Mechanistic Studies of Dichloro(1,4,7-triazacyclononane)copper(II)-Catalyzed Phosphate Diester Hydrolysis

Abstract

In order to explore the role of labile metal complexes in promoting phosphodiester hydrolysis, detailed kinetic and mechanistic studies with Cu[9]aneN3Cl2 (1) were performed. The hydrolysis of bis(4-nitrophenyl) phosphate (2) by 1 is catalytic, as determined by the observation of both rate enhancement and turnover. The catalyst is selective for phosphodiesters; the rate of hydrolysis for 4-nitrophenyl phosphate (4) is 50 times slower than the hydrolysis rate of 2. A rate enhancement of 2000 is observed relative to hydroxide ion mediated hydrolysis, and the rates reported herein are comparable to the rates reported for phosphodiester hydrolysis by other labile metal complexes. The reaction of 1 with 2 showed a half-order dependence on the catalyst, implicating a monomer−dimer equilibrium with the monomer as the catalyst. The kinetically determined equilibrium constant is 1220 M-1, favoring the dimer. The reaction of 1 with ethyl 4-nitrophenyl phosphate (3) follows Michaelis−Menten kinetics (K M = 62.3 mM and k cat = 1.96 × 10-5 s-1), providing evidence for the formation of a catalyst−substrate complex. The pH vs rate profile indicates that deprotonation of the metal-coordinated water (pK 1 = 7.3) occurs to form the active catalyst, and the reaction becomes pH independent above pH 8.5. The activation parameters for 3 hydrolysis by 1 (pH 9.0) are ΔH ⧧ = 90 kJ mol-1 and ΔS ⧧ = −128 J mol-1 K-1. A mechanism consistent with the kinetic data is presented.

DNA damage and induction of apoptosis in pancreatic cancer cells by a new dinuclear bis(triazacyclonane) copper complex

“…S2). The pK a value for the deprotonation of the first of the two terminally bound water ligands in mononuclear [Cu(tacn)(H 2 O) 2 ] 2+ is 7.3 [29]. Thus, the low pK a value found for 1 is in line with a strong binding of the resulting hydroxide to two Cu ions and can be assigned to the formation of the μ-OH species.…”

“…The logK value for mononuclear Cu(tacn) 2+ is 15.5, suggesting that a highly stable bcmp complex is formed under physiological conditions [27]. Furthermore, Cu complexes of tacn ligands are generally good catalysts for phosphate ester hydrolysis [28,29]. The aromatic spacer provides a rigid scaffold for the bimetallic site, while the bridging phenoxy group shields the electrostatic repulsion between the metal ions and holds the two Cu 2+ ions in close proximity.…”

Dinuclear Metal Complexes Based on all‐cis‐2,4,6‐Triaminocyclohexane‐1,3,5‐triol as Catalysts for Cleavage of Phosphate Esters

“…The main reason for this finding is quite likely to be ascribed to the easier formation of µ-hydroxo bridges between two copper ions than between two zinc ions. Such bridged species are known to be poorly active also in monometallic systems, [20,21] as in the case of Cu II ·TACI complexes, which have a greater tendency to form dimeric forms than do complexes of other tripodal ligands. [22,23] In the dimetallic complex, the two Cu II ions may face each other readily so that the formation of intramolecular bridges (Figure 3) is further favored and, hence, their disruption, which is a prerequisite for the productive binding of a phosphate ester, is more difficult.…”

Hydrolysis of Phosphodiesters through Transformation of the Bacterial Phosphotriesterase

“…The exceptional chemical stability of the phosphodiester backbone in molecules such as RNA and DNA facilitates the conservation of genetic information. An array of model compounds that promote the catalytic hydrolysis of phosphodiester bonds has been designed and synthesized (17)(18)(19)(20)(21)(22)(23). Nearly all of the model compounds constructed to date utilize metal ions as essential cofactors to activate the substrate and nucleophile while holding the reactants together in close proximity (17-21).…”

“…An array of model compounds that promote the catalytic hydrolysis of phosphodiester bonds has been designed and synthesized (17)(18)(19)(20)(21)(22)(23). Nearly all of the model compounds constructed to date utilize metal ions as essential cofactors to activate the substrate and nucleophile while holding the reactants together in close proximity (17)(18)(19)(20)(21). However, the enzymatic hydrolysis of the phosphodiester bond is typically much faster than the small molecule mimics.…”