12<i>N</i>-Substituted Matrinol Derivatives Inhibited the Expression of Fibrogenic Genes via Repressing Integrin/FAK/PI3K/Akt Pathway in Hepatic Stellate Cells

12<i>N</i>-Substituted Matrinol Derivatives Inhibited the Expression of Fibrogenic Genes via Repressing Integrin/FAK/PI3K/Akt Pathway in Hepatic Stellate Cells

Twenty new 12<i>N</i>-substituted matrinol derivatives were synthesized and evaluated for their inhibitory effects on collagen &#945;1 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells. The structure-activity relationship (SAR) revealed that introducing a 12<i>N</i&...

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Main Authors: Yunyang Bao, Yudong Pang, Sheng Tang, Tianyun Niu, Zhihao Guo, Hongwei He, Yinghong Li, Danqing Song
Format: Article
Language:English
Published: MDPI AG 2019-10-01
Series:Molecules
Subjects:
liver fibrosis
matrinol
structure−activity relationship
col1a1
integrin/fak pathway
Online Access:https://www.mdpi.com/1420-3049/24/20/3748
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spelling doaj-3bf1a3c2b9204d3d82a064d9ab5cdea12020-11-24T23:56:52ZengMDPI AGMolecules1420-30492019-10-012420374810.3390/molecules24203748molecules2420374812<i>N</i>-Substituted Matrinol Derivatives Inhibited the Expression of Fibrogenic Genes via Repressing Integrin/FAK/PI3K/Akt Pathway in Hepatic Stellate CellsYunyang Bao0Yudong Pang1Sheng Tang2Tianyun Niu3Zhihao Guo4Hongwei He5Yinghong Li6Danqing Song7Institute 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, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaTwenty new 12<i>N</i>-substituted matrinol derivatives were synthesized and evaluated for their inhibitory effects on collagen &#945;1 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells. The structure-activity relationship (SAR) revealed that introducing a 12<i>N</i>-benzeneaminoacylmethyl substitution might significantly enhance the activity. Compound <b>8a</b> exhibited the highest inhibitory potency against COL1A1, and its inhibition activity against COL1A1 was further confirmed on both the mRNA and protein levels. It also effectively inhibited the expression of &#945; smooth muscle actin (&#945;-SMA), fibronectin and transforming growth factor &#946;1 (TGF&#946;1), indicating an extensive inhibitory effect on the expression of fibrogenic genes. The primary mechanism study indicated that it might take action via the Integrin/FAK/PI3K/Akt signaling pathway. The results provided powerful information for further structure optimization, and compound <b>8a</b> was selected as a novel anti-fibrogenic lead for further investigation.https://www.mdpi.com/1420-3049/24/20/3748liver fibrosismatrinolstructure−activity relationshipcol1a1integrin/fak pathway
collection DOAJ
language English
format Article
sources DOAJ
author Yunyang Bao
Yudong Pang
Sheng Tang
Tianyun Niu
Zhihao Guo
Hongwei He
Yinghong Li
Danqing Song
spellingShingle Yunyang Bao
Yudong Pang
Sheng Tang
Tianyun Niu
Zhihao Guo
Hongwei He
Yinghong Li
Danqing Song
12<i>N</i>-Substituted Matrinol Derivatives Inhibited the Expression of Fibrogenic Genes via Repressing Integrin/FAK/PI3K/Akt Pathway in Hepatic Stellate Cells
Molecules
liver fibrosis
matrinol
structure−activity relationship
col1a1
integrin/fak pathway
author_facet Yunyang Bao
Yudong Pang
Sheng Tang
Tianyun Niu
Zhihao Guo
Hongwei He
Yinghong Li
Danqing Song
author_sort Yunyang Bao
