有效全合成来源于 Pladienolide 的剪接体调节剂。

Expedient Total Syntheses of Pladienolide-Derived Spliceosome Modulators.

机构信息

Department of Pharmacology and Chemical Biology and Center for Drug Discovery, Baylor College of Medicine, Houston, Texas 77030, United States

Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California 92093, United States.

出版信息

J Am Chem Soc. 2021 Apr 7;143(13):4915-4920. doi: 10.1021/jacs.1c01135. Epub 2021 Mar 23.

DOI:10.1021/jacs.1c01135

PMID:33755462

Abstract

Atom and step economical total syntheses of spliceosome modulating natural products pladienolides A and B are described. The strategic functionalization of an unsaturated macrolide precursor enabled the most concise syntheses of these natural products to date and provides convenient, flexible access to stereodefined macrolides to streamline medicinal chemistry explorations. Notably, this synthetic route does not depend on protecting group manipulations that traditionally define synthesis planning for polyhydroxylated natural products of polyketide origin. Its utility is further demonstrated by the enantioselective total synthesis of H3B-8800, a hitherto semisynthetic pladienolide-derived spliceosome modulator undergoing clinical trials for hematological malignancies.

摘要

本文描述了剪接体调节天然产物普乐迪醇 A 和 B 的原子经济性和步骤经济性全合成。不饱和大环内酯前体的战略官能化使得这些天然产物的最简洁合成成为可能，并为立体定义大环内酯提供了方便、灵活的途径，以简化药物化学探索。值得注意的是，该合成路线不依赖于传统上定义聚酮源多羟基天然产物合成规划的保护基操作。其用途还通过 H3B-8800 的对映选择性全合成得到进一步证明，H3B-8800 是一种迄今为止半合成的普乐迪醇衍生剪接体调节剂，正在进行血液系统恶性肿瘤的临床试验。