Strategic Diastereoselective C1 Functionalization in the Aza-Rocaglamide Scaffold toward Natural Product-Inspired eIF4A Inhibitors
2020
Rocaglates,
rocaglamides, and related flavagline natural products
exert their remarkable anticancer activity through inhibition of eukaryotic
initiation factor 4A (eIF4A) but generally display suboptimal drug-like
properties. In our efforts to identify potent drug-like eIF4A inhibitors,
we developed synthetic strategies for diastereoselectively functionalizing
the C1 position of aza-rocaglamide scaffolds (cf. 14 and 18), which proceed via retention or inversion of configuration
at C1 depending on the C2 substituent (cf. 15 and 21) and ultimately enabled the discovery of novel and potent
eIF4A inhibitors such as 25.
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