{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T09:55:59Z","timestamp":1768730159552,"version":"3.49.0"},"reference-count":31,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,2,11]],"date-time":"2020-02-11T00:00:00Z","timestamp":1581379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81903695"],"award-info":[{"award-number":["81903695"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019018","name":"CAMS initiative for innovative medicine","doi-asserted-by":"publisher","award":["2019I2M-1\u2013001"],"award-info":[{"award-number":["2019I2M-1\u2013001"]}],"id":[{"id":"10.13039\/501100019018","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Beijing Natural Science Foundation","award":["7202131"],"award-info":[{"award-number":["7202131"]}]},{"name":"Chinese Pharmaceutical Association-Yiling Pharmaceutical Innovation Fund for Biomedicine","award":["GL-1-B04-20190397"],"award-info":[{"award-number":["GL-1-B04-20190397"]}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["3332019083"],"award-info":[{"award-number":["3332019083"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Twenty 9O-substituted palmatine derivatives were prepared and tested for their biological effect against collagen \u03b11 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells. The structure\u2212activity relationship (SAR) indicated that the introduction of a benzyl motif on the 9O atom was favorable for activity. Among them, compound 6c provided the highest inhibitory effect against COL1A1 with an IC50 value of 3.98 \u03bcM, and it also dose-dependently inhibited the expression of fibrogenic COL1A1, \u03b1-soomth muscle actin (\u03b1-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-\u03b21)\/Smads and non-canonical janus-activated kinase 1 (JAK1)\/singal transducer and activator of transcription 3 (STAT3) signaling pathways. Additionally, 6c owned a high safety profile with the LD50 value of over 1000 mg\u00b7kg\u22121 in mice. These results identified palmatine derivatives as a novel class of anti-fibrogenic agents, and provided powerful information for further structure optimization.<\/jats:p>","DOI":"10.3390\/molecules25040773","type":"journal-article","created":{"date-parts":[[2020,2,11]],"date-time":"2020-02-11T11:45:30Z","timestamp":1581421530000},"page":"773","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Discovery of 9O-Substituted Palmatine Derivatives as a New Class of Anti-COL1A1 Agents Via Repressing TGF-\u03b21\/Smads and JAK1\/STAT3 Pathways"],"prefix":"10.3390","volume":"25","author":[{"given":"Tianyun","family":"Fan","sequence":"first","affiliation":[{"name":"Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maoxu","family":"Ge","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhihao","family":"Guo","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongwei","family":"He","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Na","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yinghong","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danqing","family":"Song","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lachiondo-Ortega, S., Mercado-G\u00f3mez, M., Serrano-Maci\u00e1, M., Lopitz-Otsoa, F., Salas-Villalobos, T.B., Varela-Rey, M., Delgado, T.C., and Mart\u00ednez-Chantar, M.L. (2019). Ubiquitin-Like Post-Translational Modifications (Ubl-PTMs): Small Peptides with Huge Impact in Liver Fibrosis. Cells, 8.","DOI":"10.3390\/cells8121575"},{"key":"ref_2","first-page":"189","article-title":"Cell therapy in chronic liver disease","volume":"32","author":"Nicolas","year":"2016","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1055\/s-0036-1571295","article-title":"Antifibrotic Therapies: Where Are We Now?","volume":"36","author":"Yoon","year":"2016","journal-title":"Semin. Liver Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.jhep.2012.12.005","article-title":"The burden of liver disease in Europe: A review of available epidemiological data","volume":"58","author":"Blachier","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.bpg.2017.04.005","article-title":"Reversal of liver fibrosis: From fiction to reality","volume":"31","author":"Zoubek","year":"2017","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/S0168-8278(03)00360-X","article-title":"Oxidative stress, KLF6 and transforming growth factor-beta up-regulation differentiate non-alcoholic steatohepatitis progressing to fibrosis from uncomplicated steatosis in rats","volume":"39","author":"Starkel","year":"2003","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.yexcr.2017.02.038","article-title":"Modulation of hepatic stellate cells and reversibility of hepatic fibrosis","volume":"352","author":"Huang","year":"2017","journal-title":"Exp. Cell Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrgastro.2017.38","article-title":"Mechanisms of hepatic stellate cell activation","volume":"14","author":"Tsuchida","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1002\/cphy.c120035","article-title":"Hepatic stellate cells and liver fibrosis","volume":"3","author":"Puche","year":"2013","journal-title":"Compr. Physiol."},{"key":"ref_10","first-page":"169","article-title":"Establishment and application of a high-throughput drug screening model based on COL1A1 promoter for anti-liver fibrosis","volume":"50","author":"Zhao","year":"2015","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1111\/bph.13766","article-title":"The anti-hepatic fibrosis effects of dihydrotanshinone I are mediated by disrupting the yes-associated protein and transcriptional enhancer factor D2 complex and stimulating autophagy","volume":"174","author":"Ge","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Niu, T., Niu, W., Bao, Y., Liu, T., Song, D., Li, Y., and He, H. (2018). Discovery of matrinic thiadiazole derivatives as a novel family of anti-liver fibrosis agents via repression of the TGF\u03b2\/Smad pathway. Molecules, 23.","DOI":"10.3390\/molecules23071644"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"103032","DOI":"10.1016\/j.bioorg.2019.103032","article-title":"Novel cytisine derivatives exert anti-liver fibrosis effect via PI3K\/Akt\/Smad pathway","volume":"90","author":"Tang","year":"2019","journal-title":"Bioorg. