Anthranilic acid derivatives as nuclear receptor modulators—Development of novel PPAR selective and dual PPAR/FXR ligands

Merk, Daniel; Lamers, Christina; Wéber, Júlia; Flesch, Daniel; Gabler, Matthias; Proschak, Ewgenij; Schubert‐Zsilavecz, Manfred

doi:10.1016/j.bmc.2014.12.013

Cited by 26 publications

(26 citation statements)

References 39 publications

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“…Table. Compounds tentatively identified as candidate constituents of Maerua subcordata. These compounds are reported in the literature to be ligands of PPARγ and/or influence PPARγ functions [47,56,61,[79][80][81][82][83][84][85][86][87][88][89][90][91].…”

Section: Supplementary Informationmentioning

confidence: 99%

Induction of peroxisome proliferator activated receptor γ (PPARγ) mediated gene expression and inhibition of induced nitric oxide production by Maerua subcordata (Gilg) DeWolf

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Haan

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et al. 2020

BMC Complement Med Ther

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Background: The health benefits of botanicals is linked to their phytochemicals that often exert pleiotropic effects via targeting multiple molecular signaling pathways such as the peroxisome proliferator-activated receptors (PPARs) and the nuclear factor kappaB (NFκB). The PPARs are transcription factors that control metabolic homeostasis and inflammation while the NF-κB is a master regulator of inflammatory genes such as the inducible nitric-oxide synthase that result in nitric oxide (NO) overproduction. Methods: Extracts of Maerua subcordata (MS) and selected candidate constituents thereof, identified by liquid chromatography coupled to mass spectroscopy, were tested for their ability to induce PPARγ mediated gene expression in U2OS-PPARγ cells using luciferase reporter gene assay and also for their ability to inhibit lipopolysaccharide (LPS) induced NO production in RAW264.7 macrophages. While measuring the effect of test samples on PPARγ mediated gene expression, a counter assay that used U2OS-Cytotox cells was performed to monitor cytotoxicity or any non-specific changes in luciferase activity.

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Section: Supplementary Informationmentioning

confidence: 99%

Induction of peroxisome proliferator activated receptor γ (PPARγ) mediated gene expression and inhibition of induced nitric oxide production by Maerua subcordata (Gilg) DeWolf

Hiben

Haan

Spenkelink

et al. 2020

BMC Complement Med Ther

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“…Based on these preliminary SAR observations, we probed further substituents in 4-and 5-positions. A 4-chlorine substituent (20) as well as a hydroxyl group in 4-position (21) failed to increase potency on PPARs and were not favored by FXR. 4-Methoxy analog 22 gained in potency on PPARα and PPARδ but markedly diminished FXR agonism.…”

Section: Resultsmentioning

confidence: 97%

“…Chemistry. Synthesis of compounds 5, 8, 10, and 11 has been reported previously 20 . Compounds 6, 7, 9, and 12-41 were prepared in five-step procedures ( Fig.…”

Section: Resultsmentioning

confidence: 99%

A triple farnesoid X receptor and peroxisome proliferator-activated receptor α/δ activator reverses hepatic fibrosis in diet-induced NASH in mice

et al. 2020

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Non-alcoholic steatohepatitis (NASH) - a hepatic manifestation of the metabolic syndrome - is a multifactorial disease with alarming global prevalence. It involves steatosis, inflammation and fibrosis in the liver, thus demanding multiple modes of action for robust therapeutic efficacy. Aiming to fuse complementary validated anti-NASH strategies in a single molecule, we have designed and systematically optimized a scaffold for triple activation of farnesoid X receptor (FXR), peroxisome proliferator-activated receptor (PPAR) α and PPARδ. Pilot profiling of the resulting triple modulator demonstrated target engagement in native cellular settings and in mice, rendering it a suitable tool to probe the triple modulator concept in vivo. In DIO NASH in mice, the triple agonist counteracted hepatic inflammation and reversed hepatic fibrosis highlighting the potential of designed polypharmacology in NASH.

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“…Thus, compound 29 containing an anthranilic acid methyl ester fragment on the 3-ethynylcoumarin nucleus showed greater activity than compounds with 4-tolyl- or pyridine substituents at the triple bond in 3-ethynylcoumarin. It should be noted that the biological effect of anthranilic acid derivatives is based on their ability to act as modulators of the nuclear peroxisome proliferator activated receptors (PRAR) and the farnesoid X (FXR) receptors, which fulfill crucial roles in metabolic balance [25,26]. In this direction the antibacterial activity of compounds 37a – c , having a methylene-triazolyl-furocoumarin substituent on the triple bond of 3-ethynylcoumarin was dependent on the length of the C-methylene linker.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis and Antibacterial Activity of Coumarin-1,2,3-triazole Hybrids Obtained from Natural Furocoumarin Peucedanin

et al. 2019

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Synthesis of 1,2,3-triazole-substituted coumarins and also 1,2,3-triazolyl or 1,2,3-triazolylalk-1-inyl-linked coumarin-2,3-furocoumarin hybrids was performed by employing the cross-coupling and copper catalyzed azide-alkyne cycloaddition reaction approaches. The synthesized compounds were evaluated for their in vitro antibacterial activity against Staphylococcus aureus, Bacillius subtilis, Actinomyces viscosus and Escherichia coli bacterial strains. Coumarin-benzoic acid hybrids 4с, 42с and 3-((4-acetylamino-3-(methoxycarbonyl)phenyl)ethynyl)coumarin (29) showed promising activity against S. aureus strains, and the 1,2,3-triazolyloct-1-inyl linked coumarin-2,3-furocoumarin hybrid 37c was endowed with high selectivity against B. subtilis and E. coli species. The in vitro antibacterial activity of 4с, 29, 37c and 42с can potentially be compared with that of a number of modern antibiotic drugs used in the clinic, suggesting promising prospects for further research. A detailed study of the molecular interactions with the targeted protein MurB was performed using docking simulations and the obtained results are quite promising.

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Anthranilic acid derivatives as nuclear receptor modulators—Development of novel PPAR selective and dual PPAR/FXR ligands

Cited by 26 publications

References 39 publications

Induction of peroxisome proliferator activated receptor γ (PPARγ) mediated gene expression and inhibition of induced nitric oxide production by Maerua subcordata (Gilg) DeWolf

Induction of peroxisome proliferator activated receptor γ (PPARγ) mediated gene expression and inhibition of induced nitric oxide production by Maerua subcordata (Gilg) DeWolf

A triple farnesoid X receptor and peroxisome proliferator-activated receptor α/δ activator reverses hepatic fibrosis in diet-induced NASH in mice

Design, Synthesis and Antibacterial Activity of Coumarin-1,2,3-triazole Hybrids Obtained from Natural Furocoumarin Peucedanin

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