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Synthesis and Anti‐Inflammatory Activity of 2‐Amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐Derived NRF2 Activators

This is the first study investigating the nuclear factor (erythroid‐derived 2)‐like 2 (NRF2) activity of compounds containing a new scaffold, tetrahydrobenzo[b]thiophene. Eighteen compounds were synthesised and confirmed their NRF2 activation through NQO1 enzymatic activity and mRNA expression of NQ...

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Detalles Bibliográficos
Autores principales: Mak, Kit‐Kay, Shiming, Zhang, Epemolu, Ola, Dinkova‐Kostova, Albena T., Wells, Geoffrey, Gazaryan, Irina G., Sakirolla, Raghavendra, Mohd, Zulkefeli, Pichika, Mallikarjuna Rao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9596610/
https://www.ncbi.nlm.nih.gov/pubmed/36284193
http://dx.doi.org/10.1002/open.202200181
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author Mak, Kit‐Kay
Shiming, Zhang
Epemolu, Ola
Dinkova‐Kostova, Albena T.
Wells, Geoffrey
Gazaryan, Irina G.
Sakirolla, Raghavendra
Mohd, Zulkefeli
Pichika, Mallikarjuna Rao
author_facet Mak, Kit‐Kay
Shiming, Zhang
Epemolu, Ola
Dinkova‐Kostova, Albena T.
Wells, Geoffrey
Gazaryan, Irina G.
Sakirolla, Raghavendra
Mohd, Zulkefeli
Pichika, Mallikarjuna Rao
author_sort Mak, Kit‐Kay
collection PubMed
description This is the first study investigating the nuclear factor (erythroid‐derived 2)‐like 2 (NRF2) activity of compounds containing a new scaffold, tetrahydrobenzo[b]thiophene. Eighteen compounds were synthesised and confirmed their NRF2 activation through NQO1 enzymatic activity and mRNA expression of NQO1 and HO‐1 in Hepa‐1c1c7 cells. The compounds disrupted the interaction between Kelch‐like ECH‐associated protein 1 (KEAP1) and NRF2 via interfering with the KEAP1’s Kelch domain. The compounds exhibited anti‐inflammatory activity in Escherichia coli Lipopolysaccharide (LPS( Ec ))‐stimulated RAW 264.7 cells. The anti‐inflammatory activity of the compounds was associated with their ability to activate NRF2. The compounds reversed the elevated levels of pro‐inflammatory cytokines (IL‐1β, IL‐6, TNF‐α, and IFN‐γ) and inflammatory mediators (PGE2, COX‐2, and NF‐κB). The compounds were metabolically stable in human, rat, and mouse liver microsomes and showed optimum half‐life (T(1/2)) and intrinsic clearance (Cl(int)). The binding mode of the compounds and physicochemical properties were predicted via in silico studies.
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spelling pubmed-95966102022-10-27 Synthesis and Anti‐Inflammatory Activity of 2‐Amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐Derived NRF2 Activators Mak, Kit‐Kay Shiming, Zhang Epemolu, Ola Dinkova‐Kostova, Albena T. Wells, Geoffrey Gazaryan, Irina G. Sakirolla, Raghavendra Mohd, Zulkefeli Pichika, Mallikarjuna Rao ChemistryOpen Research Articles This is the first study investigating the nuclear factor (erythroid‐derived 2)‐like 2 (NRF2) activity of compounds containing a new scaffold, tetrahydrobenzo[b]thiophene. Eighteen compounds were synthesised and confirmed their NRF2 activation through NQO1 enzymatic activity and mRNA expression of NQO1 and HO‐1 in Hepa‐1c1c7 cells. The compounds disrupted the interaction between Kelch‐like ECH‐associated protein 1 (KEAP1) and NRF2 via interfering with the KEAP1’s Kelch domain. The compounds exhibited anti‐inflammatory activity in Escherichia coli Lipopolysaccharide (LPS( Ec ))‐stimulated RAW 264.7 cells. The anti‐inflammatory activity of the compounds was associated with their ability to activate NRF2. The compounds reversed the elevated levels of pro‐inflammatory cytokines (IL‐1β, IL‐6, TNF‐α, and IFN‐γ) and inflammatory mediators (PGE2, COX‐2, and NF‐κB). The compounds were metabolically stable in human, rat, and mouse liver microsomes and showed optimum half‐life (T(1/2)) and intrinsic clearance (Cl(int)). The binding mode of the compounds and physicochemical properties were predicted via in silico studies. John Wiley and Sons Inc. 2022-10-25 /pmc/articles/PMC9596610/ /pubmed/36284193 http://dx.doi.org/10.1002/open.202200181 Text en © 2022 The Authors. Published by Wiley-VCH GmbH https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research Articles
Mak, Kit‐Kay
Shiming, Zhang
Epemolu, Ola
Dinkova‐Kostova, Albena T.
Wells, Geoffrey
Gazaryan, Irina G.
Sakirolla, Raghavendra
Mohd, Zulkefeli
Pichika, Mallikarjuna Rao
Synthesis and Anti‐Inflammatory Activity of 2‐Amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐Derived NRF2 Activators
title Synthesis and Anti‐Inflammatory Activity of 2‐Amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐Derived NRF2 Activators
title_full Synthesis and Anti‐Inflammatory Activity of 2‐Amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐Derived NRF2 Activators
title_fullStr Synthesis and Anti‐Inflammatory Activity of 2‐Amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐Derived NRF2 Activators
title_full_unstemmed Synthesis and Anti‐Inflammatory Activity of 2‐Amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐Derived NRF2 Activators
title_short Synthesis and Anti‐Inflammatory Activity of 2‐Amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐Derived NRF2 Activators
title_sort synthesis and anti‐inflammatory activity of 2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐derived nrf2 activators
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9596610/
https://www.ncbi.nlm.nih.gov/pubmed/36284193
http://dx.doi.org/10.1002/open.202200181
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