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Unusually high phosphodiesterolytic activity of La(III) hydroxide complexes stabilized by glycine derivatives

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Abstract

Glycine and N,N-dimethylglycine stabilize La(III) hydroxide complexes of the type La2L2(OH)4 which possess phosphodiesterolytic activity close to that observed with most active tetravalent cations like Ce(IV).

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Testing phosphodiesterase activity of Eu(III) in the presence of native cyclodextrins revealed capacity of β-cyclodextrin (β-CD) to stabilize catalytically active metal hydroxocomplexes in mildly basic solutions. Kinetics of the hydrolysis of bis(4-nitrophenyl) phosphate (BNPP) and transesterification of 2-hydroxypropyl 4-nitrophenyl phosphate (HPNP) as models of DNA and RNA respectively has been studied with La(III), Pr(III), Nd(III), Eu(III), Gd(III) and Dy(III) cations in the presence of β-CD in the range of pH 7.0-9.0. The overall catalytic effect with 2 mM lanthanide-β-CD complexes was up to 105 for HPNP and 108 for BNPP at pH 8 demonstrating the highest catalytic activity among so far reported artificial phosphodiesterases. Analysis of concentration and pH-dependences of observed rate constants for different lanthanides showed that active species are binuclear polyhydroxocomplexes of general type [M2(β-CD)(OH)n]6-n with n = 3-5. The metal-β-CD and phosphodiester-β-CD interactions were studied by 1H NMR spectroscopy. Mechanistic implications of much higher catalytic efficiency in BNPP hydrolysis as compared to HPNP transesterification are discussed.
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Lanthanide ions are remarkably effective catalysts for the hydrolytic cleavage of phosphate ester bonds, including the robust bonds of DNA. This makes Ln(III) and Ce(IV) ions attractive candidates for developing selective and efficient artificial nucleases, which could have many biochemical and clinical applications. Both small-molecule-based and biopolymer-based lanthanide complexes are being pursued.
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Potentiometric titrations of the mixtures of lanthanide(III) perchlorates and bis-Tris propane (BTP) reveal formation of dinuclear hydroxo complexes M2(BTP)2(OH)n(6-n), where M = La(III), Pr(III), Nd(III), Eu(III), Gd(III), and Dy(III) and n = 2, 4, 5, or 6, in the pH range 7-9. ESI-MS data confirm the presence of dinuclear species. Kinetics of the hydrolysis of bis(4-nitrophenyl) phosphate (BNPP), mono-4-nitrophenyl phosphate (NPP), and 4-nitrophenyl acetate (NPA) in the lanthanide(III)-BTP systems has been studied at 25 degrees C in the pH range 7-9. The second-order rate constants for the hydrolysis of BNPP by individual lanthanide hydroxo complexes have been estimated by using the multiple regression on observed rate constants obtained at variable pH. For a given metal, the rate constants increase with increasing in the number n of coordinated hydroxide ions. In a series of complexes with a given n, the second-order rate constants decrease in the order La > Pr > Nd > Eu > Gd > Dy. Hydrolysis of NPP follows Michaelis-Menten-type "saturation" kinetics. This difference in kinetic behavior can be attributed to stronger binding of NPP dianion than BNPP monoanion to the lanthanide(III) species. Activities of lanthanide complexes in the hydrolysis of NPA, which is 10(6) times more reactive than BNPP in alkaline or aqueous hydrolysis, are similar to those in BNPP hydrolysis indicating unique capability of lanthanide(III) cations to stabilize the transition state of phosphate diester hydrolysis. Results of this study are analyzed together with literature data for other metal cations in terms of the Brønsted correlation and transition state-catalyst complexation strength.
Article
Eu(III) complexes of 1,4,7,10-tetraazacyclododecane derivatives with mixed alcohol and amide pendent groups are more resistant to Eu(III) ion dissociation under most conditions than are analogous complexes containing all alcohol pendent groups. Pseudo-first-order rate constants for intramolecular phosphate diester transesterification by these complexes decrease with increasing number of amide pendent groups; however, reactions where the hydroxyalkyl group of the macrocyclic complex is itself a nucleophile proceed rapidly in macrocycles with mixed alcohol and amide pendent groups.
Article
The lanthanide ion based macrocyclic complexes 1.Ln mimic the hydrophobic nature of ribonucleases, where the lanthanide ions induce the formation of a hydrophobic cavity for 1, giving rise to a large order of magnitude enhancement in the hydrolytic cleavage of HPNP.