Syntheses and biological activities of disaccharide daunorubicins

    Authors

    G. S. Zhang; L. Y. Fang; L. Z. Zhu; J. E. Aimiuwu; J. Shen; H. Cheng; M. T. Muller; G. E. Lee; D. X. Sun;P. G. Wang

    Comments

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    Abbreviated Journal Title

    J. Med. Chem.

    Keywords

    II DNA CLEAVAGE; TOPOISOMERASE-II; ANTITUMOR ANTHRACYCLINES; SEQUENCE; SPECIFICITY; GLYCOSIDIC LINKAGES; SUGAR MOIETY; ANALOG; OLIGOSACCHARIDES; DERIVATIVES; DOXORUBICIN; Chemistry, Medicinal

    Abstract

    Carbohydrate moiety is found in many anticancer nature products. To explore the carbohydrate moiety of daunorubicin in enhancing anticancer efficacy, several daunorubicin derivatives bearing disaccharide (1-8) have been synthesized. Their cytotoxicities were tested in leukemia K562 and colon cancer SW620 cells. Topoisomerase II (topo II) poisoning was performed with the in vivo complex of topoisomerase bioassay. In both cell lines, compounds with various terminal 2,6-dideoxy sugars (compounds 1, 3, 5, and 8) showed 30- to 60-fold higher anticancer activity than compounds with 2-deoxy- or 6-deoxy sugar (compounds 6 and 7). Compounds with an alpha-linkage between two sugar units (compound 3) showed 35-fold higher anticancer activity than compounds with a beta-linkage (compound 4). In addition, the anticancer activities of these compounds correlated with their ability to target topo II mediated genomic DNA damage in vivo. Compounds 1 and 3 with 2,6-dideoxy sugars produced more covalent topo-DNA complex than compounds with 2-deoxy sugar (6) and 6-deoxy sugar (7). Compounds with an alpha-configuration of terminal 2,6-dideoxy sugar (compounds 1 and 3) showed higher topo II poisoning than their counterparts with the beta-configuration (compounds 2 and 4). These results indicate that sugar moieties in daunorubicin play a significant role in its anticancer activity and topo II inhibition. The second sugar of disaccharide daunorubicin should possess 2,6-dideoxy with alpha-linkage to the first sugar to exhibit better anticancer activity.

    Journal Title

    Journal of Medicinal Chemistry

    Volume

    48

    Issue/Number

    16

    Publication Date

    1-1-2005

    Document Type

    Article

    Language

    English

    First Page

    5269

    Last Page

    5278

    WOS Identifier

    WOS:000231055300022

    ISSN

    0022-2623

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