Role of the sugar moiety in the pharmacological activity of anthracyclines: development of a novel series of disaccharide analogs.
The sugar moiety is an essential component of anthracycline antibiotics for their topoisomerase poisoning activity and antitumor efficacy. Since the sugar interacts with the minor groove, modifications in this moiety could enhance the recognition potential of the drug at the target level. Based on this hypothesis, novel anthracyclines, disaccharides lacking the amino group in the first (aglycone-linked) sugar, were designed. The 3'-amino group in the first sugar was replaced by an hydroxyl group, and the second sugar residue was bound to the first sugar via an alpha (1-4) linkage. The cytotoxic and antitumor activities of disaccharide analogs of idarubicin were critically dependent on the optimal (axial) orientation of the second sugar residue. Although configurational requirements of the sugar moiety for optimal drug activity support a critical role of the external (non-intercalating) drug domains in the interaction of anthracyclines with the DNA-topoisomerase (ternary complex), the antitumor efficacy of disaccharide analogs is not fully explained by effects mediated by the nuclear enzyme target. The development of this novel disaccharide series may provide insights for a rational synthesis of anthracycline analogs with improved pharmacological profile.
Zunino
F
F
Istituto Nazionale per lo Studio e la Cura dei Tumori, via Venezian 1, 20133, Milan, Italy. zunino@istitutotumori.mi.it
Pratesi
G
G
Perego
P
P
D018943:Anthracyclines / Q000737:chemistry / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D004187:Disaccharides / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004187:Disaccharides