title: Steric constraints for DNA binding and biological activity in the amsacrine series.
abstract: To determine the relation between DNA binding mode and biological activity in compounds related to the clinical anti-leukaemia drug amsacrine, a series of acridine-substituted derivatives has been synthesized and compared for lipophilicity, DNA-binding affinity, DNA-binding geometry and anti-leukaemia activity in vitro and in vivo. DNA-binding affinity, as estimated either by ethidium displacement or equilibrium dialysis, decreased progressively as the bulk of the substituent increased. Substitution at the 2 position provided the largest effects. The DNA unwinding angles, estimated by changes in viscosity of closed circular duplex DNA in the presence of drug, decreased significantly with ethyl and isopropyl substituents. However, with tertbutyl groups in the 2, 3 or 4 position of the acridine ring, unwinding was not observed even though DNA binding was measurable. Anti-leukaemia activity in vivo was also abolished when the acridine ring was substituted with a tertbutyl group. The results suggest that methyl substitution of the acridine ring inhibits DNA binding at the 2 position but not at the 3 and 4 positions, that ethyl and isopropyl substitution inhibits intercalative binding at all positions and that tertbutyl substitution abolishes intercalative binding. Biological activity in vitro is dependent on both lipophilicity and DNA binding and activity in vivo requires intercalative DNA binding.
authors.affiliation: Cancer Research Laboratory, University of Auckland Medical School, New Zealand.
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
authors.forename: S J
authors.initials: SJ
authors.lastname: Twigden
authors.forename: B C
authors.initials: BC
authors.lastname: Baguley
mesh_terms: D000677:Amsacrine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004247:DNA / Q000378:metabolism*; D051379:Mice; D013329:Structure-Activity Relationship
chemical_list: D000677:Amsacrine; D004247:DNA