Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Kim, Jinsoo, Son, Jinyoung, Ahn, Dohee, Nam, Gibeom, Zhao, Xiaodi, Park, Hyuna, Jeong, Woojoo, Chung, Sang J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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
_version_ 1784685305748520960
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
work_keys_str_mv AT kimjinsoo structureactivityrelationshipofsyntheticginkgolicacidanalogsfortreatingtype2diabetesbyptpn9inhibition
AT sonjinyoung structureactivityrelationshipofsyntheticginkgolicacidanalogsfortreatingtype2diabetesbyptpn9inhibition
AT ahndohee structureactivityrelationshipofsyntheticginkgolicacidanalogsfortreatingtype2diabetesbyptpn9inhibition
AT namgibeom structureactivityrelationshipofsyntheticginkgolicacidanalogsfortreatingtype2diabetesbyptpn9inhibition
AT zhaoxiaodi structureactivityrelationshipofsyntheticginkgolicacidanalogsfortreatingtype2diabetesbyptpn9inhibition
AT parkhyuna structureactivityrelationshipofsyntheticginkgolicacidanalogsfortreatingtype2diabetesbyptpn9inhibition
AT jeongwoojoo structureactivityrelationshipofsyntheticginkgolicacidanalogsfortreatingtype2diabetesbyptpn9inhibition
AT chungsangj structureactivityrelationshipofsyntheticginkgolicacidanalogsfortreatingtype2diabetesbyptpn9inhibition