Flavaglines such as silvestrol (1) and rocaglamide (2) constitute an interesting class of natural products with promising anticancer activities. Their mode of action is based on inhibition of eukaryotic initiation factor 4A (eIF4A) dependent translation through formation of a stable ternary complex with eIF4A and mRNA, thus blocking ribosome scanning. Herein we describe initial SAR studies in a novel series of 1-aminomethyl substituted flavagline-inspired eIF4A inhibitors. We discovered that a variety of N-substitutions at the 1-aminomethyl group are tolerated, making this position pertinent for property and ADME profile tuning. The findings presented herein are relevant to future drug design efforts towards novel eIF4A inhibitors with drug-like properties.

中文翻译：

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1-氨基甲基 SAR 在一系列新型黄酮类药物启发的 eIF4A 抑制剂中：胺取代对细胞效力和体外 PK 特性的影响。

Flavaglines，如 silvestrol (1) 和 rocaglamide (2) 构成了一类有趣的天然产物，具有良好的抗癌活性。它们的作用模式基于通过与 eIF4A 和 mRNA 形成稳定的三元复合物来抑制真核起始因子 4A (eIF4A) 依赖性翻译，从而阻断核糖体扫描。在本文中，我们描述了一系列受 1-氨基甲基取代的黄酮苷启发的 eIF4A 抑制剂的初步 SAR 研究。我们发现 1-氨基甲基上的各种 N 取代是可以容忍的，这使得该位置与属性和 ADME 配置文件调整相关。本文提出的发现与未来具有类似药物特性的新型 eIF4A 抑制剂的药物设计工作相关。