ANTITUMOR AGENTS .167. SYNTHESIS AND STRUCTURE-ACTIVITY CORRELATIONS OF THE CYTOTOXIC ANTHRAQUINONE 4-BIS-(2,3-EPOXYPROPYLAMINO)-9,10-ANTHRACENEDIONE, AND OF RELATED-COMPOUNDS

,4-Bis-(2,3-epoxypropylamino)-9,10-anthracenedione (3) was synthesized in this laboratory and was found to be a patent antitumor agent. Deri vatives of this compound containing anthraquinone, naphthoquinone, and quinone skeletons were also prepared and evaluated for in vitro cytot oxic activity in several cell lines. These molecules were designed as bifunctional antitumor agents with the potential to act as (1) interca lating agents due to their planar backbones, and (2) alkylating agents due to the presence of alkylating moieties in their side chains. Comp ounds with an anthraquinone skeleton and propylamino side chains conta ining epoxides or halohydrins as the alkylating species showed greater activity than similar compounds with naphthoquinone or quinone skelet ons. Compounds without these alkylating functionalities (e.g., with al kene or amino groups) were generally inactive. Hydroxy substitution on the planar skeleton in conjunction with alkylating side chains gave c ompounds with the most potent cytotoxic activity. The position of the hydroxy groups and side chains could be varied without substantially a ffecting activity. Activity was retained when an epoxypropyloxy side c hain was substituted for the epoxypropylamino side chain in the parent compound. (C) 1997 Elsevier Science Ltd.