Selective DNA binding of (N-alkylamine)-substituted naphthalene imides and diimides to G+C-rich DNA.
Alkylamine-substituted naphthalene imides and diimides bind DNA by intercalation and have applications as anticancer agents. The unique structures of these imides in which two adjacent carbonyl groups lie coplanar to an extended aromatic ring system allow the possibility of sequence-selective interactions between the intercalated chromophore and guanine amino groups situated in the DNA minor groove. The binding affinities of N-[3-(dimethylamino)propyl amine]-1,8-naphthalenedicarboxylic imide (N-DMPrNI) and N,N'-bis [3,3'-(dimethylamino)propylamine]-naphthalene-1,4,5,8-tetracarboxylic diimide (N-BDMPrNDI) for natural DNAs of differing base composition were determined spectroscopically and by equilibrium dialysis. In agreement 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 association constants on DNA base composition are consistent with a requirement for one G:C pair in the binding site of the monomide, and two G:C pairs in binding sites of the diimide. These selectivities are comparable to or exceed that of actinomycin D, a classic G:C-selective drug. Protection footprinting with DNase I confirmed that the naphthalene monoiimide (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 good binding sites as indicated by nuclease protection, but few GC:GC or GG:CC steps were protected. The naphthalene diimide inhibited DNase I digestion, but did not yield a footprint. The base recognition ability and versatile chemistry make naphthalene imides and diimides attractive building blocks for design of highly sequence-specific, DNA-directed drug candidates including conjugated oligonucleotides or oligopeptides.
Liu
Z R
ZR
Department of Chemistry, Florida State University, Tallahassee 32306-3006, USA.
Hecker
K H
KH
Rill
R L
RL
D000588:Amines / Q000737:chemistry* / Q000378:metabolism; D001482:Base Composition; D001483:Base Sequence; D003596:Cytosine / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D018983:DNA Footprinting; D006147:Guanine / Q000737:chemistry / Q000378:metabolism; D007094:Imides / Q000737:chemistry* / Q000378:metabolism; D008956:Models, Chemical; D008969:Molecular Sequence Data; D009281:Naphthalenes / Q000737:chemistry* / Q000378:metabolism*; D010618:Phenanthrolines / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000588:Amines; D007094:Imides; C104332:N-(3-(dimethylamino)propylamine)-1,8-naphthalenedicarboxylic imide; C104333:N-N'-bis(3,3'-(dimethylamino)propylamine)naphthalene-1,4,5,8-tetracarboxylic diimide; D009281:Naphthalenes; D010618:Phenanthrolines; C542131:naphthalenediimide; D006147:Guanine; D003596:Cytosine; D004247:DNA