MOLECULAR PHARMACOLOGY, 31:552-556 Function of the Anthracycline Amino Group in Cellular Transport

Using a number of derivatives of doxorubicin (Adnamycin) and daunomycin, we have examined how substitution of the anthra-cycline amine affected net cellular accumulation and cytotoxic potency in HL-60 leukemia cells. Octanol/buffer partitioning dem-onstrated 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 pK value. The steady state cellular drug levels for the Adnamycin and daunomycin series decreased in the following order: N,N-dimethyl-> morpholino-> parent> cyano-morpholino-. Thus, the net cellular accumulation of an anthracy-dine 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->> parent&gt