Exploring the Effects of Glycosylation and Etherification of the Side Chains of the Anticancer Drug Mitoxantrone

• Published in: ChemMedChem 2015-09, Vol.10 (9), p.1528-1538
• Main Authors: Shaul, Pazit, Steinbuch, Kfir B., Blacher, Eran, Stein, Reuven, Fridman, Micha
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antitumor agents; Chemistry Techniques, Synthetic; Crystal structure; cytotoxic agents; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA - metabolism; DNA intercalating drugs; Drug Design; drug metabolism; Drug Screening Assays, Antitumor - methods; Female; Glycosylation; Hep G2 Cells - drug effects; HT29 Cells - drug effects; Humans; Intercalating Agents - chemistry; Intercalating Agents - pharmacology; Male; Melanoma, Experimental - drug therapy; Melanoma, Experimental - pathology; Metabolites; Mice, Inbred C57BL; mitoxantrone; Mitoxantrone - analogs & derivatives; Mitoxantrone - chemistry; Mitoxantrone - pharmacology; Rabbits; Structure-Activity Relationship
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201500274

Herein we report the synthesis and biological evaluation of symmetric and asymmetric analogues of the DNA intercalating drug mitoxantrone (MTX) in which the side chains of the parent drug were modified through glycosylation or methyl etherification. Several analogues with glycosylated side chains exhibited higher DNA affinity than the parent MTX. The most potent in vitro cytotoxicity was observed for MTX analogue 8 (1,4‐dimethoxy‐5,8‐bis[2‐(2‐methoxyethylamino)ethylamino]anthracene‐9,10‐dione) with methoxy ether containing side chains. Treatment of melanoma‐bearing mice with MTX or analogue 8 decreased the intraperitoneal tumor burden relative to untreated mice; the effect of 8 was less pronounced than that of MTX. In vitro metabolism assays of MTX with rabbit liver S9 fraction gave rise to several metabolites; almost no metabolites were detected for MTX analogue 8. The results presented indicate that derivatization of the MTX side chain primary hydroxy groups may result in a significant improvement in DNA affinity and lower susceptibility to the formation of potentially toxic metabolites. Sweets on the side: Derivatization of the antitumor drug mitoxantrone trough symmetric and asymmetric O‐glycosylation or methyl etherification of the drugs’ side chains can improve DNA affinity, affects both in vitro and in vivo activity, and can inhibit the formation of potentially toxic metabolites.