Department of Chemistry, Center for Molecular Discovery (BU-CMD) , Boston University , 590 Commonwealth Avenue , Boston , Massachusetts 02215 , United States of America.
Laboratory of Vector-borne Viral Diseases, Division of Viral Products, Center for Biologics Evaluation and Research , Food and Drug Administration , Silver Spring , Maryland 20903 , United States.
J Am Chem Soc. 2019 Aug 14;141(32):12891-12900. doi: 10.1021/jacs.9b06446. Epub 2019 Jul 30.
Rocaglates are a family of natural products isolated from the genus which possess a highly substituted cyclopenta[]benzofuran skeleton and inhibit cap-dependent protein synthesis. Rocaglates are attractive compounds due to their potential for inhibiting tumor cell maintenance by specifically targeting eukaryotic initiation factor 4A (eIF4A) and interfering with recruitment of ribosomes to mRNA. In this paper, we describe an intercepted retro-Nazarov reaction utilizing intramolecular tosyl migration to generate a reactive oxyallyl cation on the rocaglate skeleton. Trapping of the oxyallyl cation with a diverse range of nucleophiles has been used to generate over 50 novel amidino-rocaglate (ADR) and amino-rocaglate derivatives. Subsequently, these derivatives were evaluated for their ability to inhibit cap-dependent protein synthesis where they were found to outperform previous lead compounds including the rocaglate hydroxamate CR-1-31-B.
罗卡利特是从罗卡利特属中分离出来的一类天然产物，具有高度取代的环戊[]苯并呋喃骨架，能抑制依赖 cap 的蛋白合成。由于其潜在的通过特异性靶向真核起始因子 4A（eIF4A）和干扰核糖体与 mRNA 的募集来抑制肿瘤细胞维持的能力，罗卡利特是一种有吸引力的化合物。在本文中，我们描述了一个截获的反纳扎罗夫反应，利用分子内甲苯磺酰基迁移在罗卡利特骨架上生成反应性氧烯丙基阳离子。用各种亲核试剂捕获氧烯丙基阳离子，已生成 50 多个新型脒基罗卡利特（ADR）和氨基罗卡利特衍生物。随后，对这些衍生物抑制 cap 依赖性蛋白合成的能力进行了评估，结果发现它们的性能优于包括罗卡利特羟肟酸盐 CR-1-31-B 在内的以前的先导化合物。
