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Article(id=1218263398471618896, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263392100467355, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2017-0835, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1503849600000, receivedDateStr=2017-08-28, revisedDate=1506441600000, revisedDateStr=2017-09-27, acceptedDate=null, acceptedDateStr=null, onlineDate=1768386228434, onlineDateStr=2026-01-14, pubDate=1513008000000, pubDateStr=2017-12-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1768386228434, onlineIssueDateStr=2026-01-14, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1768386228434, creator=13701087609, updateTime=1768386228434, updator=13701087609, issue=Issue{id=1218263392100467355, tenantId=1146029695717560320, journalId=1189982191388893191, year='2017', volume='52', issue='12', pageStart='1777', pageEnd='1974', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1768386226916, creator=13701087609, updateTime=1768386745881, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1218265568860357555, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263392100467355, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1218265568860357556, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263392100467355, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1895, endPage=1902, ext={EN=ArticleExt(id=1218263398916215127, articleId=1218263398471618896, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Design, synthesis and evaluation of anti-inflammatory effect of novel berberine derivatives on IL-6/STAT signaling pathway, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=ORIGINAL ARTICLES, runingTitle=null, highlight=null, articleAbstract=

Interleukin-6 (IL-6)/signal transducers and activators of transcription (STAT) signaling pathway is closely related to the development and progression of atherosclerosis (AS). Taking Chinese natural product berberine (BBR) as the leading compound, a series of novel BBR analogues defined on different types of substituents on position 3 or/and 9 were designed, synthesized and evaluated for their inhibitory activities on phosphorylation of STAT-1 and STAT-3 induced by IL-6. The structure-activity relationship indicated that introduction of rigid fragment on position 3 or 9 was beneficial for enhancing their activities. Among them, compounds 2b and 9 exhibited the most satisfactory potency. The study revealed that the compounds 2b and 9 exhibit anti-inflammatory potencies via activating AMPK, and down-regulation of phosphorylation of STAT1 and STAT3 induced by IL-6 in HUVEC cells. These results suggest that BBR derivatives may inhibit the inflammatory response mediated by the IL-6/STAT signaling pathway through regulation of AMPK, which provides useful insight into the development of BBR derivatives for treatment of atherosclerosis.

, correspAuthors=Yan-xiang WANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2017 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Qing-xuan ZENG, Na ZHANG, Hong-bin DENG, Dan-qing SONG, Jian-dong JIANG, Yan-xiang WANG), CN=ArticleExt(id=1218263401260831115, articleId=1218263398471618896, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=基于阻断IL-6/STAT信号通路的全新小檗碱衍生物的设计、合成及其抗炎作用评价, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

白介素-6（IL-6）/转录激活因子（STAT）信号通路的活化与动脉粥样硬化（AS）的发生发展密切相关。本研究以我国天然产物单体盐酸小檗碱（BBR）为先导物，通过在其3-位或/和9-位引入不同类型的侧链基团，设计合成了一系列全新结构BBR衍生物，并对其抑制IL-6诱导的STAT1/3的磷酸化进行了评价。构效关系表明，3-位或9-位引入刚性结构有利于活性提高，其中，化合物2b和9显示出最优的抑制活性。进一步研究提示，化合物2b和9通过激活HUVEC细胞中AMPK活性，抑制IL-6诱导的STAT1和STAT3磷酸化。研究结果显示，BBR衍生物通过AMPK途径抑制IL-6/STAT信号通路介导的炎症反应，为此类化合物发展成为抗AS候选物提供了有益的科学数据。

