Chromophore-modified 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-1,4-dione (8). The 1-[(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.
Gandolfi
C A
CA
Research Center, Boehringer Mannheim Italia S.p.A., Monza, Italy.
Beggiolin
G
G
Menta
E
E
Palumbo
M
M
Sissi
C
C
Spinelli
S
S
Johnson
F
F
D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008942:Mitoxantrone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D004247:DNA; D008942:Mitoxantrone