Evolution and Discovery of Matrine Derivatives as a New Class of Anti-Hepatic Fibrosis Agents Targeting Ewing Sarcoma Breakpoint Region 1 (EWSR1)

A series of new tricyclic matrinane derivatives were continuously synthesized and evaluated for their inhibitory effects on genes and proteins related to hepatic fibrosis at the cellular level, including collagen type I α1 chain (COL1A1), α smooth muscle actin (α-SMA), connective tissue growth facto...

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Published inJournal of medicinal chemistry Vol. 66; no. 12; pp. 7969 - 7987
Main Authors Bao, Yunyang, Niu, Tianyu, Zhu, Jingyang, Mei, Yuheng, Shi, Yulong, Meng, Runze, Duan, Qionglu, Zhang, Na, Fan, Tianyun, Wang, Yanxiang, Pang, Yudong, Li, Yinghong, He, Hongwei, Song, Danqing
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 22.06.2023
Amer Chemical Soc
Subjects
Animals
Antifibrotic Agents
Chemistry, Medicinal
Fibrosis
Life Sciences & Biomedicine
Liver
Liver Cirrhosis - pathology
Matrines
Mice
Pharmacology & Pharmacy
Rats
RNA-Binding Protein EWS
Sarcoma, Ewing - pathology
Science & Technology
STELLATE CELLS
ACTIVATION
PROTEIN
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Abstract A series of new tricyclic matrinane derivatives were continuously synthesized and evaluated for their inhibitory effects on genes and proteins related to hepatic fibrosis at the cellular level, including collagen type I α1 chain (COL1A1), α smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and matrix metalloprotein 2 (MMP-2). Among them, compound 6k exerted an appealing potency and significantly reduced liver injury and fibrosis in both bile duct ligation (BDL) rats and Mdr2 knockout mice. An activity-based protein profiling (ABPP) assay indicated that 6k might directly bind to Ewing sarcoma breakpoint region 1 (EWSR1) to inhibit its function and affect the expression of downstream liver fibrosis-related genes and thus regulate liver fibrosis. These results provided a potential novel target for the treatment of liver fibrosis and powerful information for the development of tricyclic matrinanes into promising anti-hepatic fibrosis agents.
AbstractList A series of new tricyclic matrinane derivatives werecontinuouslysynthesized and evaluated for their inhibitory effects on genes andproteins related to hepatic fibrosis at the cellular level, includingcollagen type I alpha 1 chain (COL1A1), alpha smooth muscle actin(alpha-SMA), connective tissue growth factor (CTGF), and matrixmetalloprotein 2 (MMP-2). Among them, compound 6k exertedan appealing potency and significantly reduced liver injury and fibrosisin both bile duct ligation (BDL) rats and Mdr2 knockout mice. An activity-basedprotein profiling (ABPP) assay indicated that 6k mightdirectly bind to Ewing sarcoma breakpoint region 1 (EWSR1) to inhibitits function and affect the expression of downstream liver fibrosis-relatedgenes and thus regulate liver fibrosis. These results provided a potentialnovel target for the treatment of liver fibrosis and powerful informationfor the development of tricyclic matrinanes into promising anti-hepaticfibrosis agents.
