DNA binding, cleavage, and cytotoxic activity of the preorganized dinuclear zinc(II) complex of triazacyclononane derivatives

A preorganized cleft dinuclear zinc(II) complex of 2,6-bis(1-methyl-1,4,7-triazacyclonon-1-yl)pyridine 1 as an artificial nuclease was prepared via an improved method. The interactions of 1, 2 [1,4,7-triazacyclononane (TACN)], and their zinc(H) complexes with calf thymus DNA were studied by spectroscopic techniques, including fluorescence and CD spectroscopy. The results indicate that the DNA binding affinities of these compounds are in the following order: Zn-2(II)-1 > Zn-II-2 > 1 > 2. The binding constants of the Zn-2(II)-1 and Zn-II-2 complexes are 3.57 x 10(6) and 1.43 x 10(5) M-1, respectively. Agarose gel electrophoresis was used to assess the plasmid pUC 19 DNA cleavage activities in the presence of the dinuclear Zn-2(II)-1 complex, which exhibits powerful DNA cleavage efficiency, Kinetic data for DNA cleavage promoted by the Zn,)-l complex under physiological conditions give the observed rate constant (k(obs)) of 0. 136 h(-1), which shows an 10(7)-fold rate acceleration over uncatalyzed supercoiled DNA. The comparison of the dinuclear Zn-2(II)-1 complex with the mononuclear zinc(II) complex of 1.4,7-triazacyclononane indicates that the DNA cleavage acceleration promoted by the Zn-2(II)-1 complex is due to the efficient cooperative catalysis of the two proximate zinc(II) cation centers. A hydrolytic mechanism of the cleavage process was suggested, and a preliminary study of the antitumor activity was also conducted.