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The synthesis and biological activities of representatives of a new class of antitumor agent, the N-[2-(dialkylamino)ethyl ]-9-aminoacridine-4-carboxamides, are reported. Members of this class are stable and very water soluble with high levels of in vitro and in vivo antitumor activity. The compounds bind tightly to double-stranded DNA by intercalation, but the requirements for antitumor activity are more restrictive. They depend critically on the separation distance, positioning, and pKa values of the two cationic centers. For in vivo activity, significant bulk tolerance exists for lipophilic but not hydrophilic groups about the C-9 acridine position and for both lipophilic and hydrophilic groups on the side-chain cationic moiety. Significant attenuation of the pKa of the side-chain cationic center abolishes activity, as does alteration of either the disposition or separation distance of the side-chain charge with respect to the chromophore.

In an investigation of the structure-activity relationships in the 4'-(9-acridinylamino)methanesulfonanilide (AMSA) tumor inhibitory analogues, the DNA-binding properties of a series of simple 9-anilinoacridines were examined. Positional numbering as in the AMSA series has been employed. DNA binding was determined by drug competition with the fluorochrome ethidium for available sites. The decrease in fluorescence of a DNA-ethidium complex by the addition of drug is due to both drug displacement of bound ethidium and quenching of the fluorescence of bound ethidium by bound drug; measurement of both factors allows drug-DNA association constants (K) to be determined. DNA binding is augmented by 1' or 2' electron donor substituents, and significant correlation equations have been derived with Hammett's sigma p or sigma m constants. Group molar refractivity (MR) for 1'-substituents is an additional significant regression equation term for binding, while the values for 2' and 3' groups play no significant role. Most 3'-substituents decrease binding, presumably as a result of steric inhibition of entry of the acridine nucleus into intercalation sites. A 3'-NHSO2CH3 and 3'-NHCOCH3 substituent confer selectivity of binding to poly[d(G-C)] and poly[d(A-T)], respectively. It is suggested that a combination of H-bond formation and stereochemical features, coupled with steric hindrance, provides the selectivity observed. Binding data are consistent with a model in which the acridine nucleus occupies an intercalation site and the noncoplanar 9-anilino ring resides in the DNA minor groove.

Quantitative relationships (QSAR) have been derived between antileukemic (L1210) activity and agent physicochemical properties for 509 tumor-active members of the general class of 9-anilinoacridines. One member of this class is the clinical agent m-AMSA (NSC 249992). Agent hydrophobicity proved a significant but not a dominant influence on in vivo potency. The electronic properties of substituent groups proved important, but the most significant effects on drug potency were shown by the steric influence of groups placed at various positions on the 9-anilinoacridine skeleton. The results are entirely consistent with the physiologically important step in the action of these compounds being their binding to double-stranded DNA by intercalation of the acridine chromophore between the base pairs and positioning of the anilino group in the minor groove, as previously suggested. An equation was also derived for the acute toxicities of 643 derivatives of 9-anilinoacridine. This equation took a somewhat similar form to the one modeling antileukemia potency, emphasizing the usual fairly close relationship between potency and acute toxicity for antitumor agents in general. This study demonstrated the power of QSAR techniques to structure very large amounts of biological data and to allow the extraction of useful information from them bearing on the possible site of action of the compounds concerned.

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