N4-(ω-aminoalkyl)-1-[(ω-aminoalkyl)amino]-4-acridinecarboxamides : Novel, potent, cytotoxic, and DNA-binding agents

A series of DNA-binding potential antitumor agents, (ω-aminoalkyl)-4-acridinecarboxamides, has been prepared either by reduction of the corresponding (ω-aminoalkyl)-9-oxo-9,10-dihydro-4-acridinecarboxamides with aluminum amalgam or by aminolysis of the corresponding (ω-aminoalkyl)-1-chloro-4-acridinecarboxamides with the suitable amine. The noncovalent DNA-binding properties of these compounds have been examined using a fluorometric technique. In vitro cytotoxic potencies of these derivatives toward six tumor cell lines, including human colon adenocarcinoma (HT29) and human ovarian carcinoma (A2780-sensitive, A2780cisR cisplatin-resistant, CH1-sensitive, CH1cisR cisplatin-resistant, and SKOV-3) cells, are described and compared to that of reference drugs. One highly DNA affinic analogue (3a) has been identified with a useful broad spectrum of cytotoxic activity in the 4−7 nM range (mean IC50 of 6 nM).