title: Function of the anthracycline amino group in cellular transport and cytotoxicity.
abstract: Using a number of derivatives of doxorubicin (Adriamycin) and daunomycin, we have examined how substitution of the anthracycline amine affected net cellular accumulation and cytotoxic potency in HL-60 leukemia cells. Octanol/buffer partitioning demonstrated that each of the derivatives had an amino group titratable between pH 5 and 8, with the exception of derivatives containing a cyanomorpholino-substituted amine, which had a significantly lower pKa value. The steady state cellular drug levels for the Adriamycin and daunomycin series decreased in the following order: N,N-dimethyl-greater than morpholino-greater than parent greater than cyanomorpholino-. Thus, the net cellular accumulation of an anthracycline was found to be influenced by the basicity of the amino group; drugs with a non-basic amino group exhibited reduced uptake. Soft agar clonogenic assays showed the following order of cytotoxicity for both series: cyanomorpholino-much greater than parent greater than morpholino-approximately equal to N,N-dimethyl-. The data demonstrate an inverse correlation between uptake and potency; thus, differences in net cellular accumulation do not account for the order of anthracycline potency.
authors.forename: T G
authors.initials: TG
authors.lastname: Burke
authors.forename: M J
authors.initials: MJ
authors.lastname: Morin
authors.forename: A C
authors.initials: AC
authors.lastname: Sartorelli
authors.forename: P E
authors.initials: PE
authors.lastname: Lane
authors.forename: T R
authors.initials: TR
authors.lastname: Tritton
mesh_terms: D000588:Amines; D000903:Antibiotics, Antineoplastic; D001692:Biological Transport; D002460:Cell Line; D006801:Humans; D007700:Kinetics; D009279:Naphthacenes / Q000378:metabolism / Q000633:toxicity*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000903:Antibiotics, Antineoplastic; D009279:Naphthacenes