Natural and synthetic double-stranded DNA binding studies of macrocyclic tetraamine zinc(II) complexes appended with polyaromatic groups

摘要

The characteristic binding mode of zinc(II) complexes of macrocyclic tetraamines (1, 4, 7, 10-tetraazacyclododecane, cyclen) appended with one or two arylmethyl group(s) [(4-quinolyl)methyl-, 1, 7-bis(4-quinolyl)methyl-, (1-naphthyl)methyl-, 1, 7-bis(1-naphthyl)methyl-, and (9-acridinyl) methyl-cyclen] to double-stranded calf thymus DNA and synthetic DNAs [poly(dA) centre dot poly(dT), poly(dA-dT)_2, poly(dI) centre dot poly(dC), poly(dI-dC)_2, poly(dG) centre dot poly(dC), and poly(dG-dC)_2] has been examined by spectrophotometric methods, T_m measurement, and inhibition of these DNA-directed transcriptions in vitro. Various hypochromic and bathochromic effects on the pendant aromatic absorption spectra of the complexes were observed in titration with the native and synthetic DNA. The binding constants K_app (=[bound cyclen derivatives]/[unbound cyclen derivatives] [DNA phosphates] M~(-1)), at 25 deg C in 10 mM EPPS (pH 8.0) containing 0.1 M Na~+, were determined and compared with those of the corresponding Zn~(2+)-free ligands. The results showed that the Zn~(2+)-cyclen complexes interact with the DNA more strongly than the corresponding diprotonated ligands, leading to a stronger stacking of the pendant aromatic rings. The binding of Zn~(2+)-(9-acridinyl) methyl-cyclen to calf thymus DNA was competed by an AT-selective, minor groove binder, distamycin, but not by a major groove binder, methyl green. In an unusual interaction of excess Zn~(2+)-(9-acridinyl) methyl-cyclen with poly(dA) centre dot poly(dT), the Zn~(2+)-cyclen moiety went into the minor groove to make coordination bonds with the deprotonated imides of the thymines, resulting in disruption of the poly(dA) centre dot poly(dT) duplex. Thymine-containing DNA-directed transcription with Escherichia coli RNA polymerase in vitro was inhibited by the Zn~(2+)-(9-acridinyl) methyl-cyclen. The 50% inhibition concentrations of the transcription (IC_(50)) were 22-45 #mu#M with poly(dA) centre dot poly(dT) or poly(dA-dT)_2 as templates, while with poly(dG-dC)_2 as a template the IC_(50) value was 110 #mu#M.