Natural and synthetic double-stranded DNA binding studies of macrocyclic tetraamine zinc(II) complexes appended with polyaromatic groups.
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)-poly(dT), poly(dA-dT)2, poly(dI).poly(dC), poly(dI-dC)2, poly(dG) poly(dC), and poly(dG-dC)2] has been examined by spectrophotometric methods, Tm 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 Kapp (=[bound cyclen derivatives]/[unbound cyclen derivatives][DNA phosphates] M(-1)), at 25 degrees C in 10 mM EPPS (pH 8.0) containing 0.1 M Na+, were determined and compared with those of the corresponding Zn2+ -free ligands. The results showed that the Zn2+ -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 Zn2+ -(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 Zn2+ -(9-acridinyl)methyl-cyclen with poly(dA).poly(dT), the Zn2+ -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).poly(dT) duplex. Thymine-containing DNA-directed transcription with Escherichia coli RNA polymerase in vitro was inhibited by the Zn2+ -(9-acridinyl)methyl-cyclen. The 50% inhibition concentrations of the transcription (IC50) were 22-45 microM with poly(dA).poly(dT) or poly(dA-dT)2 as templates, while with poly(dG-dC)2 as a template the IC50 value was 110 microM.
Kikuta
E
E
Department of Medicinal Chemistry, Faculty of Medicine Hiroshima University, Japan.
Katsube
N
N
Kimura
E
E
D000588:Amines / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002417:Cattle; D000080027:Cyclams; D004247:DNA / Q000138:chemical synthesis / Q000187:drug effects / Q000378:metabolism*; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry* / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism*; D011072:Poly U / Q000378:metabolism; D011067:Poly dA-dT / Q000737:chemistry / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013698:Templates, Genetic; D013950:Thymus Gland / Q000502:physiology; D014158:Transcription, Genetic; D017967:Zinc Compounds / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology
D000588:Amines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D009942:Organometallic Compounds; D017967:Zinc Compounds; C401403:zinc(II) ((9-acridinyl)methyl)cyclen; D011067:Poly dA-dT; D011072:Poly U; D004247:DNA; C038072:cyclen; D012321:DNA-Directed RNA Polymerases