Relationships between DNA-binding kinetics and biological activity for the 9-aminoacridine-4-carboxamide class of antitumor agents.
The kinetics of dissociation of calf thymus DNA complexes of the new intercalating antitumor drug N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide (5) and selected derivatives have been investigated by using the surfactant-sequestration method. The derivatives studied include those where the position (14 and 15) and nature of attachment (20 and 21) of the cationic side chain is modified, those where the distance (16-19) and composition (22-24) of the cationic group are varied, and those in which the chromophore is further substituted (25-31). While all of the compounds dissociate by a mechanism that involves at least three intermediate bound forms, derivatives bearing a 4-CONH(CH2)2NR1R2 side chain (where R1 and R2 are groups that permit the nitrogen to be protonated at neutral pH) have access to an additional binding mode of greater kinetic stability. A positive correlation is found between in vivo antitumor activity, selectivity of binding to GC-rich DNAs, and the presence of this fourth, long-lived transient species. We have interpreted our kinetic findings in terms of a molecular model for acridinecarboxamide-DNA complexes that accounts for the appearance of the fourth component. The acridine chromophore is postulated to intercalate from the narrow groove, its major axis lying at an angle to the major axis of the base pairs so that the CH atoms of positions 5 and 6 protrude into the groove. An important feature of the model is a bifurcated hydrogen bond between the O2 oxygen atom of a cytosine base adjacent to the binding site and the NH atoms of the carboxamide and protonated terminal amino functions of the drug molecule. Since the structural features required to form this bonding interaction are necessary, although not sufficient, conditions for in vivo antitumor activity, it is suggested that the model may describe the essential characteristics of the biologically active form of the bound drug. These findings further attest to the value of investigating the kinetics of DNA-drug interaction in studies of the mode of action of antitumor intercalating agents.
D000577:Amides; D000585:Aminacrine / Q000378:metabolism*; D000609:Aminoacridines / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000378:metabolism*; D007700:Kinetics; D011119:Polynucleotides / Q000378:metabolism; D013053:Spectrophotometry; D013329:Structure-Activity Relationship
D000577:Amides; D000609:Aminoacridines; D000970:Antineoplastic Agents; D011119:Polynucleotides; D000585:Aminacrine; D004247:DNA