Configurational requirements of the sugar moiety for the pharmacological activity of anthracycline disaccharides

The amino sugar is recognized to be a critical determinant of the activity of anthracycline monosaccharides related re, doxorubicin and daunorubicin. In an attempt to improve the pharmacological properties of such agents, nov el anthracycline disaccharides have been designed in which the amino sugar, daunosamine, is separated from the aglycone by another carbohydrate moiety . In the present study, we examined the influence of the orientation of the second sugar residue on drug biochemical and biological properties in a se ries of closely related analogs. This structure-activity relationship study showed chat the substitution of the daunosamine for the disaccharide moiet y dramatically reduced the cytotoxic potency of the drug in the 4-methoxy s eries (daunorubicin analogs). In contrast, in the 4-demethoxy series (idaru bicin analogs), the C-4 axial, but not the equatorial, configuration confer red a cytotoxic potency and antitumor activity comparable to that of doxoru bicin. The configuration also influenced the drug's ability to stimulate to poisomerase II alpha-mediated DNA cleavage. Indeed, the glycosides with the equatorial orientation were ineffective as topoisomerase II poisons, where as the compounds with axial orientation were active, although the daunorubi cin analog exhibited a lower activity than the idarubicin analog. It is con ceivable that the axial orientation allows an optimal interaction of the dr ug with the DNA-enzyme complex only in the absence of the methoxy group. Ou r results are consistent with a critical role of the sugar moiety in drug i nteraction with the target emzyme in the ternary complex. (C) 1999 Elsevier Science Inc.