Syntheses and biological activities of disaccharide daunorubicins.

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.

• Authors: Guisheng Zhang, Lanyan Fang, Lizhi Zhu, Josephine E Aimiuwu, Jie Shen, Hao Cheng, Mark T Muller, Gun Eui Lee, Duxin Sun, Peng George Wang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 16 Pg. 5269-78 (Aug 11 2005) ISSN: 0022-2623 [Print] United States
• PMID: 16078845 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Disaccharides
• Topoisomerase II Inhibitors
• Daunorubicin

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Cell Line, Tumor
• Daunorubicin (analogs & derivatives, chemical synthesis, pharmacology)
• Disaccharides (chemical synthesis, pharmacology)
• Drug Screening Assays, Antitumor
• HeLa Cells
• Humans
• Molecular Conformation
• Structure-Activity Relationship
• Topoisomerase II Inhibitors