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Structure–Activity Relationship of Synthetic Ginkgolic Acid Analogs for Treating Type 2 Diabetes by PTPN9 Inhibition
Ginkgolic acid (C13:0) (GA), isolated from Ginkgo biloba, is a potential therapeutic agent for type 2 diabetes. A series of GA analogs were designed and synthesized for the evaluation of their structure–activity relationship with respect to their antidiabetic effects. Unlike GA, the synthetic analog...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8999917/ https://www.ncbi.nlm.nih.gov/pubmed/35409287 http://dx.doi.org/10.3390/ijms23073927 |
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author | Kim, Jinsoo Son, Jinyoung Ahn, Dohee Nam, Gibeom Zhao, Xiaodi Park, Hyuna Jeong, Woojoo Chung, Sang J. |
author_facet | Kim, Jinsoo Son, Jinyoung Ahn, Dohee Nam, Gibeom Zhao, Xiaodi Park, Hyuna Jeong, Woojoo Chung, Sang J. |
author_sort | Kim, Jinsoo |
collection | PubMed |
description | Ginkgolic acid (C13:0) (GA), isolated from Ginkgo biloba, is a potential therapeutic agent for type 2 diabetes. A series of GA analogs were designed and synthesized for the evaluation of their structure–activity relationship with respect to their antidiabetic effects. Unlike GA, the synthetic analog 1e exhibited improved inhibitory activity against PTPN9 and significantly stimulated glucose uptake via AMPK phosphorylation in differentiated 3T3-L1 adipocytes and C2C12 myotubes; it also induced insulin-dependent AKT activation in C2C12 myotubes in a concentration-dependent manner. Docking simulation results showed that 1e had a better binding affinity through a unique hydrophobic interaction with a PTPN9 hydrophobic groove. Moreover, 1e ameliorated palmitate-induced insulin resistance in C2C12 cells. This study showed that 1e increases glucose uptake and suppresses palmitate-induced insulin resistance in C2C12 myotubes via PTPN9 inhibition; thus, it is a promising therapeutic candidate for treating type 2 diabetes. |
format | Online Article Text |
id | pubmed-8999917 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-89999172022-04-12 Structure–Activity Relationship of Synthetic Ginkgolic Acid Analogs for Treating Type 2 Diabetes by PTPN9 Inhibition Kim, Jinsoo Son, Jinyoung Ahn, Dohee Nam, Gibeom Zhao, Xiaodi Park, Hyuna Jeong, Woojoo Chung, Sang J. Int J Mol Sci Article Ginkgolic acid (C13:0) (GA), isolated from Ginkgo biloba, is a potential therapeutic agent for type 2 diabetes. A series of GA analogs were designed and synthesized for the evaluation of their structure–activity relationship with respect to their antidiabetic effects. Unlike GA, the synthetic analog 1e exhibited improved inhibitory activity against PTPN9 and significantly stimulated glucose uptake via AMPK phosphorylation in differentiated 3T3-L1 adipocytes and C2C12 myotubes; it also induced insulin-dependent AKT activation in C2C12 myotubes in a concentration-dependent manner. Docking simulation results showed that 1e had a better binding affinity through a unique hydrophobic interaction with a PTPN9 hydrophobic groove. Moreover, 1e ameliorated palmitate-induced insulin resistance in C2C12 cells. This study showed that 1e increases glucose uptake and suppresses palmitate-induced insulin resistance in C2C12 myotubes via PTPN9 inhibition; thus, it is a promising therapeutic candidate for treating type 2 diabetes. MDPI 2022-04-01 /pmc/articles/PMC8999917/ /pubmed/35409287 http://dx.doi.org/10.3390/ijms23073927 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kim, Jinsoo Son, Jinyoung Ahn, Dohee Nam, Gibeom Zhao, Xiaodi Park, Hyuna Jeong, Woojoo Chung, Sang J. Structure–Activity Relationship of Synthetic Ginkgolic Acid Analogs for Treating Type 2 Diabetes by PTPN9 Inhibition |
title | Structure–Activity Relationship of Synthetic Ginkgolic Acid Analogs for Treating Type 2 Diabetes by PTPN9 Inhibition |
title_full | Structure–Activity Relationship of Synthetic Ginkgolic Acid Analogs for Treating Type 2 Diabetes by PTPN9 Inhibition |
title_fullStr | Structure–Activity Relationship of Synthetic Ginkgolic Acid Analogs for Treating Type 2 Diabetes by PTPN9 Inhibition |
title_full_unstemmed | Structure–Activity Relationship of Synthetic Ginkgolic Acid Analogs for Treating Type 2 Diabetes by PTPN9 Inhibition |
title_short | Structure–Activity Relationship of Synthetic Ginkgolic Acid Analogs for Treating Type 2 Diabetes by PTPN9 Inhibition |
title_sort | structure–activity relationship of synthetic ginkgolic acid analogs for treating type 2 diabetes by ptpn9 inhibition |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8999917/ https://www.ncbi.nlm.nih.gov/pubmed/35409287 http://dx.doi.org/10.3390/ijms23073927 |
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