A new series of reductive amination derivatives of daunorubicin: syntheses, partition coefficients, and DNA binding.
A series of daunorubicin derivatives were prepared by sodium cyanoborohydride reductive amination of daunorubicin with appropriate amines. All derivatives were found to bind quite strongly to DNA and viscosity increases with linear DNA indicated that each formed an intercalation complex. A range of octanol-aqueous buffer partition coefficients was obtained, around the values of daunorubicin and dauxorubicin hydrochloride, by varying the character of the starting amine. All monoamine derivatives had activity against P388 leukemia in mice which was similar to that of daunorubicin. A diamine derivative had reduced activity against P388. Several anthracyclines administered as DNA complexes had similar activity against P388 but significantly reduced toxicity compared to the uncomplexed compounds. For anthracyclines which bind strongly to DNA, optimum activity against P388 leukemia in mice seems to be centered on compounds with octanol-buffer partition coefficients in the range of 0.5-0.8.
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000378:metabolism*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D007941:Leukemia P388 / Q000188:drug therapy; D008297:Male; D051379:Mice; D012995:Solubility
D004247:DNA; D012321:DNA-Directed RNA Polymerases; D003630:Daunorubicin