ELECTRON-DEFICIENT DNA-INTERCALATING AGENTS AS ANTITUMOR DRUGS - AZA ANALOGS OF THE EXPERIMENTAL CLINICAL AGENT N-[2-(DIMETHYLAMINO)ETHYL]ACRIDINE-4-CARBOXAMIDE

A series of azaacridine (benzonaphthyridine) analogues of the drug N-[ 2-(dimethylamino)ethyl]-acridine-4-carboxamide (DACA) (currently in cl inical trial) were synthesized. These compounds showed DNA binding aff inities similar to that of DACA, as determined by the fluorometric eth idium displacement assay, but were generally less potent cytotoxins ag ainst P388 leukemia in vitro. The only compounds showing higher cytoto xicity than DACA were analogues with nitro substituents at the (acridi ne) 1-position; by analogy with the 1-nitroacridine nitracrine, these compounds probably undergo reductive metabolism. The only azaacridine to show significant in vivo antileukemic activity was benzo[b][1,5]nap hthyridine-6-carboxamide. A possible reason for the unexpectedly low a ctivity of these compounds (given the wide acceptability of substituen ts in DACA) may be their much lower lipophilicities, which are likely to result in lower rates of cell uptake.