title: Azatoxin is a mechanistic hybrid of the topoisomerase II-targeted anticancer drugs etoposide and ellipticine.
abstract: One approach to broadening the diversity of topoisomerase II-targeted anticancer agents is to generate novel compounds by combining structural elements of drugs known to stimulate enzyme-mediated DNA cleavage. The first agent to emerge from such a rational drug design is azatoxin, a hybrid drug that fuses chemical structures from etoposide and ellipticine. Since these drugs differ significantly in their structural and mechanistic attributes, azatoxin may preferentially retain the functional properties of one of these two drugs, behave as a hybrid molecule, or act as a novel pharmacophore. Therefore, the properties of azatoxin were characterized to determine relationships between its mechanism of action and those of its parent compounds. Azatoxin, like etoposide, binds to DNA in a nonintercalative fashion. However, similar to ellipticine, the drug has no effect on enzyme-mediated DNA religation and apparently stimulates scission primarily by enhancing cleavage complex formation. Depending on the species of topoisomerase II examined, the cleavage potency of azatoxin resembles that of either of its chemical parents. Furthermore, out of 43 DNA cleavage sites analyzed, approximately 90% of those induced by azatoxin are shared with either etoposide, ellipticine, or both drugs. Finally, competition studies indicate that azatoxin interacts with topoisomerase II in the enzyme domain utilized by etoposide and ellipticine. Taken together, these results strongly suggest that azatoxin is a mechanistic hybrid of its parent compounds and shares functional properties with both drugs.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Cline
authors.forename: T L
authors.initials: TL
authors.lastname: Macdonald
authors.forename: N
authors.initials: N
authors.lastname: Osheroff
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004330:Drosophila / Q000201:enzymology; D015195:Drug Design; D004611:Ellipticines / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005047:Etoposide / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D007364:Intercalating Agents; D007700:Kinetics; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D013950:Thymus Gland / Q000201:enzymology; D059005:Topoisomerase II Inhibitors
chemical_list: D000970:Antineoplastic Agents; D004611:Ellipticines; D004791:Enzyme Inhibitors; D007211:Indoles; D007364:Intercalating Agents; D011994:Recombinant Proteins; D059005:Topoisomerase II Inhibitors; C034192:ellipticine; C075996:azatoxin; D005047:Etoposide; D004247:DNA