Influence of substituent modifications on DNA binding energetics of acridine-based anticancer agents.
The DNA binding energetics of a series of analogues derived from the anticancer agent N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide (AAC) are investigated. The effects of substituent modification at the C5 position of the acridine chromophore on the interaction of AAC with DNA are determined using spectrophotometry and isothermal titration calorimetry (ITC). The binding affinity and binding free energy associated with the interaction of AAC with DNA are significantly enhanced upon substitution at the C5 position. Energetic profiles describing ligand-DNA complex formation obtained from ITC indicate that C5 substitution significantly enhances binding enthalpy relative to the parent AAC. In many cases, the enhanced binding enthalpies of the C5-substituted analogues correlate with anticancer activity. Because of the cationic character of AAC and its analogues, the DNA binding properties of these compounds are dependent on ionic strength. To quantitate the ionic contributions to complex formation, the observed binding free energy of each compound is parsed into its polyelectrolyte and nonelectrostatic components. Enhanced nonelectrostatic contributions to the overall binding free energies observed with C5-substituted analogues relative to the parent AAC suggest that C5 substituents play a critical role in directing both thermodynamic mechanisms associated with complex formation and molecular interactions between the ligand and its DNA binding site. These studies have demonstrated that substitution of AAC at the C5 position results in enhanced DNA binding affinity and energetics.
Hutchins
Rachel A
RA
Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South, Birmingham, Alabama 35294, USA.
Crenshaw
James M
JM
Graves
David E
DE
Denny
William A
WA
D000166:Acridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002151:Calorimetry / Q000379:methods; D002417:Cattle; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004573:Electrolytes / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009994:Osmolar Concentration; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D017186:Titrimetry
D000166:Acridines; D000970:Antineoplastic Agents; D004573:Electrolytes; D004247:DNA; C427203:calf thymus DNA