Chromophore-Modifíed Antitumor Anthracenediones: Synthesis, DNA Binding, and Cytotoxic Activity of 1,4-Bis[(aminoalkyl)amino]benzo[g]-phthalazine-5,10-diones

As part of a program aimed at exploring the effect of the introduction of heteroatoms into the anthracene-9,10-dione chromophore, we have synthesized novel 1,4-bis[(aminoalkyl)amino]-benzo[g]phthalazine-5,10-diones (BPDs) 1 which are related to the antitumor agents ametantrone and mitoxantrone. Derivatives 1 were prepared by chromic acid oxidation of acylated benzo[g]phthalazines 5 followed by acid hydrolysis or by silylation-amination of 5,10- dihydroxybenzo[g]phthalazine-l,4-dione (8). The l-[(aminoalkyl)amino]-4-amino congeners 2 were isolated in low yields as byproducts from the oxidation of 5. Against a panel of human tumor cell lines, the benzo[g′]phthalazine-5,10-diones 1 and 2 exhibited cytotoxic activity comparable or even superior to that of mitoxantrone. In compounds 1, structure–activity relationships different than those operative in the carbocyclic series appeared to emerge. DNA-binding studies with the ametantrone-like compound 1c and its single-armed congener 2c indicated that the introduction of a 2,3-diaza subunit into the anthracene-9,10-dione chromophore reduces the affinity of the drug for DNA in comparison with ametantrone. On the other hand, the number of side-chain groups does not affect binding to a great extent. These findings seem to suggest mechanisms of cell death other than those induced by simple interaction of the 1,4-BPDs 1 and 2 with DNA.