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Org Lett. 2020 Aug 21;22(16):6257-6261. doi: 10.1021/acs.orglett.0c01944. Epub 2020 Jul 30.
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. and ), which proceed via retention or inversion of configuration at C1 depending on the C2 substituent (cf. and ) and ultimately enabled the discovery of novel and potent eIF4A inhibitors such as .
罗卡格列酯、罗卡酰胺和相关的黄烷啉天然产物通过抑制真核起始因子 4A（eIF4A）发挥其显著的抗癌活性，但通常显示出较差的类药性。在我们努力识别强效类药性 eIF4A 抑制剂的过程中，我们开发了对氮杂罗卡酰胺支架的 C1 位进行非对映选择性官能化的合成策略（参见和），这些方法取决于 C2 取代基（参见和），在 C1 位保留或反转构型，最终发现了新型强效的 eIF4A 抑制剂，如。
