eFFECTOR Therapeutics, 11120 Roselle Street, Suite A, San Diego, CA 92121, United States.
eFFECTOR Therapeutics, 11120 Roselle Street, Suite A, San Diego, CA 92121, United States.
Bioorg Med Chem Lett. 2021 Sep 1;47:128111. doi: 10.1016/j.bmcl.2021.128111. Epub 2021 Aug 2.
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.
黄酮烷类化合物，如 silvestrol（1）和 rocaglamide（2），是一类具有潜在抗癌活性的天然产物，很有研究意义。它们的作用机制是通过与 eIF4A 和 mRNA 形成稳定的三元复合物，从而抑制真核起始因子 4A（eIF4A）依赖性翻译，阻止核糖体扫描。本文描述了一系列新型 1-氨甲基取代的黄酮烷类 eIF4A 抑制剂的初步 SAR 研究。我们发现 1-氨甲基上的各种 N-取代基是可以耐受的，这使该位置成为调节性质和 ADME 特征的关键。本文的研究结果与未来开发具有类药性的新型 eIF4A 抑制剂的药物设计工作密切相关。
