Cooperativity between Metal Ions in the Cleavage of Phosphate Diesters and RNA by Dinuclear Zn(II) Catalysts

Abstract

A series of ligands containing linked 1,4,7-triazacyclononane macrocycles are studied for the preparation of dinuclear Zn(II) complexes including 1,3-bis(1,4,7-triazacyclonon-1-yl)-2-hydroxypropane (L2OH), 1,5-bis(1,4,7-triazacyclonon-1-yl)pentane (L3), 2,9-bis(1-methyl-1,4,7-triazacyclonon-1-yl)-1,10-phenanthroline (L4), and alpha,alpha'-bis(1,4,7-triazacyclonon-1-yl)-m-xylene (L5). The titration of these ligands with Zn(NO(3))(2) was monitored by (1)H NMR. Each ligand was found to bind two Zn(II) ions with a very high affinity at near neutral pH under conditions of millimolar ligand and 2 equiv of Zn(NO(3))(2). In contrast, a stable mononuclear complex was formed in solutions containing 5.0 mM L2OH and 1 equiv of Zn(NO(3))(2). (1)H and (13)C NMR spectral data are consistent with formation of a highly symmetric mononuclear complex Zn(L2OH) in which a Zn(II) ion is sandwiched between two triazacyclononane units. The second-order rate constant k(Zn) for the cleavage of 2-hydroxypropyl-4-nitrophenyl phosphate (HPNP) at pH 7.6 and 25 degrees C catalyzed by Zn(2)(L2O) is 120-fold larger than that for the reaction catalyzed by the closely related mononuclear complex Zn(L1) (L1 = 1,4,7-triazacyclononane). By comparison, the observation that the values of k(Zn) determined under similar reaction conditions for cleavage of HPNP catalyzed by the other Zn(II) dinuclear complexes are only 3-5-fold larger than values of k(Zn) for catalysis by Zn(L1) provides strong evidence that the two Zn(II) cations in Zn(2)(L2O) act cooperatively in the stabilization of the transition state for cleavage of HPNP. The extent of cleavage of an oligoribonucleotide by Zn(L1), Zn(2)(L5), and Zn(2)(L2O) at pH 7.5 and 37 degrees C after 24 h incubation is 4,10, and 90%. The rationale for the observed differences in catalytic activity of these dinuclear Zn(II) complexes is discussed in terms of the mechanism of RNA cleavage and the structure and speciation of these complexes in solution.

An efficient synthesis of 1,3-bis(1,4,7-triazacyclonon-1-yl)-2-hydroxypropane, [1,3-bis(TACN)-2-propanol]

“…The ethyl acetate layer was concentrated to yield pure Boc 3 TACN 8 (8.48 g, 10%). The 1 H and 13 C NMR and ESI mass spectral data were consistent with literature values (4,7,8).…”

“…The free base was then converted to the bis-carbamate 7 as the precursor compound for use in the coupling reaction, (7 09). For the bis-N-protection of TACN 6, Iranzo et al (4) used Boc-anhydride (1.9 equivalents) under standard conditions, to achieve the transformation (6 07) in 62% yield after chromatography (4). Using the same conditions, in our hands, we were only able to achieve after repetitive experiments a more modest 43% yield of the pure material (see Table 1, Entry 1), with the concomitant formation of the tris-carbamate 8 in 38% yield.…”

“…The synthesis of 1,3-bis(1,4,7-triaza-cyclonon-1-yl)-2-hydroxypropane 1 was first reported in 1993 by Sessler et al (2), with confirmatory syntheses subsequently published (3,4). Whilst all of these syntheses are amenable to the laboratory scale preparation of 1Á2 g of the desired product, they are not practical for the larger scale reactions necessary for the preparation of 100 gÁKg quantities of 1, since they involve a variety of reactants, which is from a green chemistry point of view, are undesirable for multiple reasons (Figure 1).…”

A Novel Dinucleating Ligand-Containing Hexabenzimidazoles and Its Dinuclear Zinc Complex Bridged by a Carboxylate Group for the Hydrolysis of 2-Hydroxypropyl-p-nitrophenyl phosphate

“…Cooperative interaction between metal ions can be promoted by incorporation of functionality within the tether, which will allow it to serve as a scaffold for chelation of the two metal ions [27].…”

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

“…A range of ligands with the two aza-crown rings separated by spacers of different length, rigidity and geometry have been studied to date. [18][19][20][21] The dinuclear zinc complex of 1,3-bis(1,4,7-triazacyclonon-1-yl)-2-hydroxypropane reported by Morrow et al is one of the best dinuclear catalysts for the transesterification of the RNA model compound 2-hydroxypropyl p-nitrophenyl phosphate (HPNP). [22] Scrimin et al attached two tacn units to a heptapeptide.…”