Potential antitumor agents. 43. Synthesis and biological activity of dibasic 9-aminoacridine-4-carboxamides, a new class of antitumor agent

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.