Synthesis of Protoberberine Alkaloids by C-H Functionalization and Anionic Aza-6π-Electrocyclization: Dual Activity as AMPK Activators and Inhibitors.

IF 8.5 Q1 CHEMISTRY, MULTIDISCIPLINARY
JACS Au Pub Date : 2025-02-27 eCollection Date: 2025-03-24 DOI:10.1021/jacsau.5c00047
Yujie Cao, Justin S M Perry, Eryun Zhang, Andy Trinh, Arnav Kacker, Shayne Cruz, Hannah Ceballos, Aaron Pan, Wendong Huang, Kevin G M Kou
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引用次数: 0

Abstract

5'-Adenosine monophosphate-activated protein kinase (AMPK) plays a critical role in maintaining cellular energy homeostasis, and its activation has garnered attention for treating chronic metabolic diseases. Inhibitors of AMPK are underdeveloped but bear implications in treating cancers, controlling autophagy, and elderly wasting. Protoberberine alkaloids are typically regarded as AMPK activators. Herein, we report a modular synthesis strategy to access a collection of oxyberberine alkaloids, including the first synthesis of stepharotudine. In vitro assays reveal how subtle structural modifications can negate AMPK activation while conferring unprecedented inhibitory properties within the same class of compounds, which was previously unknown. Key steps in the synthesis include an oxidative Rh(III)-catalyzed C-H functionalization using electron-rich alkenes, NaH-mediated reductive N-O bond cleavage, and a rare example of an anionic aza-6π-electrocyclization. Additionally, we provide mechanistic support for nucleophilic hydride transfer reactivity with NaH in DMF.

C-H功能化和阴离子偶氮-6π电环化合成原小檗碱类生物碱:作为AMPK激活剂和抑制剂的双重活性。
5'-腺苷单磷酸活化蛋白激酶(AMPK)在维持细胞能量稳态中起着关键作用,其激活已引起慢性代谢性疾病治疗的关注。AMPK抑制剂尚不发达,但在治疗癌症、控制自噬和老年人消瘦方面具有重要意义。原小檗碱生物碱通常被认为是AMPK激活剂。在这里,我们报告了一个模块化的合成策略,以获得一系列的oxyberberine生物碱,包括首次合成的stepharotudine。体外实验揭示了微妙的结构修饰如何能够抑制AMPK的激活,同时在同类化合物中赋予前所未有的抑制特性,这是以前未知的。合成的关键步骤包括Rh(III)氧化催化的富电子烯烃C-H功能化,nah介导的N-O键还原裂解,以及罕见的阴离子偶氮-6π电环化。此外,我们还提供了DMF中亲核氢化物与NaH转移反应的机理支持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
9.10
自引率
0.00%
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0
审稿时长
10 weeks
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