title: Exploring the Effects of Glycosylation and Etherification of the Side Chains of the Anticancer Drug Mitoxantrone.
abstract: 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.
authors.affiliation: School of Chemistry, Beverly and Raymond Sackler Faculty of Exact, Sciences, Tel Aviv University, Tel Aviv 6997801 (Israel).
authors.forename: Pazit
authors.initials: P
authors.lastname: Shaul
authors.affiliation: School of Chemistry, Beverly and Raymond Sackler Faculty of Exact, Sciences, Tel Aviv University, Tel Aviv 6997801 (Israel).
authors.forename: Kfir B
authors.initials: KB
authors.lastname: Steinbuch
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801 (Israel).
authors.forename: Eran
authors.initials: E
authors.lastname: Blacher
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801 (Israel). reuvens@tauex.tau.ac.il.
authors.forename: Reuven
authors.initials: R
authors.lastname: Stein
authors.affiliation: School of Chemistry, Beverly and Raymond Sackler Faculty of Exact, Sciences, Tel Aviv University, Tel Aviv 6997801 (Israel). mfridman@post.tau.ac.il.
authors.forename: Micha
authors.initials: M
authors.lastname: Fridman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D006031:Glycosylation; D019073:HT29 Cells / Q000187:drug effects; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D008810:Mice, Inbred C57BL; D008942:Mitoxantrone / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007364:Intercalating Agents; D004247:DNA; D008942:Mitoxantrone
keywords: DNA intercalating drugs; antitumor agents; cytotoxic agents; drug metabolism; mitoxantrone