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bao, Y., Pang, Y., Tang, S., Niu, T., Guo, Z., He, H., Li, Y., and Song, D. (2019). 12N-Substituted matrinol derivatives inhibited the expression of fibrogenic genes via repressing Integrin\/FAK\/PI3K\/Akt pathway in hepatic stellate cells. Molecules, 24.","DOI":"10.3390\/molecules24203748"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4675","DOI":"10.1016\/j.bmcl.2008.07.005","article-title":"Synthesis and structure-activity relationships of berberine analogues as a novel class of low-density-lipoprotein receptor up-regulators","volume":"18","author":"Yang","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1021\/jm801157z","article-title":"Berberine analogues as a novel class of the low-density-lipoprotein receptor up-regulators: Synthesis, structure-activity relationships, and cholesterol-lowering efficacy","volume":"52","author":"Li","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ejmech.2018.08.050","article-title":"Synthesis and antibacterial evaluation of 13-substituted cycloberberine derivatives as a novel class of anti-MRSA agents","volume":"157","author":"Fan","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103490","DOI":"10.1016\/j.bioorg.2019.103490","article-title":"Synthesis and biological evaluation of berberine derivatives as a new class of broad-spectrum antiviral agents against Coxsackievirus B","volume":"95","author":"Zeng","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wang, Y.X., Yang, L., Wang, H.Q., Zhao, X.Q., Liu, T., Li, Y.H., Zeng, Q.X., Li, Y.H., and Song, D.Q. (2018). Synthesis and evolution of berberine derivatives as a new class of antiviral agents against enterovirus 71 through the MEK\/ERK pathway and autophagy. Molecules, 23.","DOI":"10.3390\/molecules23082084"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Yang, Y.S., Wei, W., Hu, X.X., Tang, S., Pang, J., You, X.F., Fan, T.Y., Wang, Y.X., and Song, D.Q. (2019). Evolution and antibacterial evaluation of 8-hydroxy-cycloberberine derivatives as a novel family of antibacterial agents against MRSA. Molecules, 24.","DOI":"10.3390\/molecules24050984"},{"key":"ref_21","first-page":"629","article-title":"Design, synthesis and anti-MRSA activities of cycloberberine derivatives with a novel chemical scaffold","volume":"8","author":"Fan","year":"2018","journal-title":"Acta Pharm. Sin."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1021\/acsmedchemlett.8b00094","article-title":"Discovery and development of 8-substituted cycloberberine derivatives as novel antibacterial agents against MRSA","volume":"9","author":"Fan","year":"2018","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/aps.2014.155","article-title":"The anti-fibrotic effects of epigallocatechin-3-gallate in bile duct-ligated cholestatic rats and human hepatic stellate LX-2 cells are mediated by the PI3K\/Akt\/Smad pathway","volume":"36","author":"Yu","year":"2015","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"G245","DOI":"10.1152\/ajpgi.2000.279.2.G245","article-title":"Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis","volume":"279","author":"Arthur","year":"2000","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1055\/s-2001-17557","article-title":"Hepatic stellate cell behavior during resolution of liver injury","volume":"21","author":"Iredale","year":"2001","journal-title":"Semin. Liver Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.bbrc.2019.03.156","article-title":"A novel STAT3 inhibitor, STX-0119, attenuates liver fibrosis by inactivating hepatic stellate cells in mice","volume":"513","author":"Choi","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4302","DOI":"10.1074\/jbc.M116.773085","article-title":"TGF-\u03b2 directly activates the JAK1-STAT3 axis to induce hepatic fibrosis in coordination with SMAD pathway","volume":"292","author":"Tang","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1038\/s41467-017-01236-6","article-title":"Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis","volume":"24","author":"Chakraborty","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Cao, S., Cao, R., Liu, X., Luo, X., and Zhong, W. (2016). Design, Synthesis and Biological Evaluation of Novel Benzothiazole Derivatives as Selective PI3K\u03b2 Inhibitors. Molecules, 21.","DOI":"10.3390\/molecules21070876"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1248\/cpb.39.1462","article-title":"Relative inhibitory activity of berberine-type alkaloids against 12-O-tetradecanoylphorbol-13-acetate-induced inflammation in mice","volume":"39","author":"Ken","year":"1991","journal-title":"Chem. Pharm. Bull."},{"key":"ref_31","first-page":"699","article-title":"Synthesis and characterization of 9-O-alkyl substituted palmatine derivatives","volume":"39","author":"Lu","year":"2014","journal-title":"Zhong Guo Zhong Yao Za Zhi"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/4\/773\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:56:50Z","timestamp":1760173010000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/4\/773"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,11]]},"references-count":31,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["molecules25040773"],"URL":"https:\/\/doi.org\/10.3390\/molecules25040773","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,11]]}}}