, correspAuthors=汪燕翔, authorNote=null, correspAuthorsNote=
* 汪燕翔, Tel:86-10-63033012, E-mail:
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journalId=1189982191388893191, articleId=1218263398471618896, language=EN, orderNo=5, keyword=STAT-1/3), Keyword(id=1218968405869249375, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, language=CN, orderNo=1, keyword=小檗碱), Keyword(id=1218968407198843760, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, language=CN, orderNo=2, keyword=动脉粥样硬化), Keyword(id=1218968407320478590, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, language=CN, orderNo=3, keyword=构效关系), Keyword(id=1218968407425336203, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, language=CN, orderNo=4, keyword=IL-6), Keyword(id=1218968407576331162, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, language=CN, orderNo=5, keyword=STAT-1/3)], refs=[Reference(id=1218968409866420406, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[1], rfOrder=0, authorNames=null, journalName=null, refType=null, unstructuredReference=van Diepen JA, Berbee JF, Havekes LM, et al. Interactions between inflammation and lipid metabolism:relevance for efficacy of anti-inflammatory drugs in the treatment of atherosclerosis[J]. Atherosclerosis, 2013, 228:306-315., articleTitle=null, refAbstract=null), Reference(id=1218968409992249541, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[2], rfOrder=1, authorNames=null, journalName=null, refType=null, unstructuredReference=Taleb S. Inflammation in atherosclerosis[J]. Arch Cardiovasc Dis, 2016, 109:708-715., articleTitle=null, refAbstract=null), Reference(id=1218968410151633106, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[3], rfOrder=2, authorNames=null, journalName=null, refType=null, unstructuredReference=Viola J, Soehnlein O. Atherosclerosis-a matter of unresolved inflammation[J]. Semin Immunol, 2015, 27:184-193., articleTitle=null, refAbstract=null), Reference(id=1218968410290045149, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[4], rfOrder=3, authorNames=null, journalName=null, refType=null, unstructuredReference=Marciniak A, Nawrocka Rutkowska J, Brodowska A, et al. Cardiovascular system diseases in patients with polycystic ovary syndrome-the role of inflammation process in this pathology and possibility of early diagnosis and prevention[J]. Ann Agric Environ Med, 2016, 23:537-541., articleTitle=null, refAbstract=null), Reference(id=1218968410382319854, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[5], rfOrder=4, authorNames=null, journalName=null, refType=null, unstructuredReference=Hartman J, Frishman WH. Inflammation and atherosclerosis:a review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy[J]. Cardiol Rev, 2014, 22:147-151., articleTitle=null, refAbstract=null), Reference(id=1218968411623833851, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[6], rfOrder=5, authorNames=null, journalName=null, refType=null, unstructuredReference=Rutherford C, Speirs C, Williams JJ, et al. Phosphorylation of Janus kinase 1(JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling[J]. Sci Signal, 2016, 9:ra109., articleTitle=null, refAbstract=null), Reference(id=1218968411850326288, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[7], rfOrder=6, authorNames=null, journalName=null, refType=null, unstructuredReference=Voloshyna I, Littlefield MJ, Reiss AB. Atherosclerosis and interferon-gamma:new insights and therapeutic targets[J]. Trends Cardiovasc Med, 2014, 24:45-51., articleTitle=null, refAbstract=null), Reference(id=1218968412022292773, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[8], rfOrder=7, authorNames=null, journalName=null, refType=null, unstructuredReference=Szelag M, Piaszyk-Borychowska A, Plens-Galaska M, et al. Targeted inhibition of STATs and IRFs as a potential treatment strategy in cardiovascular disease[J]. Oncotarget, 2016, 7:48788-48812., articleTitle=null, refAbstract=null), Reference(id=1218968412127150379, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[9], rfOrder=8, authorNames=null, journalName=null, refType=null, unstructuredReference=Yao J, Kong W, Jiang JD. Learning from berberine:treating chronic diseases through multiple targets[J]. Sci China Life Sci, 2015, 58:854-859., articleTitle=null, refAbstract=null), Reference(id=1218968412315894079, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[10], rfOrder=9, authorNames=null, journalName=null, refType=null, unstructuredReference=Heidarian E, Rafieian-Kopaei M, Khoshdel A, et al. Metabolic effects of berberine on liver phosphatidate phosphohydrolase in rats fed on high lipogenic diet:an additional mechanism for the hypolipidemic effects of berberine[J]. Asian Pac J Trop Biomed, 2014, 4:S429-S435., articleTitle=null, refAbstract=null), Reference(id=1218968412437528911, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[11], rfOrder=10, authorNames=null, journalName=null, refType=null, unstructuredReference=Bi