title 12<i>N</i>-Substituted Matrinol Derivatives Inhibited the Expression of Fibrogenic Genes via Repressing Integrin/FAK/PI3K/Akt Pathway in Hepatic Stellate Cells
title_short 12<i>N</i>-Substituted Matrinol Derivatives Inhibited the Expression of Fibrogenic Genes via Repressing Integrin/FAK/PI3K/Akt Pathway in Hepatic Stellate Cells
title_full 12<i>N</i>-Substituted Matrinol Derivatives Inhibited the Expression of Fibrogenic Genes via Repressing Integrin/FAK/PI3K/Akt Pathway in Hepatic Stellate Cells
title_fullStr 12<i>N</i>-Substituted Matrinol Derivatives Inhibited the Expression of Fibrogenic Genes via Repressing Integrin/FAK/PI3K/Akt Pathway in Hepatic Stellate Cells
title_full_unstemmed 12<i>N</i>-Substituted Matrinol Derivatives Inhibited the Expression of Fibrogenic Genes via Repressing Integrin/FAK/PI3K/Akt Pathway in Hepatic Stellate Cells
title_sort 12<i>n</i>-substituted matrinol derivatives inhibited the expression of fibrogenic genes via repressing integrin/fak/pi3k/akt pathway in hepatic stellate cells
publisher MDPI AG
series Molecules
issn 1420-3049
publishDate 2019-10-01
description Twenty new 12<i>N</i>-substituted matrinol derivatives were synthesized and evaluated for their inhibitory effects on collagen &#945;1 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells. The structure-activity relationship (SAR) revealed that introducing a 12<i>N</i>-benzeneaminoacylmethyl substitution might significantly enhance the activity. Compound <b>8a</b> exhibited the highest inhibitory potency against COL1A1, and its inhibition activity against COL1A1 was further confirmed on both the mRNA and protein levels. It also effectively inhibited the expression of &#945; smooth muscle actin (&#945;-SMA), fibronectin and transforming growth factor &#946;1 (TGF&#946;1), indicating an extensive inhibitory effect on the expression of fibrogenic genes. The primary mechanism study indicated that it might take action via the Integrin/FAK/PI3K/Akt signaling pathway. The results provided powerful information for further structure optimization, and compound <b>8a</b> was selected as a novel anti-fibrogenic lead for further investigation.
topic liver fibrosis
matrinol
structure−activity relationship
col1a1
integrin/fak pathway
url https://www.mdpi.com/1420-3049/24/20/3748
work_keys_str_mv AT yunyangbao 12inisubstitutedmatrinolderivativesinhibitedtheexpressionoffibrogenicgenesviarepressingintegrinfakpi3kaktpathwayinhepaticstellatecells
AT yudongpang 12inisubstitutedmatrinolderivativesinhibitedtheexpressionoffibrogenicgenesviarepressingintegrinfakpi3kaktpathwayinhepaticstellatecells
AT shengtang 12inisubstitutedmatrinolderivativesinhibitedtheexpressionoffibrogenicgenesviarepressingintegrinfakpi3kaktpathwayinhepaticstellatecells
AT tianyunniu 12inisubstitutedmatrinolderivativesinhibitedtheexpressionoffibrogenicgenesviarepressingintegrinfakpi3kaktpathwayinhepaticstellatecells
AT zhihaoguo 12inisubstitutedmatrinolderivativesinhibitedtheexpressionoffibrogenicgenesviarepressingintegrinfakpi3kaktpathwayinhepaticstellatecells
AT hongweihe 12inisubstitutedmatrinolderivativesinhibitedtheexpressionoffibrogenicgenesviarepressingintegrinfakpi3kaktpathwayinhepaticstellatecells
AT yinghongli 12inisubstitutedmatrinolderivativesinhibitedtheexpressionoffibrogenicgenesviarepressingintegrinfakpi3kaktpathwayinhepaticstellatecells
AT danqingsong 12inisubstitutedmatrinolderivativesinhibitedtheexpressionoffibrogenicgenesviarepressingintegrinfakpi3kaktpathwayinhepaticstellatecells
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