Novel Recognition of Thymine Base in Double-Stranded DNA by Zinc(II)−Macrocyclic Tetraamine Complexes Appended with Aromatic Groups

DNase I footprinting has revealed that zinc(II) complexes with macrocyclic tetraamines (1,4,7,10-tetraazacyclododecane,cyclen) appended with one or two aryl-methyl group(s), ((9-acridinyl)methyl-, (4-quinolyl)methyl-, 1,7-bis(4-quinolyl)methyl-, (1-naphthyl)methyl-, and 1,7-bis(1-naphthyl)methyl-cyclen) selectively bind to native double-stranded DNA (150 base pairs), at AT-rich regions like classical minor groove binders (distamycin A and 4,6-diamidino-2-phenylindole (DAPI)). The selectivity and affinity depend on the stacking ability and number of the aromatic ring. Zn 2+ is an essential metal ion for the DNA binding, which cannot be replaced by other metal ions such as Cu 2+ or Ni 2+ . The DNA binding by these Zn 2+ −cyclen derivatives was inhibited by captopril having a stronger affinity for the fifth coordination site of the Zn 2+ −cyclen complexes. Micrococcal nuclease footprinting, moreover, revealed that those Zn 2+ −cyclen derivatives bound only to the thymine groups in the A−T base pairs, while distamycin A and DAPI simultaneously bound to the thymine and adenine groups in the A−T base pairs. Distamycin A and the Zn 2+ −(4-quinolyl)methyl-cyclen reversibly competed for common AT-rich regions of minor groove. The DNA binding mode by the Zn 2+ −cyclen derivatives was due to the selective and strong complex formation between the Zn 2+ −cyclen moiety and the imide-deprotonated thymine at neutral pH.