SELECTIVE DNA-BINDING OF (N-ALKYLAMINE)-SUBSTITUTED NAPHTHALENE IMIDES AND DIIMIDES TO G-RICH DNA(C)

Alkylamine-substituted naphthalene imides and diimides bind DNA by int ercalation and have applications as anticancer agents. The unique stru ctures of these imides in which two adjacent carbonyl groups lie copla nar to an extended aromatic ring system allow the possibility of seque nce-selective interactions between the intercalated chromophore and gu anine amino groups situated in the DNA minor groove. The binding affin ities of N-[3-(dimethylamino)propyl amine]-1,8-naphthalenedicarboxylic imide (N-DMPrNI) and no)propylamine]-napthalene-1,4,5,8-tetracarboxyl ic diimide (N-BDMPrNDI) for natural DNAs of differing base composition were determined spectroscopically and by equilibrium dialysis. In agr eement with the above proposition, binding studies indicated that both the naphthalene imide and diimide strongly prefer to intercalate into steps containing at least one G:C base pair. The dependencies of asso ciation constants on DNA base composition are consistent with a requir ement for one G:C pair in the binding site of the monoimide, and two G :C pairs in binding sites of the diimide. These selectivities are comp arable to or exceed that of actinomycin D, a classic G:C-selective dru g. Protection footprinting with DNase I confirmed that the naphthalene monoimide (N-DMPrNI) prefers to bind adjacent to G:C base pairs, with a most consistent preference for ''mixed'' steps containing both a G: C and an A:T pair, excepting GA:TC. Several 5'-CG-3' steps were also g ood binding sites as indicated by nuclease protection, but few GC:GC o r GG:CC steps were protected. The naphthalene diimide inhibited DNase I digestion, but did not yield a footprint. The base recognition abili ty and versatile chemistry make naphthalene imides and diimides attrac tive building blocks for design of highly sequence-specific, DNA-direc ted drug candidates including conjugated oligonucleotides or oligopept ides.