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

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. On the contrary! Alkyne metathesis powered a synthesis‐driven (re)evaluation of bipartite glutarimide antibiotics, including lactimidomycin and isomigrastatin, which feature highly strained polyunsaturated macrolide head groups. Rather than being potent cell migration inhibitors as previously claimed, lactimidomycin and progeny were found to be acutely cytotoxic, causing cell death before any specific interference with cell motility could set in.