Maximizing macrolides
Natural product analogs often provide a simple means by which to expand chemical space and retain or improve biological activity. Chemical synthesis and enzymatic manipulations can generate some molecular diversity, but can also be limited by the inherent reactivity of the compound or protein, respectively. Lewis et al. now report an alternate method for introducing modifications using a series of pentapeptide catalysts to acetylate apoptolidin A, a multiply glycosylated macrolide that induces apoptosis. In order to develop a method that would be generally applicable to natural products that are often in scarce supply, the authors employed a screen using only 5 mg of apoptolidin A for initial screening, investigating approximately 150 catalysts against 20 μg of compound per run. Interesting catalysts were identified by searching for those reactions whose product profile differed in the presence or absence of the peptides. The capped peptide Boc-Dπ(Me)His-Pro-Aib-Trp(Boc)-Phe-OMe enhanced selectivity of acylation, yielding a novel compound. Using slightly different conditions, other peptides were identified that could add multiple acyl groups; in particular, the enantiomer—the Boc-π(Me)His-DPro-Aib-DTrp(Boc)-DPhe-OMe sequence—resulted in two new compounds, each of which was triply acylated. Though the final compounds were approximately equipotent to the parent compound, these results demonstrate that alternate synthetic strategies can broaden the scope of natural product diversity. (J. Nat. Prod., published online 21 September 2009, doi: 10.1021/np9004932) CG
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