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