New synthetic AICAR derivatives with enhanced AMPK and ACC activation |
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Authors: | Olga Scudiero Ersilia Nigro Maria Ludovica Monaco Rita Polito Nicola Borbone |
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Affiliation: | 1. CEINGE – Advanced Biotechnologies S.C a r.l., Napoli, Italy,;2. Department of Molecular Medicine and Medical Biotechnologies and;3. CEINGE – Advanced Biotechnologies S.C a r.l., Napoli, Italy,;4. Department of Pharmacy, University of Naples Federico II, Napoli, Italy, |
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Abstract: | 5-Aminoimidazole-4-carboxamide riboside (AICAR) has an important role in the regulation of the cellular metabolism showing a broad spectrum of therapeutic activities against different metabolic processes. Due to these proven AICAR properties, we have designed, synthesized and tested the biological activity of two ribose-modified AICAR derivatives, named A3 and A4, in comparison to native AICAR and its 5′-phosphorylated counterpart ZMP. Our findings have shown that A3 and A4 derivatives induce the phosphorylation of 5′-AMP activated protein kinase α (AMPKα), which leads to the inhibition of acetyl-CoA carboxylase (ACC), and down-regulate the activity of the extracellular signal-regulated kinases (ERK1/2). Cytotoxicity tests demonstrated that A3 and A4 do not significantly reduce cell viability up to 24?h. Taken together our results indicate that A3 and A4 have a comparable activity to AICAR and ZMP at 0.5 and 1?mM suggesting their potential use in future pharmacological strategies relating to metabolic diseases. |
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Keywords: | AICAR AMPK ACC cell lines cytotoxicity p-ERK1/2 |
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