CW, Zhang CX, Li YB, et al. Synthesis and structure-activity relationship of cycloberberine as anti-cancer agent[J]. Acta Pharm Sin (药学学报), 2013, 48:1800-1806., articleTitle=null, refAbstract=null), Reference(id=1218968412596912482, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[12], rfOrder=11, authorNames=null, journalName=null, refType=null, unstructuredReference=Li YH, liu YX, Wang YX, et al. Synthesis and biological evaluation of new 13-n-nonylprotoberberine derivatives as antitubercular agents[J]. Acta Pharm Sin B, 2013, 3:38-45., articleTitle=null, refAbstract=null), Reference(id=1218968412710158702, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[13], rfOrder=12, authorNames=null, journalName=null, refType=null, unstructuredReference=Wang YX, Fu HG, Li YH, et al. Synthesis and biological evaluation of 8-substituted berberine derivatives as novel anti-mycobacterial agents[J]. Acta Pharm Sin B, 2012, 2:581-587., articleTitle=null, refAbstract=null), Reference(id=1218968412831793533, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[14], rfOrder=13, authorNames=null, journalName=null, refType=null, unstructuredReference=Feng M, Zou Z, Zhou X, et al. Comparative effect of berberine and its derivative 8-cetylberberine on attenuating atherosclerosis in ApoE-/- mice[J]. Int Immunopharmacol, 2017, 43:195-202., articleTitle=null, refAbstract=null), Reference(id=1218968412936651145, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[15], rfOrder=14, authorNames=null, journalName=null, refType=null, unstructuredReference=Wang YX, Kong WJ, Li YH, et al. Synthesis and structure-activity relationship of berberine analogues in LDLR up-regulation and AMPK activation[J]. Bioorg Med Chem, 2012, 20:6552-6558., articleTitle=null, refAbstract=null), Reference(id=1218968413054091675, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[16], rfOrder=15, authorNames=null, journalName=null, refType=null, unstructuredReference=Ma Y, Ou TM, Tan JH, et al. Quinolino-benzo-[5, 6]-dihydroisoquindolium compounds derived from berberine:a new class of highly selective ligands for G-quadruplex DNA in c-myc oncogene[J]. Eur J Med Chem, 2011, 46:1906-1913., articleTitle=null, refAbstract=null), Reference(id=1218968413179920815, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[17], rfOrder=16, authorNames=null, journalName=null, refType=null, unstructuredReference=Li YH, Wang L, Hong B, et al. Synthesis and structure-activity relationship of 13-hexylberberine analogues as CD36 antagonists[J]. Acta Pharm Sin (药学学报), 2010, 45:1128-1133., articleTitle=null, refAbstract=null), Reference(id=1218968413297361339, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[18], rfOrder=17, authorNames=null, journalName=null, refType=null, unstructuredReference=Ren G, Zhang MR, Song DQ, et al. Study on hypoglycemic activity of 9-substituted berberine derivatives in vitro[J]. Acta Pharm Sin (药学学报), 2017, 52:1282-1286., articleTitle=null, refAbstract=null), Reference(id=1218968413414801865, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[19], rfOrder=18, authorNames=null, journalName=null, refType=null, unstructuredReference=Mancini SJ, White AD, Bijland S, et al. Activation of AMP-activated protein kinase rapidly suppresses multiple pro-inflammatory pathways in adipocytes including IL-1 receptor-associated kinase-4 phosphorylation[J]. Mol Cell Endocrinol, 2017, 440:44-56., articleTitle=null, refAbstract=null), Reference(id=1218968413599351264, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[20], rfOrder=19, authorNames=null, journalName=null, refType=null, unstructuredReference=Kelly M, Keller C, Avilucea PR, et al. AMPK activity is diminished in tissues of IL-6 knockout mice:the effect of exercise[J]. Biochem Biophys Res Commun, 2004, 320:449-454., articleTitle=null, refAbstract=null)], funds=[Fund(id=1218968409623150739, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, awardId=2016-12M-1-011, language=CN, fundingSource=中国医学科学院医学与健康科技创新工程资助(2016-12M-1-011), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1218968402996150850, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, xref=null, ext=[AuthorCompanyExt(id=1218968403004539459, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, companyId=1218968402996150850, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Institute of Medicinal Biotechnology, China Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1218968403012928068, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, companyId=1218968402996150850, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院医药生物技术研究所, 北京 100050)])], figs=[ArticleFig(id=1218968407815406515, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, language=EN, label=null, caption=null, figureFileSmall=OFmyI+RK6UQFYx9G60A6CQ==, figureFileBig=jojz7lLaKWp1ZvjxJ3lksw==, tableContent=null), ArticleFig(id=1218968407945429953, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, language=CN, label=Figure 1, caption=

