Phenolic Lipids Derived from Cashew Nut Shell Liquid to Treat Metabolic Diseases

Metabolic diseases are increasing at staggering rates globally. The peroxisome proliferator-activated receptors (PPARα/γ/δ) are fatty acid sensors that help mitigate imbalances between energy uptake and utilization. Herein, we report compounds derived from phenolic lipids present in cashew nut shell...

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Published in:	Journal of medicinal chemistry Vol. 65; no. 3; pp. 1961 - 1978
Main Authors:	Sahin, Cigdem, Magomedova, Lilia, Ferreira, Thais A. M, Liu, Jiabao, Tiefenbach, Jens, Alves, Priscilla S, Queiroz, Fellipe J. G, Oliveira, Andressa S. de, Bhattacharyya, Mousumi, Grouleff, Julie, Nogueira, Patrícia C. N, Silveira, Edilberto R, Moreira, Daniel C, Leite, José Roberto Souza de Almeida, Brand, Guilherme D, Uehling, David, Poda, Gennady, Krause, Henry, Cummins, Carolyn L, Romeiro, Luiz A. S
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 10-02-2022
Subjects:	3T3-L1 Cells Anacardic Acids - chemical synthesis Anacardic Acids - metabolism Anacardic Acids - pharmacokinetics Anacardic Acids - pharmacology Anacardium - chemistry Animals Drug Design Gene Expression - drug effects HEK293 Cells Humans Lipid Metabolism - drug effects Lipid Metabolism - genetics Male Mice Mice, Inbred C57BL Molecular Docking Simulation Nuts - chemistry PPAR alpha - agonists PPAR alpha - chemistry PPAR delta - agonists PPAR delta - chemistry PPAR gamma - agonists PPAR gamma - chemistry Protein Domains Zebrafish
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Summary:	Metabolic diseases are increasing at staggering rates globally. The peroxisome proliferator-activated receptors (PPARα/γ/δ) are fatty acid sensors that help mitigate imbalances between energy uptake and utilization. Herein, we report compounds derived from phenolic lipids present in cashew nut shell liquid (CNSL), an abundant waste byproduct, in an effort to create effective, accessible, and sustainable drugs. Derivatives of anacardic acid and cardanol were tested for PPAR activity in HEK293 cell co-transfection assays, primary hepatocytes, and 3T3-L1 adipocytes. In vivo studies using PPAR-expressing zebrafish embryos identified CNSL derivatives with varying tissue-specific activities. LDT409 (23) is an analogue of cardanol with partial agonist activity for PPARα and PPARγ. Pharmacokinetic profiling showed that 23 is orally bioavailable with a half-life of 4 h in mice. CNSL derivatives represent a sustainable source of selective PPAR modulators with balanced intermediate affinities (EC50 ∼ 100 nM to 10 μM) that provide distinct and favorable gene activation profiles for the treatment of diabetes and obesity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.1c01542