Molecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a PPARα-selective agonist

Arnesen, Henriette; Haj-Yasein, Nadia Nabil; Tungen, Jørn Eivind; Soedling, Helen; Matthews, Jason; Paulsen, Steinar M.; Nebb, Hilde I.; Sylte, Ingebrigt; Hansen, Trond Vidar; Sæther, Thomas

doi:10.1016/j.bmc.2019.07.032

Cited by 9 publications

(8 citation statements)

References 50 publications

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“…Specifically, they are two isomeric oxo-fatty acids from the microalgae Chaetoceros karianus , namely ( 7E )-9-oxohexadec-7-enoic acid and ( 10E )-9-oxohexadec-10-enoic acid ( Figure 3 ), also showing an opposite potency toward the two isoforms, albeit at high concentration (100 μM) [ 44 ]. In this view, these two compounds have been used as a starting point for the design and synthesis of a selective PPARα agonist (EC 50 47 μM) by replacing the α,β-unsaturated ketone moiety with a bioisosteric isoxazole ring [ 55 ]. Molecular modeling studies have shown that this compound engages a network of H-bonds in the PPARα ligand binding domain (LBD) between its carboxylate moiety and PPARα polar amino acids, including Ser280, Tyr314, His440, and Tyr464, which recapitulate the canonical binding mode of full PPAR agonists.…”

Section: Marine Natural and Nature-inspired Compounds As Ppar Modulatorsmentioning

confidence: 99%

Marine Natural and Nature-Inspired Compounds Targeting Peroxisome Proliferator Activated Receptors (PPARs)

2023

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Peroxisome proliferator-activated receptors α, γ and β/δ (PPARα, PPARγ, and PPARβ/δ) are a family of ligand-activated transcriptional factors belonging to the superfamily of nuclear receptors regulating the expression of genes involved in lipid and carbohydrate metabolism, energy homeostasis, inflammation, and the immune response. For this reason, they represent attractive targets for the treatment of a variety of metabolic diseases and, more recently, for neurodegenerative disorders due to their emerging neuroprotective effects. The degree of activation, from partial to full, along with the selectivity toward the different isoforms, greatly affect the therapeutic efficacy and the safety profile of PPAR agonists. Thus, there is a high interest toward novel scaffolds with proper combinations of activity and selectivity. This review intends to provide an overview of the discovery, optimization, and structure–activity relationship studies on PPAR modulators from marine sources, along with the structural and computational studies that led to their identification and/or elucidation, and rationalization of their mechanisms of action.

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Section: Marine Natural and Nature-inspired Compounds As Ppar Modulatorsmentioning

confidence: 99%

Marine Natural and Nature-Inspired Compounds Targeting Peroxisome Proliferator Activated Receptors (PPARs)

2023

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“…Synthesis of novel 3,5‐disubstituted isoxazole analogue 6‐(5‐heptyl‐1,2‐oxazol‐3‐yl)hexanoic acid. Reaction conditions: (A) DABCO, EtOH, 80°C, 73 h; (B) DIBAL‐H, dry CH 2 Cl 2 , −78°C, 6 h; (C) LiHMDS, BrPh 3 P(CH 2 ) 4 CO 2 H (8), THF, −78°C to rt, 18 h; (D) H 2 , Pd/C, EtOAc, 12 h [80]. …”

Section: Biological Activities Of Isoxazole Derivativesmentioning

confidence: 99%

“…PPARs (peroxisome proliferator‐activated receptors) are key therapeutic targets for metabolic and inflammatory illnesses. Through its ligand‐binding domain, ADAM demonstrates a distinct receptor preference and considerable dose‐dependent activation of PPARa (EC = 47 μM) by its ligand‐binding domain (LBD) [80]. In the Huh7 cell line and primary mouse hepatocytes, ADAM also increases the expression of critical PPARa target genes including CPT1A.…”

Section: Biological Activities Of Isoxazole Derivativesmentioning

confidence: 99%

A review of recent synthetic strategies and biological activities of isoxazole

Pandhurnekar¹,

Pandhurnekar

Mungole³

et al. 2022

Journal of Heterocyclic Chem

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Among different heterocyclic compounds, isoxazole and their analogues are very important classes of heterocyclic compounds as they display an extensive range of biological actions. This makes such scaffolds very important structures in the field of medicinal chemistry. From an extensive literature assessment, isoxazole is clinically proven to be very effective as an anti‐bacterial, anti‐fungal, anti‐inflammatory, anti‐cancer, anti‐tubercular, and anti‐neoplastic agent. The different derivatives of isoxazole which exhibits adjustment in their structure have shown a high degree of variety in their medicinal properties which makes evident them as very beneficial in the progress of novel bioactive drugs which show enhanced effectiveness along with minor harmfulness. Structural aspects of isoxazole having aromaticity with weaker nitrogen‐oxygen bonding provide a potential site for the ring cleavage. Thus, this isoxazole ring system allows easier modifications of substituents in their ring structure which consequently make isoxazole very useful intermediates in various synthetic routes of bioactive compounds. Hence, the synthesis and evaluation of isoxazole‐containing molecules with wider therapeutic consequences are always the topic of interest for chemists. Hence, in light of this comprehensive research on isoxazole, it is thought worthwhile to review various pathways for the synthesis of isoxazole analogues and having a broad spectrum of bioactive actions.

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“…Moreover, they had trouble attaching with the polar part of amino acid residues in PPARγ that is responsible for the AF2 stabilization and co-activator recruitment ( Figure 17 ). The pharmacological evaluation revealed that ADAM increases the expression of CPT1A in the primary mouse hepatocytes and Huh 7 cell line [ 90 ].…”

Section: Recent Developments In the Medicinal Chemistry Of Pparsmentioning

confidence: 99%

Development of Heterocyclic PPAR Ligands for Potential Therapeutic Applications

et al. 2022

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The family of nuclear peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, and PPARγ) is a set of ligand-activated transcription factors that regulate different functions in the body. Whereas activation of PPARα is known to reduce the levels of circulating triglycerides and regulate energy homeostasis, the activation of PPARγ brings about insulin sensitization and increases the metabolism of glucose. On the other hand, PPARβ when activated increases the metabolism of fatty acids. Further, these PPARs have been claimed to be utilized in various metabolic, neurological, and inflammatory diseases, neurodegenerative disorders, fertility or reproduction, pain, and obesity. A series of different heterocyclic scaffolds have been synthesized and evaluated for their ability to act as PPAR agonists. This review is a compilation of efforts on the part of medicinal chemists around the world to find novel compounds that may act as PPAR ligands along with patents in regards to PPAR ligands. The structure–activity relationship, as well as docking studies, have been documented to better understand the mechanistic investigations of various compounds, which will eventually aid in the design and development of new PPAR ligands. From the results of the structural activity relationship through the pharmacological and in silico evaluation the potency of heterocycles as PPAR ligands can be described in terms of their hydrogen bonding, hydrophobic interactions, and other interactions with PPAR.

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Molecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a PPARα-selective agonist

Cited by 9 publications

References 50 publications

Marine Natural and Nature-Inspired Compounds Targeting Peroxisome Proliferator Activated Receptors (PPARs)

Marine Natural and Nature-Inspired Compounds Targeting Peroxisome Proliferator Activated Receptors (PPARs)

A review of recent synthetic strategies and biological activities of isoxazole

Development of Heterocyclic PPAR Ligands for Potential Therapeutic Applications

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