雷巴他汀、自溶菌素和非苯醌类似物的合成：热休克蛋白 90 的有效抑制剂。

Synthesis of reblastatin, autolytimycin, and non-benzoquinone analogues: potent inhibitors of heat shock protein 90.

机构信息

Department of Chemistry and Center for Chemical Methodology and Library Development (CMLD-BU), Metcalf Center for Science and Engineering, 590 Commonwealth Avenue, Boston University, Boston, Massachusetts 02215, USA.

出版信息

J Org Chem. 2010 May 7;75(9):2820-35. doi: 10.1021/jo1000109.

DOI:10.1021/jo1000109

PMID:20392070

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2906235/

Abstract

A full account of an asymmetric synthesis of reblastatin (1) and the first total synthesis of autolytimycin (2) and related structural compounds is described. The syntheses expand the utility of a highly regio- and diastereoselective hydrometalation aldehyde addition sequence to assemble the fully functionalized ansa chain of the natural products. Also documented is an intramolecular copper-mediated amidation reaction to close the 19-membered macrolactams. The amidation reaction was also employed for the generation of structural derivatives (6-9) of phenolic ansamycins. Ansamycin natural products and selected structural analogues were evaluated in a competitive binding assay to breast cancer cell lysate and a cytotoxicity assay. Both reblastatin (1) and autolytimycin (2) were shown to bind the heat shock protein 90 with enhanced binding activity (approximately 25 nM) than 17-allylamino-17-demethoxygeldanamycin (17-AAG, 4), a geldanamycin (3) derivative currently under evaluation for treatment of cancer (approximately 100 nM).

摘要

本文描述了雷巴他汀（1）的不对称全合成以及自溶菌素（2）和相关结构化合物的首次全合成。这些合成方法扩展了高度区域和立体选择性的水合金属化醛加成序列的用途，可组装天然产物的全功能化ansa 链。此外，还记录了一种分子内铜介导的酰胺化反应，以封闭 19 元大环内酯。酰胺化反应还用于生成酚类 ansamycin 的结构衍生物（6-9）。对 ansamycin 天然产物和选定的结构类似物进行了竞争性结合测定，以评估乳腺癌细胞裂解物和细胞毒性测定。雷巴他汀（1）和自溶菌素（2）均显示与热休克蛋白 90 结合，结合活性增强（约 25 nM），优于geldanamycin（3）衍生物 17-allylamino-17-demethoxygeldanamycin（17-AAG，4），后者目前正在评估用于癌症治疗（约 100 nM）。