Hydrolysis of a Model for the 5‘-Cap of mRNA by Dinuclear Copper(II) and Zinc(II) Complexes. Rapid Hydrolysis by Four Copper(II) Ions

Abstract

Two bis(triazacyclononane) ligands, 1,3-bis(1,4,7-triaza-1-cyclononyl)-p-xylene (pXTD) and 1,3-bis(1,4,7-triaza-1-cyclononyl)-m-xylene (mXTD), form stable dinuclear Cu(II) complexes (Cu(2)L). At pH 7.3, the predominant species are bis(hydroxide) complexes (Cu(2)L(OH)(2)(2+)) as determined by equilibrium modeling of pH-potentiometric measurements. Several dinuclear and mononuclear Cu(II) complexes and a dinuclear Zn(II) complex promote the hydrolysis of GpppG, a model for the 5'-cap of mRNA. At 0.125 mM complex, both Cu(2)(pXTD) and Cu(2)(mXTD) promote hydrolysis of GpppG approximately 100-fold more rapidly than does the monomeric Cu(TACN) complex (0.250 mM) at pH 7.3 and 37 degrees C (TACN = 1,4,7-triazacyclononane). The dependence of the rate constant on dinuclear Cu(II) complex concentration suggests that Cu(2)(pXTD) promotes hydrolysis through both a 1:1 complex (Cu(2)L-GpppG) and a 2:1 complex ((Cu(2)L)(2)-GpppG). The 2:1 complex is 20-fold more reactive than the 1:1 complex; a first-order rate constant of 1.1 x 10(-)(4) s(-)(1) is determined for hydrolysis of the 2:1 complex. Cu(2)(mXTD) effectively promotes the hydrolysis of GpppG only through a 2:1 complex which hydrolyzes with a first-order rate constant of 4.3 x 10 (-)(5) s(-)(1). Cu(2)(pXTD) binds as a 1:1 complex to m(7)GpppG with a binding constant of 27 000 M(-)(1) as determined by use of fluorescence spectroscopy. Two Cu(2)(mXTD) complexes bind stepwise to m(7)GpppG with binding constants of 5300 and 12 000 M(-)(1) for the first complex and second complex, respectively.

Hydrolysis of a mRNA 5′-cap model substrate, 5′,5′-ApppA by di- and trinuclear zinc(II) complexes of a polyamino-polyol ligand

“…According to the reported activities, the Lewis-acidity of the metal ions plays a rather important but certainly not exclusive role in promoting the process. Examples of efficient cleavage by complexes of copper(II) and trivalent lanthanide ions have been reported [26][27][28][29][30][31][32], whereas the catalysis by monomeric zinc(II) complexes is modest [26][27][28]31]. The rate of the cleavage was found to be second-order on the concentration of simple copper(II) complexes [26].…”

“…In another study, the rate acceleration provided by a mononuclear europium(III) complex was significantly enhanced by the presence of zinc(II) ions [32]. Consequently, the catalysis seems to require two metal ions, therefore bimetallic species are generally more efficient catalysts for the cleavage of cap-models than their mononuclear counterparts [24,27,30,31].…”

“…Similarly to the internucleosidic phosphodiester bonds of RNA or RNA model substrates, the hydrolysis of the triphosphate bridge in cap-models can also be enhanced by metal ions and their complexes [24][25][26][27][28][29][30][31][32]. According to the reported activities, the Lewis-acidity of the metal ions plays a rather important but certainly not exclusive role in promoting the process.…”

Copper(II) Complexes of N‐Methylated Derivatives of ortho‐ and meta‐Xylyl‐Bridged Bis(1,4,7‐triazacyclononane) Ligands: Synthesis, X‐ray Structure and Reactivity as Artificial Nucleases

“…Tacn-derived complexes have been prepared that efficiently cleave model phosphate esters, RNA, DNA and peptides. [3,[5][6][7][8][9][10] One notable finding has been that N-alkylation of the tacn ring produces copper(II) complexes that exhibit faster rates of phosphate ester cleavage. This has been attributed in part to a reduced tendency for these complexes to form hydrolytically inactive, hydroxo-bridged dimeric species in solution.…”

Ester catalytic hydrolysis by a tridentate N,N′,N″-copper bridged cyclodextrin dimer

“…In the past two decades, many metal complexes, including Cu 2+ , Co 3+ , Zn 2+ , and La 3+ complexes, have been synthesized as models of metallohydrolases and/or as catalysts for the hydrolysis of DNA, RNA and peptides in which copper complexes were the most studied as artificial nucleases. Examples include small molecule copper complexes with N,N′-bidentate bipyridyl [1][2][3][4][5], N,N′,N′′-tridentate terpyridyl [6-16] and 1,4,7-triazacyclononane ligands [17][18][19][20][21][22][23][24][25][26] and their derivatives. The catalytic activities of small molecule copper complexes for ester hydrolysis are high.…”