Kinetics of the binding of mitoxantrone, ametantrone and analogues to DNA: relationship with binding mode and anti-tumour activity.
The kinetics of association and dissociation of DNA complexes of the anti-tumour agents mitoxantrone, ametantrone and related 1,4-bis(alkylamino)anthraquinones have been determined by stopped-flow spectrophotometry, in order to study relationships between structure, kinetic parameters and biological activity. Variations in the structure of the side chains of ametantrone analogues had little effect on the kinetic stability of the complexes, but the mitoxantrone complexes dissociated about an order of magnitude more slowly, suggesting an important role for the two hydroxyl groups on the chromophore of the latter compound. The results are consistent with other n.m.r. and molecular mechanics data, which suggest a binding model where the chromophore intercalates perpendicularly to the DNA base pair axis. Dissociation studies with DNA homopolymers of varying base composition suggest the kinetic mechanism is a mixed parallel/sequential one, with the slowest dissociation processes being from GC-rich sites in both homopolymers and natural DNA. The results suggest guidelines for the design of more tumour-active analogues of the class.
Denny
W A
WA
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Wakelin
L P
LP
D000818:Animals; D000880:Anthraquinones / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001665:Binding Sites; D004247:DNA / Q000378:metabolism*; D007700:Kinetics; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008942:Mitoxantrone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013053:Spectrophotometry; D014407:Tumor Cells, Cultured
D000880:Anthraquinones; D000970:Antineoplastic Agents; D004247:DNA; D008942:Mitoxantrone; C020182:ametantrone