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Total Syntheses and Biological Reassessment of Lactimidomycin, Isomigrastatin and Congener Glutarimide Antibiotics

MPS-Authors
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Micoine,  Kevin
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Persich,  Peter
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Llaveria Cros,  Josep
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Fürstner,  Alois
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Citation

Micoine, K., Persich, P., Llaveria Cros, J., Lam, M.-H., Maderna, A., Loganzo, F., et al. (2013). Total Syntheses and Biological Reassessment of Lactimidomycin, Isomigrastatin and Congener Glutarimide Antibiotics. Chemistry – A European Journal, 19(23), 7370-7383. doi:10.1002/chem.201300393.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0014-A4F4-3
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.