Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway

A series of novel matrinic thiadiazole derivatives were designed, synthesized and evaluated for their inhibitory effect on COL1A1 promotor. The SAR indicated that: (i) the introduction of a thiadiazole on the 11-side chain was beneficial for activity; (ii) a 12-N-benzyl moiety was favorable for acti...

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Autores principales: Niu, Tianyu, Niu, Weixiao, Bao, Yunyang, Liu, Ting, Song, Danqing, Li, Yinghong, He, Hongwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099493/
https://www.ncbi.nlm.nih.gov/pubmed/29976890
http://dx.doi.org/10.3390/molecules23071644
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author Niu, Tianyu
Niu, Weixiao
Bao, Yunyang
Liu, Ting
Song, Danqing
Li, Yinghong
He, Hongwei
author_facet Niu, Tianyu
Niu, Weixiao
Bao, Yunyang
Liu, Ting
Song, Danqing
Li, Yinghong
He, Hongwei
author_sort Niu, Tianyu
collection PubMed
description A series of novel matrinic thiadiazole derivatives were designed, synthesized and evaluated for their inhibitory effect on COL1A1 promotor. The SAR indicated that: (i) the introduction of a thiadiazole on the 11-side chain was beneficial for activity; (ii) a 12-N-benzyl moiety was favorable for activity. Among them, compound 6n displayed a high activity with an inhibitory rate of 39.7% at a concentration of 40 μM. It also effectively inhibited the expression of two representative collagen proteins (COL1A1 and α-SMA) on both the mRNA and protein levels and showed a high safety profile in vivo, indicating its great promise as an anti-liver fibrosis agent. Further study indicated that it might repress hepatic fibrogenesis via the TGFβ/Smad pathway. This study provided powerful information for further strategic optimization and the top compound 6n was selected for further study as an ideal liver fibrosis lead for next investigation.
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spelling pubmed-60994932018-11-13 Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway Niu, Tianyu Niu, Weixiao Bao, Yunyang Liu, Ting Song, Danqing Li, Yinghong He, Hongwei Molecules Article A series of novel matrinic thiadiazole derivatives were designed, synthesized and evaluated for their inhibitory effect on COL1A1 promotor. The SAR indicated that: (i) the introduction of a thiadiazole on the 11-side chain was beneficial for activity; (ii) a 12-N-benzyl moiety was favorable for activity. Among them, compound 6n displayed a high activity with an inhibitory rate of 39.7% at a concentration of 40 μM. It also effectively inhibited the expression of two representative collagen proteins (COL1A1 and α-SMA) on both the mRNA and protein levels and showed a high safety profile in vivo, indicating its great promise as an anti-liver fibrosis agent. Further study indicated that it might repress hepatic fibrogenesis via the TGFβ/Smad pathway. This study provided powerful information for further strategic optimization and the top compound 6n was selected for further study as an ideal liver fibrosis lead for next investigation. MDPI 2018-07-05 /pmc/articles/PMC6099493/ /pubmed/29976890 http://dx.doi.org/10.3390/molecules23071644 Text en © 2018 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Niu, Tianyu
Niu, Weixiao
Bao, Yunyang
Liu, Ting
Song, Danqing
Li, Yinghong
He, Hongwei
Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway
title Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway
title_full Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway
title_fullStr Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway
title_full_unstemmed Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway
title_short Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway
title_sort discovery of matrinic thiadiazole derivatives as a novel family of anti-liver fibrosis agents via repression of the tgfβ/smad pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099493/
https://www.ncbi.nlm.nih.gov/pubmed/29976890
http://dx.doi.org/10.3390/molecules23071644
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