Chromophore-modified antitumor anthracenediones: synthesis, DNA binding and cytotoxic activity of 1,4-bis[(aminoalkil)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,lO-dione chromophore, we have synthesized novel 1,4-bis[(aminoalkyl)aminolbenzo[ glphthalazine-5,l0-diones (BPDs) 1 which are related to the antitumor agents ametantrone and mitoxantrone. Derivatives 1 were prepared by chromic acid oxidation of acylated benzo[glphthalazines 5 followed by acid hydrolysis or by silylation-amination of 5,lOdihydroxybenzo[ glphthalazine-1,4-dione( 8). The l-[(aminoalkyl)aminol-4-amincoo ngeners 2 were isolated in low yields as byproducts from the oxidation of 5. Against a panel of human tumor cell lines, the benzo~lphthalazine-5,l0-dione1s 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. DNAbinding studies with the ametantrone-like compound IC and its single-armed congener 2c indicated that the introduction of a 2,3-diaza subunit into the anthracene-9,lO-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.