal complexes have been used extensively to model the active site of phosphoesterases. 81 Moreover, dinuclear complexes have been shown to bind phosphates more strongly and to be significantly more reactive for the cleavage of phosphate esters compared to their mononuclear counterparts. [86][87][88][89] Some of the most active dimetallic systems are those in which the ligand structure places the metal ions in a way that it promotes cooperative interactions with the substrate (either via double Lewis acid activation, or Lewis acid activation coupled with provision of a metal-bound hydroxide nucleophile).…”

“…Among others, phenolate-, alkoxo-, and imidazolate have been deployed as scaffolds for a range of ligands varying in the aminomethyl-substituents (depicted as R x in Chart 3) in order to tune the coordination behavior of the ligands towards specific metal ions. 81,[90][91][92][93][94][95][96][97][98][99] The phenolate-linker is one of the most commonly used ligand scaffolds, 90,[92][93][94][95][96]99 for example in the symmetric ligands HL 1 and H3L 3 (see Chart 4). 100,101 (The nomenclature of the ligands denotes the number of protons which can potentially be abstracted from the ligands upon deprotonation; HL 1 contains one potentially acidic phenolate residue, accordingly HL 1 , while H3L 3 bears three acidic protons and the nomenclature is adjusted accordingly.…”