A series of new tricyclic matrinane derivatives were continuously synthesized and evaluated for their inhibitory effects on genes and proteins related to hepatic fibrosis at the cellular level, including collagen type I α1 chain (COL1A1), α smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and matrix metalloprotein 2 (MMP-2). Among them, compound 6k exerted an appealing potency and significantly reduced liver injury and fibrosis in both bile duct ligation (BDL) rats and Mdr2 knockout mice. An activity-based protein profiling (ABPP) assay indicated that 6k might directly bind to Ewing sarcoma breakpoint region 1 (EWSR1) to inhibit its function and affect the expression of downstream liver fibrosis-related genes and thus regulate liver fibrosis. These results provided a potential novel target for the treatment of liver fibrosis and powerful information for the development of tricyclic matrinanes into promising anti-hepatic fibrosis agents.A series of new tricyclic matrinane derivatives were continuously synthesized and evaluated for their inhibitory effects on genes and proteins related to hepatic fibrosis at the cellular level, including collagen type I α1 chain (COL1A1), α smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and matrix metalloprotein 2 (MMP-2). Among them, compound 6k exerted an appealing potency and significantly reduced liver injury and fibrosis in both bile duct ligation (BDL) rats and Mdr2 knockout mice. An activity-based protein profiling (ABPP) assay indicated that 6k might directly bind to Ewing sarcoma breakpoint region 1 (EWSR1) to inhibit its function and affect the expression of downstream liver fibrosis-related genes and thus regulate liver fibrosis. These results provided a potential novel target for the treatment of liver fibrosis and powerful information for the development of tricyclic matrinanes into promising anti-hepatic fibrosis agents.
A series of new tricyclic matrinane derivatives were continuously synthesized and evaluated for their inhibitory effects on genes and proteins related to hepatic fibrosis at the cellular level, including collagen type I α1 chain (COL1A1), α smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and matrix metalloprotein 2 (MMP-2). Among them, compound 6k exerted an appealing potency and significantly reduced liver injury and fibrosis in both bile duct ligation (BDL) rats and Mdr2 knockout mice. An activity-based protein profiling (ABPP) assay indicated that 6k might directly bind to Ewing sarcoma breakpoint region 1 (EWSR1) to inhibit its function and affect the expression of downstream liver fibrosis-related genes and thus regulate liver fibrosis. These results provided a potential novel target for the treatment of liver fibrosis and powerful information for the development of tricyclic matrinanes into promising anti-hepatic fibrosis agents.
A series of new tricyclic matrinane derivatives were continuously synthesized and evaluated for their inhibitory effects on genes and proteins related to hepatic fibrosis at the cellular level, including collagen type I α1 chain (COL1A1), α smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and matrix metalloprotein 2 (MMP-2). Among them, compound exerted an appealing potency and significantly reduced liver injury and fibrosis in both bile duct ligation (BDL) rats and Mdr2 knockout mice. An activity-based protein profiling (ABPP) assay indicated that might directly bind to Ewing sarcoma breakpoint region 1 (EWSR1) to inhibit its function and affect the expression of downstream liver fibrosis-related genes and thus regulate liver fibrosis. These results provided a potential novel target for the treatment of liver fibrosis and powerful information for the development of tricyclic matrinanes into promising anti-hepatic fibrosis agents.
Author Bao, Yunyang
Pang, Yudong
Mei, Yuheng
Zhang, Na
Shi, Yulong
Wang, Yanxiang
Niu, Tianyu
Duan, Qionglu
Song, Danqing
He, Hongwei
Zhu, Jingyang
Meng, Runze
Li, Yinghong
Fan, Tianyun
AuthorAffiliation Institute of Medicinal Biotechnology
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Snippet A series of new tricyclic matrinane derivatives were continuously synthesized and evaluated for their inhibitory effects on genes and proteins related to...
A series of new tricyclic matrinane derivatives werecontinuouslysynthesized and evaluated for their inhibitory effects on genes andproteins related to hepatic...
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StartPage 7969
SubjectTerms Animals
Antifibrotic Agents
Chemistry, Medicinal
Fibrosis
Life Sciences & Biomedicine
Liver
Liver Cirrhosis - pathology
Matrines
Mice
Pharmacology & Pharmacy
Rats
RNA-Binding Protein EWS
Sarcoma, Ewing - pathology
Science & Technology
Title Evolution and Discovery of Matrine Derivatives as a New Class of Anti-Hepatic Fibrosis Agents Targeting Ewing Sarcoma Breakpoint Region 1 (EWSR1)
URI http://dx.doi.org/10.1021/acs.jmedchem.3c00286
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https://www.ncbi.nlm.nih.gov/pubmed/37294950
https://www.proquest.com/docview/2824695605
Volume 66
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