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

JACS Au, Journal Year: 2025, Volume and Issue: 5(3), P. 1429 - 1438

Published: Feb. 27, 2025

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 cancers, controlling autophagy, elderly wasting. Protoberberine alkaloids typically regarded as activators. Herein, we report modular synthesis strategy to access collection oxyberberine alkaloids, including the first stepharotudine. In vitro assays reveal how subtle structural modifications can negate while conferring unprecedented inhibitory properties within same class compounds, which was previously unknown. Key steps include an oxidative Rh(III)-catalyzed C–H functionalization using electron-rich alkenes, NaH-mediated reductive N–O bond cleavage, rare example anionic aza-6π-electrocyclization. Additionally, provide mechanistic support nucleophilic hydride transfer reactivity with NaH DMF.

Language: Английский

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Phospholipid Supply for Autophagosome Biogenesis

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: 436(15), P. 168691 - 168691

Published: June 27, 2024

Language: Английский

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No energy, no autophagy—Mechanisms and therapeutic implications of autophagic response energy requirements

Journal of Cellular Physiology, Journal Year: 2024, Volume and Issue: 239(11)

Published: July 3, 2024

Autophagy is a lysosome-mediated self-degradation process of central importance for cellular quality control. It also provides macromolecule building blocks and substrates energy metabolism during nutrient or deficiency, which are the main stimuli autophagy induction. However, like most biological processes, itself requires ATP, there an threshold its initiation execution. We here present first comprehensive review this often-overlooked aspect research. The studies in ATP deficiency suppressed vitro vivo were classified according to pathway involved (oxidative phosphorylation glycolysis). A mechanistic insight was provided by pinpointing critical ATP-consuming autophagic events, including transcription/translation/interaction autophagy-related molecules, autophagosome formation/elongation, fusion with lysosome, lysosome acidification. significance energy-dependent fine-tuning response preserving cell homeostasis, potential implications therapy cancer, autoimmunity, metabolic disorders, neurodegeneration discussed.

Language: Английский

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Non-apoptotic cell death in osteoarthritis: Recent advances and future

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 179, P. 117344 - 117344

Published: Aug. 27, 2024

Osteoarthritis (OA) is the most common degenerative joint disease. Multiple tissues are altered during development of OA, resulting in pain and permanent damage to osteoarticular joints. Current research has demonstrated that non-apoptotic cell death plays a crucial role OA. With continuous targeted therapies, shown great potential prevention treatment We systematically reviewed progress on pathogenesis, development, outcome including autophagy, pyroptosis, ferroptosis, necroptosis, immunogenic death, parthanatos. This article reviews mechanism OA provides theoretical basis for identification new targets treatment.

Language: Английский

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Combined Administration of Metformin and Amprolium to Rats Affects Metabolism of Free Amino Acids in the Brain, Altering Behavior, and Heart Rate

Biochemistry (Moscow), Journal Year: 2024, Volume and Issue: 89(10), P. 1692 - 1710

Published: Oct. 1, 2024

Language: Английский

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