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 to doxorubicin and daunorubicin. In an attempt to improve the pharmacological properties of such agents, novel 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 series of closely related analogs. This structure-activity relationship study showed that the substitution of the daunosamine for the disaccharide moiety dramatically reduced the cytotoxic potency of the drug in the 4-methoxy series (daunorubicin analogs). In contrast, in the 4-demethoxy series (idarubicin analogs), the C-4 axial, but not the equatorial, configuration conferred a cytotoxic potency and antitumor activity comparable to that of doxorubicin. The configuration also influenced the drug's ability to stimulate topoisomerase II alpha-mediated DNA cleavage. Indeed, the glycosides with the equatorial orientation were ineffective as topoisomerase II poisons, whereas the compounds with axial orientation were active, although the daunorubicin analog exhibited a lower activity than the idarubicin analog. It is conceivable that the axial orientation allows an optimal interaction of the drug with the DNA-enzyme complex only in the absence of the methoxy group. Our results are consistent with a critical role of the sugar moiety in drug interaction with the target enzyme in the ternary complex.
Arcamone
F
F
Menarini Ricerche Sud, Pomezia, Rome, Italy.
Animati
F
F
Bigioni
M
M
Capranico
G
G
Caserini
C
C
Cipollone
A
A
De Cesare
M
M
Ettorre
A
A
Guano
F
F
Manzini
S
S
Monteagudo
E
E
Pratesi
G
G
Salvatore
C
C
Supino
R
R
Zunino
F
F
D000818:Animals; D018943:Anthracyclines / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004187:Disaccharides / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D015255:Idarubicin / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D008968:Molecular Conformation; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D018943:Anthracyclines; D000970:Antineoplastic Agents; D004187:Disaccharides; D011994:Recombinant Proteins; D004247:DNA; D015255:Idarubicin