AMINAOALKYL)CARBAMOYL]-9-OXO-9,10-DIHYDROACRIDINES AS INTERCALATING CYTOTOXIC AGENTS - SYNTHESIS, DNA-BINDING, AND BIOLOGICAL EVALUATION

A series of DNA-intercalating potential antitumor agents, -aminoalkyl) carbamoyl]-9-oxo-9,10-dihydroacridines has been prepared by aminolysis of the corresponding 4-[N-(omega-aminoalkyl)carbamoyl]-1-chloro deriv ative with a suitable omega-aminoalkylamine. The noncovalent DNA-bindi ng properties of these bis-functionalized compounds have been examined using a combination of fluorometric and thermal denaturation techniqu es and are compared with the behaviors for established DNA intercalant s and cationic minor groove ligands. The results indicate that (i) the agents are considerably more DNA-affinic than less functionalized acr idinones, with 'apparent' binding constants of(0.1-2.1) x 10(7) and (0 .3-7.5) x 10(7) M-1 at pH 5 and 7, respectively, (ii) overall affinity is sensitive to both the length of the flexible side chain and the co mplexity of the attached amine substituents, and (iii) the pendant sid e chains effect a switch to moderate AT-preferential binding. In vitro cytotoxic potencies toward six tumor cell. lines broadly parallel the observed DNA affinities, although poor correlation is evident for cer tain compounds. The octanol/water partition coefficients have been als o calculated, but there is no correlation with cytotoxicity values. Tw o highly DNA-affinic analogs, 10 and 13, have been identified with a u seful broad spectrum of cytotoxic activity.