Synthesis and physicochemical characterization of novel 6-aminopyrido[3,4-c][1,9]phenanthrolines as aza-analogs of benzo[c]phenanthridines

Based on the 6-aminobenzo[c]phenanthridines, a compound class showing noteworthy antitumor activity, an efficient one-step synthesis consisting of a base-catalyzed condensation of 2 equiv of 4-methylpyridine-3-carbonitrile and various aldehydes causing twofold ring closure is described. The obtained 6-amino-11,12-dihydropyrido[3,4-c][1,9]phenanthrolines could be aromatized with Pd/C at high temperatures to form 6-aminopyrido[3,4-c][1,9]phenanthrolines. All compounds were systematically characterized regarding both lipophilicity and solubility and a high cytotoxic potential was evaluated in preliminary in vitro studies. Compared to formerly described 6-aminobenzo[c]phenanthridines our newly developed phenanthrolines turned out to possess improved drugability, due to significantly increased water-solubility and decreased lipophilicity.