Discovery of 9<i>O</i>-Substituted Palmatine Derivatives as a New Class of Anti-COL1A1 Agents Via Repressing TGF-β1/Smads and JAK1/STAT3 Pathways

Twenty 9<i>O</i>-substituted palmatine derivatives were prepared and tested for their biological effect against collagen α1 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells. The structure−activity relationship (SAR) indicated that the introduction of a benzyl...

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Main Authors:	Tianyun Fan, Maoxu Ge, Zhihao Guo, Hongwei He, Na Zhang, Yinghong Li, Danqing Song
Format:	Article
Language:	English
Published:	MDPI AG 2020-02-01
Series:	Molecules
Subjects:	hepatic fibrosis palmatine structure−activity relationship col1a1 tgf-β1/smads pathway jak1/stat3 pathway
Online Access:	https://www.mdpi.com/1420-3049/25/4/773

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spelling	doaj-ffd817eb7f704af29d7fabef2fcd93b62020-11-25T02:03:23ZengMDPI AGMolecules1420-30492020-02-0125477310.3390/molecules25040773molecules25040773Discovery of 9<i>O</i>-Substituted Palmatine Derivatives as a New Class of Anti-COL1A1 Agents Via Repressing TGF-β1/Smads and JAK1/STAT3 PathwaysTianyun Fan0Maoxu Ge1Zhihao Guo2Hongwei He3Na Zhang4Yinghong Li5Danqing Song6Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaTwenty 9<i>O</i>-substituted palmatine derivatives were prepared and tested for their biological effect against collagen α1 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells. The structure−activity relationship (SAR) indicated that the introduction of a benzyl motif on the 9<i>O</i> atom was favorable for activity. Among them, compound <b>6c</b> provided the highest inhibitory effect against COL1A1 with an IC<sub>50</sub> value of 3.98 μM, and it also dose-dependently inhibited the expression of fibrogenic COL1A1, α-soomth muscle actin (α-SMA), matrix metalloprotein 2 (MMP2) in both mRNA and protein levels, indicating extensive inhibitory activity against fibrogenesis. A further primary mechanism study indicated that it might repress the hepatic fibrogenesis via inhibiting both canonical transforming growth factor-beta 1 (TGF-β1)/Smads and non-canonical janus-activated kinase 1 (JAK1)/singal transducer and activator of transcription 3 (STAT3) signaling pathways. Additionally, <b>6c</b> owned a high safety profile with the LD<sub>50</sub> value of over 1000 mg·kg<sup>−1</sup> in mice. These results identified palmatine derivatives as a novel class of anti-fibrogenic agents, and provided powerful information for further structure optimization.https://www.mdpi.com/1420-3049/25/4/773hepatic fibrosispalmatinestructure−activity relationshipcol1a1tgf-β1/smads pathwayjak1/stat3 pathway
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Tianyun Fan Maoxu Ge Zhihao Guo Hongwei He Na Zhang Yinghong Li Danqing Song
spellingShingle	Tianyun Fan Maoxu Ge Zhihao Guo Hongwei He Na Zhang Yinghong Li Danqing Song Discovery of 9<i>O</i>-Substituted Palmatine Derivatives as a New Class of Anti-COL1A1 Agents Via Repressing TGF-β1/Smads and JAK1/STAT3 Pathways Molecules hepatic fibrosis palmatine structure−activity relationship col1a1 tgf-β1/smads pathway jak1/stat3 pathway
author_facet	Tianyun Fan Maoxu Ge Zhihao Guo Hongwei He Na Zhang Yinghong Li Danqing Song
author_sort	Tianyun Fan
title	Discovery of 9<i>O</i>-Substituted Palmatine Derivatives as a New Class of Anti-COL1A1 Agents Via Repressing TGF-β1/Smads and JAK1/STAT3 Pathways
title_short	Discovery of 9<i>O</i>-Substituted Palmatine Derivatives as a New Class of Anti-COL1A1 Agents Via Repressing TGF-β1/Smads and JAK1/STAT3 Pathways
title_full	Discovery of 9<i>O</i>-Substituted Palmatine Derivatives as a New Class of Anti-COL1A1 Agents Via Repressing TGF-β1/Smads and JAK1/STAT3 Pathways
title_fullStr	Discovery of 9<i>O</i>-Substituted Palmatine Derivatives as a New Class of Anti-COL1A1 Agents Via Repressing TGF-β1/Smads and JAK1/STAT3 Pathways
title_full_unstemmed	Discovery of 9<i>O</i>-Substituted Palmatine Derivatives as a New Class of Anti-COL1A1 Agents Via Repressing TGF-β1/Smads and JAK1/STAT3 Pathways
title_sort	discovery of 9<i>o</i>-substituted palmatine derivatives as a new class of anti-col1a1 agents via repressing tgf-β1/smads and jak1/stat3 pathways
publisher	MDPI AG
series	Molecules
issn	1420-3049
publishDate	2020-02-01
description	Twenty 9<i>O</i>-substituted palmatine derivatives were prepared and tested for their biological effect against collagen α1 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells. The structure−activity relationship (SAR) indicated that the introduction of a benzyl motif on the 9<i>O</i> atom was favorable for activity. Among them, compound <b>6c</b> provided the highest inhibitory effect against COL1A1 with an IC<sub>50</sub> value of 3.98 μM, and it also dose-dependently inhibited the expression of fibrogenic COL1A1, α-soomth muscle actin (α-SMA), matrix metalloprotein 2 (MMP2) in both mRNA and protein levels, indicating extensive inhibitory activity against fibrogenesis. A further primary mechanism study indicated that it might repress the hepatic fibrogenesis via inhibiting both canonical transforming growth factor-beta 1 (TGF-β1)/Smads and non-canonical janus-activated kinase 1 (JAK1)/singal transducer and activator of transcription 3 (STAT3) signaling pathways. Additionally, <b>6c</b> owned a high safety profile with the LD<sub>50</sub> value of over 1000 mg·kg<sup>−1</sup> in mice. These results identified palmatine derivatives as a novel class of anti-fibrogenic agents, and provided powerful information for further structure optimization.
topic	hepatic fibrosis palmatine structure−activity relationship col1a1 tgf-β1/smads pathway jak1/stat3 pathway
url	https://www.mdpi.com/1420-3049/25/4/773
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Discovery of 9<i>O</i>-Substituted Palmatine Derivatives as a New Class of Anti-COL1A1 Agents Via Repressing TGF-β1/Smads and JAK1/STAT3 Pathways

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