Elsevier

Biochemical Pharmacology

Volume 57, Issue 10, 15 May 1999, Pages 1133-1139
Biochemical Pharmacology

Molecular and Cellular Pharmacology
Configurational requirements of the sugar moiety for the pharmacological activity of anthracycline disaccharides

https://doi.org/10.1016/S0006-2952(99)00025-8Get rights and content

Abstract

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 α-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.

Section snippets

Drugs

The four disaccharide anthracyclines (Fig. 1) were synthesized through a convergent synthetic strategy, involving the construction of the disaccharide moieties and their successive coupling with the aglycones, as previously reported [6]. In particular, we synthesized and evaluated the biological properties of the following novel compounds: MEN 10732 and MEN 10749, where the disaccharide moiety is the daunosaminyl α(1–4)-2-deoxy-l-rhamnosyl derivative and the aglycone daunomycinone and

NMR characterization of the disaccharide analogs

The configurations at positions 4′, 1′, and 1″ were confirmed by the characteristic values of proton–proton coupling constants and chemical shifts (Table 1). The rhamnosyl analogs MEN 10732 and MEN 10749 presented an H4′ resonance upfield in comparison with the fucosyl derivatives MEN 10733 and MEN 10746 and showed a triplet of J = 9 Hz, which is indicative of a transaxial arrangement between H4′ and H5′. However, the fucosyl analogs showed a broad signal for H4′, with coupling constants

Discussion

The results of this study provide new insights into the critical role of the sugar moiety in the biological activity of anthracyclines. Comparative studies of the disaccharide and monosaccharide anthracyclines indicated that only the 4-demethoxy derivative with an axial configuration (MEN 10746) achieved a cytotoxic potency comparable to that of doxorubicin. In contrast, a marked reduced potency was shown by the other 3 disaccharide analogs. No analog of the series overcame cellular resistance

Acknowledgements

This study was performed in the framework of a project supported by IMI Contract 53658 (joint project between Menarini Industrie Farmaceutiche Riunite S.r.l. and Bristol-Myers Squibb Italia) and by the Consiglio Nazionale delle Ricerche (Finalized Project ACRO), Rome, by the Ministero della Sanita’, Rome, and by the Associazione Italiana per la Ricerca sul Cancro, Milan, Italy.

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