Chemical structure of berberine (BBR), and its structure modification strategy

, figureFileSmall=OFmyI+RK6UQFYx9G60A6CQ==, figureFileBig=jojz7lLaKWp1ZvjxJ3lksw==, tableContent=null), ArticleFig(id=1218968408155145172, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, language=EN, label=null, caption=null, figureFileSmall=JD/+RE0tvaWeTlN9i8Ep1A==, figureFileBig=fNUv/kxeNbL8g6RYa2Ez8g==, tableContent=null), ArticleFig(id=1218968408419386349, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, language=CN, label=Scheme 1, caption= Synthesis of 9-substituted BBR derivatives

Reagents and conditions: (a) 2, 4-Dimethoxybenzylamine, 120 ℃; (b) HCl, CH3OH; (c) RCOCl, triethylamine, CH3CN, reflux; (d) HCl, CH3OH; (e) RCOCl, triethylamine, CH3CN, reflux.

, figureFileSmall=JD/+RE0tvaWeTlN9i8Ep1A==, figureFileBig=fNUv/kxeNbL8g6RYa2Ez8g==, tableContent=null), ArticleFig(id=1218968408541021179, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, language=EN, label=null, caption=null, figureFileSmall=TKYefpauXOrLo96bLR7ZGQ==, figureFileBig=hGrZ9l0jfNz+Xe1WfWGFAQ==, tableContent=null), ArticleFig(id=1218968408671043598, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, language=CN, label=Scheme 2, caption= Synthesis of 3-and 9-substituted jatrorrhizine derivatives (<strong>7</strong>-<strong>11</strong>)

Reagents and conditions: (a) 2,4-Dimethoxybenzylamine, 120 ℃; (b) HCl, CH3OH; (c) RCOCl, triethylamine, CH3CN, reflux; (d) HCl, CH3OH; (e) RCOCl, triethylamine, CH3CN, reflux.

, figureFileSmall=TKYefpauXOrLo96bLR7ZGQ==, figureFileBig=hGrZ9l0jfNz+Xe1WfWGFAQ==, tableContent=null), ArticleFig(id=1218968408792678430, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, language=EN, label=null, caption=null, figureFileSmall=Hf8sKaqmvtoJBGjNUA4VXg==, figureFileBig=VWHr5uJc/G24+58C3H1Ybg==, tableContent=null), ArticleFig(id=1218968408893341737, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, language=CN, label=Figure 2, caption=

BBR analogues inhibited IL-6-induced STAT1 and STAT3 phosphorylation. Following pretreatment with BBR analogs 2a-2f, 5a-5f and 7-11 (10 μmol·L-1) for 2 h, HUVEC cells were treated with DMSO, sIL-6Ra (25 ng·mL-1)/IL-6 (5 ng·mL-1) for 30 min. The phosphorylation of STAT1 and STAT3 were measured by Western blotting using corresponding antibodies. D: DMSO. β-Actin served as the loading control. ***P < 0.001 compared with DMSO treated, IL-6-induced p-STAT1 group. ###P < 0.001 compared with DMSO treated, IL-6-induced p-STAT3 group

, figureFileSmall=Hf8sKaqmvtoJBGjNUA4VXg==, figureFileBig=VWHr5uJc/G24+58C3H1Ybg==, tableContent=null), ArticleFig(id=1218968409014976575, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, language=EN, label=null, caption=null, figureFileSmall=Q0pqJ4v0v/pPT5tN3Yra3Q==, figureFileBig=6r4ek+CXryhJfwq0QErOVQ==, tableContent=null), ArticleFig(id=1218968409132417103, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, language=CN, label=Figure 3, caption=

BBR analogues induced ACC and AMPK phosphorylation. Following pretreatment with BBR analogs 2a-2f, 5a-5f and 7-11 (10 μmol·L-1) for 2 h, HUVEC cells were treated with DMSO, sIL-6Ra (25 ng·mL-1)/IL-6 (5 ng·mL-1) for 30 min. The phosphorylation of ACC and AMPK were measured by Western blotting using corresponding antibodies. D: DMSO. β-Actin served as the loading control. *P < 0.05, **P < 0.01, ***P < 0.001 compared with DMSO treated, IL-6-induced p-ACC group. #P < 0.05, ##P < 0.01, ###P < 0.001 compared with DMSO treated, IL-6-induced p-AMPK group

