Macrocyclic zinc(II) complexes for selective recognition of nucleobases in single-and double-stranded polynucleotides

As an extension of our earlier discoveries that Zn-II-cyclen complex (1) (cyclen = 1,4,7,10-tetraazacyclododecane) and Zn-II-acridine-pendant cyclen complex Zn-II-N-(9-acridin)ylmethyl-cyclen (3) are the first compounds to selectively recognize thymidine and uridine nucleosides in aqueous solution at physiological pH, the interaction of these and a relevant complex, bis(Zn-II-cyclen) (7), has been investigated with a series of polynucleotides, single-stranded poly(U) and poly(G), and double-stranded poly(A)poly(U), poly (dA) poly(dT) and poly(dG)poly(dC). These Zn-II-cyclen complexes interact with the imide-containing nucleobases in the single-stranded poly(U), unperturbed by the presence of the anionic phosphodiester backbone. The affinity constant of 1 for each N(3)-deprotonated uracil base in poly(U) is determined to be log K= 5.1 by a kinetic measurement, which is almost the same as log K=5.2 for the interaction of 1 with uridine. Thus, they disrupt the A-U (or A-T) hydrogen bonds to unzip the duplex of poly(A)poly(U) or poly(dA) poly(dT), as demonstrated by lowering of the melting temperatures (T-m) of poly(A) poly(U) and poly(dA)poly(dT) in 5 mM Tris-HCl buffer (pH 7.6, 10 mM NaCl) with increase in their concentrations. The order of the denaturing efficiency is well correlated with that of the 1:1 affinity constants for each complex with uracil or thymine; 7>3>1., The comparison of circular dichroism (CD) spectra for poly(A) poly(U), poly(A), and poly(U) in the presence of 3 has revealed a structural change from poly(A) poly(U) to two single strands, poly(A) and poly(U), caused by 3 binding exclusively to uracils in poly(U). On the other hand, the acridine-pendant cyclen complex 3, which earlier was found to associate with guanine by the Zn-II coordinating with guanine N(7), in addition to the pi-pi stacking, interacts with guanine in the double helix of poly(dG) poly(dC) from outside and stabilized the double-stranded structure, as indicated by higher T-m.