Discovery of seneciobipyrrolidine derivatives for the amelioration of glucose homeostasis disorders through 4E-BP1/Akt/AMPK signaling activation
Copyright © 2021 Elsevier Masson SAS. All rights reserved..
Modulating the glucose transport in skeletal muscle is a promising strategy for ameliorating glucose homeostasis disorders. However, the complicated mechanisms of glucose transport make it difficult to find compounds therapeutically relevant molecular mechanisms of action, while phenotypic screening is thought to be an alternative approach to mimic the cell state of interest. Here, we report (±)-seneciobipyrrolidine (1a) is first found to enhance glucose uptake in L6 myotubes through phenotype-based screening. Further SAR investigation led to the identfication of compound A27 (EC50 = 2.7 μM). Proteomiic analysis discloses the unique function mechanism of A27 through upregulating the level of the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), subsequently enhancing the Akt and AMPK phosphorylation, thereby promoting the glucose uptake. Chronic oral administration of A27 significantly lowers blood glucose and improves glucose tolerance in db/db mice. This work is new research on seneciobipyrrolidine derivatives, providing a promising avenue for ameliorating glucose homeostasis.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:228 |
|---|---|
| Enthalten in: |
European journal of medicinal chemistry - 228(2022) vom: 15. Jan., Seite 113954 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Che, Jinxin [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 25.01.2022 Date Revised 25.01.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.ejmech.2021.113954 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM333103467 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM333103467 | ||
| 003 | DE-627 | ||
| 005 | 20231225220940.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.ejmech.2021.113954 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1110.xml |
| 035 | |a (DE-627)NLM333103467 | ||
| 035 | |a (NLM)34772527 | ||
| 035 | |a (PII)S0223-5234(21)00803-5 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Che, Jinxin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of seneciobipyrrolidine derivatives for the amelioration of glucose homeostasis disorders through 4E-BP1/Akt/AMPK signaling activation |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 25.01.2022 | ||
| 500 | |a Date Revised 25.01.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 Elsevier Masson SAS. All rights reserved. | ||
| 520 | |a Modulating the glucose transport in skeletal muscle is a promising strategy for ameliorating glucose homeostasis disorders. However, the complicated mechanisms of glucose transport make it difficult to find compounds therapeutically relevant molecular mechanisms of action, while phenotypic screening is thought to be an alternative approach to mimic the cell state of interest. Here, we report (±)-seneciobipyrrolidine (1a) is first found to enhance glucose uptake in L6 myotubes through phenotype-based screening. Further SAR investigation led to the identfication of compound A27 (EC50 = 2.7 μM). Proteomiic analysis discloses the unique function mechanism of A27 through upregulating the level of the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), subsequently enhancing the Akt and AMPK phosphorylation, thereby promoting the glucose uptake. Chronic oral administration of A27 significantly lowers blood glucose and improves glucose tolerance in db/db mice. This work is new research on seneciobipyrrolidine derivatives, providing a promising avenue for ameliorating glucose homeostasis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a 4E-BP1 | |
| 650 | 4 | |a Glucose homeostasis | |
| 650 | 4 | |a L6 myotubes | |
| 650 | 4 | |a Phenotypic screening | |
| 650 | 4 | |a Proteomic analysis | |
| 650 | 4 | |a Seneciobipyrrolidine | |
| 650 | 7 | |a Adaptor Proteins, Signal Transducing |2 NLM | |
| 650 | 7 | |a Antipsychotic Agents |2 NLM | |
| 650 | 7 | |a Blood Glucose |2 NLM | |
| 650 | 7 | |a Cell Cycle Proteins |2 NLM | |
| 650 | 7 | |a EIF4EBP1 protein, human |2 NLM | |
| 650 | 7 | |a Pyrrolidines |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-akt |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a AMP-Activated Protein Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.31 |2 NLM | |
| 700 | 1 | |a Ma, Canliang |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Jialiang |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Binhui |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Qiuqiu |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Xinxin |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Fan |e verfasserin |4 aut | |
| 700 | 1 | |a Gan, Lishe |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Jingya |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Yongzhou |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Xiaowu |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t European journal of medicinal chemistry |d 1994 |g 228(2022) vom: 15. Jan., Seite 113954 |w (DE-627)NLM106608835 |x 1768-3254 |7 nnns |
| 773 | 1 | 8 | |g volume:228 |g year:2022 |g day:15 |g month:01 |g pages:113954 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.ejmech.2021.113954 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 228 |j 2022 |b 15 |c 01 |h 113954 | ||