Induction of B- to Z-DNA transition by copper and zinc complexes with C(15) substituted macrocyclic pentaaza ligands

Abstract

The new macrocyclic ligand 15-fluoro-15-methyl-1,4,7,10,13-pentaazacyclohexadecan-14,16-dione (2) was synthesised and its crystal structure determined together with the ones of the known analogues of 2, 15-fluoro-1,4,7,10,13-pentaazacyclohexadecan-14,16-dione (1) and 15,15-difluoro-1,4,7,10,13-pentaazacyclohexadecan-14,16-dione (3). The binding behaviour of all three ligands to copper and zinc was studied in the solid state. They can bind to the metal centre by either triple coordination (N3) with all secondary amines or after double deprotonation of the two amides with all five nitrogen atoms (N5). The N5 coordination mode is favoured by the presence of one or two fluorine substituents at the C(15) position and by a high pH in the case of aqueous solutions. Circular dichroism titrations of poly d(GC) with the metal complexes showed that only 4 and 5, that is the copper complexes of 1 and 2, induced a complete B- to Z-DNA transition. The degree of cooperativity of the transition was found to be 3.4 and 7.3 for 4 and 5 respectively. As a possible hypothesis to explain this difference, the additional methyl group in 5 compared with 4 may be involved in a hydrophobic interaction with the DNA. Ligand 2, the copper complex 6 of the bis fluoro substituted ligand 3, and the zinc complex 7 of ligand 1 did not induce any change in the direction of Z-DNA. In the case of 6, the CD spectrum of the DNA actually showed no change at all, indicating that the complex was even not interacting with the B form of DNA. Therefore it is assumed that the bis fluoro substitution is causing the complex to be in the neutral N5 coordination mode at the experimental conditions of pH 7. The electrostatic contribution together with the shielding effect of the ligand might explain the absence of any interaction with the DNA.