title: Total syntheses and biological reassessment of lactimidomycin, isomigrastatin and congener glutarimide antibiotics.
abstract: Lactimidomycin (1) was described in the literature as an exquisitely potent cell migration inhibitor. Encouraged by this claim, we developed a concise and scalable synthesis of this bipartite glutarimide-macrolide antibiotic, which relies on the power of ring-closing alkyne metathesis (RCAM) for the formation of the unusually strained 12-membered head group. Subsequent deliberate digression from the successful path to 1 also brought the sister compound isomigrastatin (2) as well as a series of non-natural analogues of these macrolides into reach. A careful biological re-evaluation of this compound collection showed 1 and progeny to be potently cytotoxic against a panel of cancer cell lines, even after one day of compound exposure; therefore any potentially specific effects on tumor cell migration were indistinguishable from the acute effect of cell death. No significant cell migration inhibition was observed at sub-toxic doses. Although these findings cannot be reconciled with some reports in the literature, they are in accord with the notion that lactimidomycin is primarily a ribosome-binder able to effectively halt protein biosynthesis at the translation stage.
authors.affiliation: Max-Planck-Institut für Kohlenforschung, 45470 Mülheim/Ruhr, Germany.
authors.forename: Kévin
authors.initials: K
authors.lastname: Micoine
authors.forename: Peter
authors.initials: P
authors.lastname: Persich
authors.forename: Josep
authors.initials: J
authors.lastname: Llaveria
authors.forename: My-Hanh
authors.initials: MH
authors.lastname: Lam
authors.forename: Andreas
authors.initials: A
authors.lastname: Maderna
authors.forename: Frank
authors.initials: F
authors.lastname: Loganzo
authors.forename: Alois
authors.initials: A
authors.lastname: Fürstner
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D010881:Piperidones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D018942:Macrolides; D010881:Piperidones; C455261:isomigrastatin; C077633:lactimidomycin; C007864:glutarimide