Synthesis of Protoberberine Alkaloids by C–H Functionalization and Anionic Aza-6π-Electrocyclization: Dual Activity as AMPK Activators and Inhibitors
Year: 2025
Type: article
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 modifi-cations can negate AMPK activation while conferring unprecedented inhibitory properties within the same class of com-pounds, which was previously unknown. Key steps in the synthesis include an oxidative Rh(III)-catalyzed C–H function-alization using electron-rich alkenes, NaH-mediated reductive N–O bond cleavage, and the first example of an anionic aza-6π-electrocyclization. Additionally, we provide mechanistic support for nucleophilic hydride transfer reactivity with NaH in DMF.
Source: JACS Au
Authors: Yujie Cao, Justin S. M. Perry, Eryun Zhang, Andy Trinh, Arnav Kacker, Shayne Cruz, Hannah Ceballos, Aaron Pan, Wendong Huang, Kevin G. M. Kou
Language: English
Subfield: Pharmacology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,500
Funders: National Science Foundation, Cancer Research Coordinating Committee, National Institutes of Health, University of California, Riverside, Office of the President, University of California, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Division of Chemistry, Division of Diabetes, Endocrinology, and Metabolic Diseases
Awards: G1221236342, Bile acids and metabolic surgery, MRI: Acquisition of a Hybrid Supercritical Chromatography, High-Pressure Chromatograph, Quadrupole-Time-of-Flight Mass Spectrometer (SFC/UHPLC Q-ToF/MS), Synthesis of Benzylisoquinoline Alkaloids as Antimitotic Agents for Cancer Therapy, G5831552071, G5986892838, G6671297155, G6868247946, G7667766050, CAREER: Innovating Oxidative C–H Functionalization via Rhodium and Cobalt Catalysis, G8839305273, Targeting bile acid composition to treat metabolic diseases, MARC at University of California Riverside
OpenAlex ID: W4407999322