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FR901464和剪接抑制素A的对映选择性全合成及关键衍生物的剪接活性评估

Enantioselective total syntheses of FR901464 and spliceostatin A and evaluation of splicing activity of key derivatives.

作者信息

Ghosh Arun K, Chen Zhi-Hua, Effenberger Kerstin A, Jurica Melissa S

机构信息

Department of Chemistry and Department of Medicinal Chemistry, Purdue University , 560 Oval Drive, West Lafayette, Indiana 4790, United States.

出版信息

J Org Chem. 2014 Jun 20;79(12):5697-709. doi: 10.1021/jo500800k. Epub 2014 May 30.

Abstract

FR901464 (1) and spliceostatin A (2) are potent inhibitors of spliceosomes. These compounds have shown remarkable anticancer activity against multiple human cancer cell lines. Herein, we describe efficient, enantioselective syntheses of FR901464, spliceostatin A, six corresponding diastereomers and an evaluation of their splicing activity. Syntheses of spliceostatin A and FR901464 were carried out in the longest linear sequence of 9 and 10 steps, respectively. To construct the highly functionalized tetrahydropyran A-ring, we utilized CBS reduction, Achmatowicz rearrangement, Michael addition, and reductive amination as key steps. The remarkable diastereoselectivity of the Michael addition was specifically demonstrated with different substrates under various reaction conditions. The side chain B was prepared from an optically active alcohol, followed by acetylation and hydrogenation over Lindlar's catalyst. The other densely functionalized tetrahydropyran C-ring was derived from readily available (R)-isopropylidene glyceraldehyde through a route featuring 1,2-addition, cyclic ketalization, and regioselective epoxidation. These fragments were coupled together at a late stage through amidation and cross-metathesis in a convergent manner. Six key diastereomers were then synthesized to probe the importance of specific stereochemical features of FR901464 and spliceostatin A, with respect to their in vitro splicing activity.

摘要

FR901464(1)和剪接抑制素A(2)是剪接体的有效抑制剂。这些化合物已显示出对多种人类癌细胞系具有显著的抗癌活性。在此,我们描述了FR901464、剪接抑制素A、六种相应非对映异构体的高效对映选择性合成及其剪接活性评估。剪接抑制素A和FR901464的合成分别以最长的9步和10步线性序列进行。为构建高度官能化的四氢吡喃A环,我们将CBS还原、阿赫马托维奇重排、迈克尔加成和还原胺化作为关键步骤。在各种反应条件下,用不同底物具体证明了迈克尔加成显著的非对映选择性。侧链B由旋光醇制备,然后进行乙酰化并在林德拉催化剂上氢化。另一个高度官能化的四氢吡喃C环由易得的(R)-异亚丙基甘油醛通过一个以1,2-加成、环状缩酮化和区域选择性环氧化为特征的路线衍生而来。这些片段在后期通过酰胺化和交叉复分解以汇聚方式偶联在一起。然后合成了六种关键非对映异构体,以探究FR901464和剪接抑制素A的特定立体化学特征对其体外剪接活性的重要性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a35/4066912/dfa7c8b2f66f/jo-2014-00800k_0001.jpg

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