Interactions of acridine antitumor agents with DNA: binding energies and groove preferences.
Absorbance spectroscopy is used to examine the thermodynamic properties associated with the interaction of the experimental antitumor agents N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide (AAC) and N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) with nucleic acids. Placement of the amino substituent at the C9 position on the acridine ring results in marked changes to the acridine chromophore's electronic properties, with the overall charge of AAC increasing to +2 in comparison to DACA's charge of +1 at neutral pH. In comparative DNA binding studies, we examine the influence that the electrostatic properties of these ligands have on the binding energies as well as their effects on enthalpy and entropy contributions. These studies show that placement of the amino moiety at C9 results in 6 times greater DNA binding affinity as compared the deamino analog (DACA). Comparisons of ionic strength dependence for these two analogs reveal a difference in the binding energies of the compounds which can be attributed to electrostatic effects. Further dissection of the enthalpy and entropy components of the binding energy reveals the enhanced electrostatic effects are related to an increased entropy contribution upon formation of the AAC-DNA complex. Groove selectivity of these acridine analogs was probed by examining the binding profiles to native and groove-modified DNAs which included glycosylated T4 DNA and the distamycin-DNA complex. These studies are indicative of minor groove interactions for both compounds with DNA.
Crenshaw
J M
JM
Department of Chemistry, University of Mississippi, University 38677, USA.
Graves
D E
DE
Denny
W A
WA
D000166:Acridines / Q000737:chemistry*; D000585:Aminacrine / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D002151:Calorimetry; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D016018:Least-Squares Analysis; D009690:Nucleic Acid Conformation; D013053:Spectrophotometry; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000166:Acridines; D000970:Antineoplastic Agents; D000585:Aminacrine; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide; D004247:DNA