Hawkins Bill C, Lindqvist Lisa M, Nhu Duong, Sharp Phillip P, Segal David, Powell Andrew K, Campbell Michael, Ryan Eileen, Chambers Jennifer M, White Jonathan M, Rizzacasa Mark A, Lessene Guillaume, Huang David C S, Burns Christopher J
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052 (Australia); Department of Medical Biology, The University of Melbourne, VIC 3010 (Australia).
ChemMedChem. 2014 Jul;9(7):1556-66. doi: 10.1002/cmdc.201400024. Epub 2014 Mar 27.
The complex natural products silvestrol (1) and episilvestrol (2) are inhibitors of translation initiation through binding to the DEAD-box helicase eukaryotic initiation factor 4A (eIF4A). Both compounds are potently cytotoxic to cancer cells in vitro, and 1 has demonstrated efficacy in vivo in several xenograft cancer models. Here we show that 2 has limited plasma membrane permeability and is metabolized in liver microsomes in a manner consistent with that reported for 1. In addition, we have prepared a series of analogues of these compounds where the complex pseudo-sugar at C6 has been replaced with chemically simpler moieties to improve drug-likeness. Selected compounds from this work possess excellent activity in biochemical and cellular translation assays with potent activity against leukemia cell lines.
复杂天然产物司维司特罗（1）和表司维司特罗（2）通过与DEAD盒解旋酶真核起始因子4A（eIF4A）结合来抑制翻译起始。这两种化合物在体外对癌细胞均具有强效细胞毒性，并且1在多种异种移植癌模型中已显示出体内疗效。在此我们表明，2的质膜通透性有限，且在肝微粒体中的代谢方式与报道的1一致。此外，我们制备了这些化合物的一系列类似物，其中C6位的复杂假糖已被化学上更简单的部分取代，以改善类药性质。这项工作中挑选出的化合物在生化和细胞翻译试验中具有出色活性，对白血病细胞系具有强效活性。