, figureFileSmall=Q0pqJ4v0v/pPT5tN3Yra3Q==, figureFileBig=6r4ek+CXryhJfwq0QErOVQ==, tableContent=null), ArticleFig(id=1218968409220497501, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No. Yield /% mp/℃ (Dec.) 1H NMR 13C NMR HR-ESI-MS (m/z)
2a 35 190-192 1H NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.08 (s, 1H), 8.29 (d, J = 9.2 Hz, 1H), 8.21 (d, J = 9.2 Hz, 1H), 7.82 (s, 1H), 7.10 (s, 1H), 6.18 (s, 2H), 4.98 (t, J = 6.4 Hz, 2H), 4.03 (s, 3H), 3.23 (t, J = 6.4 Hz, 2H), 2.88 (t, J = 7.3 Hz, 2H), 1.77 (h, J = 7.3 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 171.2, 151.0, 150.6, 148.3, 145.1, 138.7, 134.2, 133.5, 131.5, 127.3, 126.5, 121.8, 121.2, 121.0, 109.1, 106.2, 102.8, 57.8, 55.8, 35.7, 26.8, 18.5, 14.0. C23H22ClNO5 [M-Cl]+: 392.148 0, found: 392.149 2
2b 37 204-206 1H NMR (500 MHz, DMSO-d6) δ 9.52 (s, 1H), 9.08 (s, 1H), 8.29 (d, J = 9.2 Hz, 1H), 8.21 (d, J = 9.2 Hz, 1H), 7.84 (s, 1H), 7.12 (s, 1H), 6.19 (s, 2H), 4.98 (t, J = 6.3 Hz, 2H), 4.02 (s, 3H), 3.22 (t, J = 6.3 Hz, 2H), 2.18 (d, J = 3.0 Hz, 6H), 2.14-2.10 (m, 3H), 1.79 (t, J = 3.0 Hz, 6H). 13C NMR (126 MHz, DMSO-d6) δ 174.8, 150.8, 150.6, 148.4, 144.5, 138.7, 134.6, 133.6, 131.5, 127.2, 126.5, 121.6, 121.4, 121.0, 109.1, 106.2, 102.8, 57.9, 56.2, 41.6, 38.8 (3), 36.5 (3), 27.9 (3), 26.8. C30H30ClNO5 [M-Cl]+: 484.211 9, found: 484.212 3
2c 41 176-178 1H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.11 (s, 1H), 8.37 (d, J = 9.3 Hz, 1H), 8.34-8.31 (m, 1H), 8.29 (d, J = 9.2 Hz, 1H), 8.15 (d, J = 2.9 Hz, 1H), 7.95-7.86 (m, 2H), 7.85 (s, 1H), 7.11 (s, 1H), 6.20 (s, 2H), 4.90 (t, J = 6.5 Hz, 2H), 4.05 (s, 3H), 3.21 (t, J = 6.4 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 162.8, 151.0, 150.7, 149.2, 148.4, 145.2, 138.9, 133.7, 133.6, 132.2, 131.6, 130.8, 130.2, 128.0, 127.9, 126.5, 123.2, 121.7, 121.3, 121.0, 120.7, 109.1, 106.2, 102.8, 58.0, 55.9, 26.8. C27H19ClF3NO6 [M-Cl]+: 510.115 9, found: 510.114 0
2d 33 180-182 1H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.12 (s, 1H), 8.36 (d, J = 9.3 Hz, 1H), 8.34 (t, J = 1.9 Hz, 1H), 8.29 (d, J = 9.2 Hz, 1H), 8.25 (dt, J = 7.8, 1.5 Hz, 1H), 7.93 (dt, J = 7.8, 1.5 Hz, 1H), 7.85 (s, 1H), 7.73 (t, J = 7.8 Hz, 1H), 6.19 (s, 2H), 4.98 (s, 2H), 4.91 (t, J = 6.4 Hz, 2H), 4.04 (s, 3H), 3.21 (t, J = 6.4 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 163.7, 151.0, 150.6, 148.4, 145.2, 139.5, 138.8, 135.6, 134.1, 133.6, 131.5, 131.2, 131.0, 130.3, 129.0, 127.7, 126.5, 121.8, 121.3, 121.0, 109.1, 106.2, 102.8, 57.9, 55.9, 45.9, 26.8. C27H21Cl2NO5 [M-Cl]+: 474.110 3, found: 474.108 6
