Macrocyclic metal complexes for selective recognition of nucleic acid bases and manipulation of gene expression

Abstract

Interaction of ZnII-cyclen complexes 1, 3, 6, and 7 with uracil and thymine bases in double-stranded poly(A)·poly(U) and poly(dA)·poly(dT) has been investigated. These zinc(II) complexes lowered the melting temperatures (Tm) of poly(A)·poly(U) and poly(dA)·poly(dT) in 5 mM Tris-HCl buffer (pH 7.6) containing 10 mM NaCl as their concentrations increased, indicating that they destabilized the duplex structure of polynucleotides. The comparison of circular dichroism (CD) spectra of poly(A)·poly(U), poly(A), and poly(U) in the presence of zinc(II) complex 3 led us to conclude that the spectral changes of poly(A)·poly(U) were due to a structural change from double to single-strand, caused by zinc(H) complex 3 binding exclusively to uracils in poly(U). The destabilization effect of zinc(II) complexes was not observed with poly(dG)·poly(dC) in thermal denaturation experiments (50 % formamide aqueous solution, 2.5 mM Tris-HCl buffer (pH 7.6) and 5 mM NaCl). However, the acridine-pendant cyclen complex 3, which associates with guanine at N7 and O6, and through π-π stacking, interacted with poly(dG) in the double helix and greatly stabilized the poly(dG)·poly(dC) double-strand, as was indicated by the higher Tm than those with reference intercalating agents. Poly(A)·poly(U) double-strand was most effectively disrupted with a bis(ZnII-cyclen) bridged by para-xylyl group 6 that was designed as a host molecule to bind to two neighboring uracils in a 1:2 complex. ZnII-cyclen complexes thus may become a prototype of small molecules that can affect the biological properties of nucleic acids at the molecular level.