title: Lactimidomycin, iso-migrastatin and related glutarimide-containing 12-membered macrolides are extremely potent inhibitors of cell migration.
abstract: Migrastatin (1), iso-migrastatin (5) and lactimidomycin (7) are all glutarimide-containing polyketides known for their unique structures and cytotoxic activities against human cancer cell lines. Migrastatin, a strong inhibitor of tumor cell migration, has been an important lead in the development of antimetastatic agents. Yet studies of the related 12-membered macrolides iso-migrastatin, lactimidomycin, and related analogues have been hampered by their limited availability. We report here the production, isolation, structural characterization, and biological activities of iso-migrastatin, lactimidomycin, and 23 related congeners. Our studies showed that, as a family, the glutarimide-containing 12-membered macrolides are extremely potent cell migration inhibitors with some members displaying activity on par or superior to that of migrastatin as exemplified by compounds 5, 7, and 9-12. On the basis of these findings, the structures and activity of this family of compounds as cell migration inhibitors are discussed.
authors.affiliation: Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53705-2222, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Ju
authors.forename: Scott R
authors.initials: SR
authors.lastname: Rajski
authors.forename: Si-Kyu
authors.initials: SK
authors.lastname: Lim
authors.forename: Jeong-Woo
authors.initials: JW
authors.lastname: Seo
authors.forename: Noël R
authors.initials: NR
authors.lastname: Peters
authors.forename: F Michael
authors.initials: FM
authors.lastname: Hoffmann
authors.forename: Ben
authors.initials: B
authors.lastname: Shen
mesh_terms: D000818:Animals; D001688:Biological Products / Q000737:chemistry; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D018942:Macrolides / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D010881:Piperidones / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001688:Biological Products; D018942:Macrolides; D010881:Piperidones; C455261:isomigrastatin; C077633:lactimidomycin; C007864:glutarimide