2e 27 193-195 1H NMR (500 MHz, methanol-d4) δ 9.82 (s, 1H), 8.88 (s, 1H), 8.32 (d, J = 9.2 Hz, 1H), 8.28 (d, J = 9.2 Hz, 1H), 7.73 (s, 1H), 6.99 (s, 1H), 6.14 (s, 2H), 5.01-4.93 (m, 2H), 4.12 (s, 3H), 3.28 (t, J = 6.3 Hz, 2H), 2.84 (s, 3H), 2.56 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 177.9, 160.5, 159.6, 151.2, 150.7, 148.4, 145.1, 138.9, 133.6, 133.2, 131.6, 127.8, 126.5, 121.9, 121.3, 121.0, 109.1, 108.1, 106.2, 102.8, 58.0, 55.9, 26.8, 14.2, 12.3. C25H21ClN2O6 [M-Cl]+: 445.139 4, found: 445.137 7
2f 34 180-182 1H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.38 (d, J = 1.8 Hz, 1H), 9.19 (d, J = 2.3 Hz, 1H), 9.09 (s, 1H), 8.82 (t, J = 2.1 Hz, 1H), 8.37 (d, J = 9.2 Hz, 1H), 8.29 (d, J = 9.1 Hz, 1H), 7.84 (s, 1H), 7.12 (s, 1H), 6.20 (s, 2H), 4.89 (t, J = 6.3 Hz, 2H), 4.06 (s, 3H), 3.22 (t, J = 6.5 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 172.7, 161.8, 156.2, 151.0, 150.7, 150.0, 148.4, 145.2, 140.7, 139.0, 133.6, 133.3, 131.6, 128.0, 126.6, 121.5, 121.3, 121.2, 121.0, 109.1, 106.2, 102.8, 58.0, 56.0, 26.8. C25H18BrClN2O5 [M-Cl]+: 505.039 4, found: 505.037 5
5a 30 225-227 1H NMR (500 MHz, methanol-d4) δ 9.47 (s, 1H), 8.79 (s, 1H), 8.26 (d, J = 9.2 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.69 (s, 1H), 6.99 (s, 1H), 6.13 (s, 2H), 5.02-4.93 (m, 2H), 4.12 (s, 3H), 3.32-3.23 (m, 3H), 2.65 (t, J = 7.4 Hz, 2H), 1.86 (h, J = 7.4 Hz, 2H), 1.13 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 173.2, 154.9, 150.5, 148.3, 146.8, 138.0, 133.8, 131.3, 127.9, 125.8, 124.6, 122.5, 121.4, 121.1, 109.1, 106.1, 102.8, 57.6, 55.9, 38.1, 26.9, 19.1, 14.4. C23H23ClN2O4 [M-Cl]+: 391.164 0, found: 391.165 2
5b 43 242-244 1H NMR (500 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.29 (d, J = 4.6 Hz, 1H), 8.21 (s, 2H), 7.82 (s, 1H), 7.11 (s, 1H), 6.18 (s, 2H), 5.00 (t, J = 6.3 Hz, 2H), 4.07-3.96 (m, 3H), 3.21 (t, J = 6.3 Hz, 2H), 2.07 (s, 9H), 1.76 (s, 6H). 13C NMR (126 MHz, DMSO-d6) δ 177.9, 155.2, 150.3, 148.1, 146.0, 137.8, 133.6, 131.2, 127.9, 125.7, 124.9, 122.9, 121.3, 120.9, 108.9, 106.0, 102.5, 57.5, 56.0, 41.3, 38.9, 36.6 (3), 28.2 (3), 26.8 (3). C30H31ClN2O4Cl [M-Cl]+: 483.227 8, found: 483.228 0
5c 37 245-247 1H NMR (500 MHz, DMSO-d6) δ 10.69 (s, 1H), 9.82 (s, 1H), 9.06 (s, 1H), 8.29 (s, 2H), 8.20 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.82-7.68 (m, 2H), 7.10 (s, 1H), 6.19 (s, 2H), 4.96 (t, J = 6.1 Hz, 2H), 4.05 (s, 3H), 3.20 (t, J = 6.2 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 165.1, 155.3, 150.3, 148.8, 148.1, 146.4, 138.1, 136.2, 133.7, 131.2, 131.1, 128.5, 127.8, 125.7, 120.6, 125.0, 124.8, 121.7, 121.3, 121.2, 120.9, 108.8, 106.0, 102.5, 57.5, 55.6, 26.7. C27H20F3N2 O5 [M-Cl]+: 509.131 9, found: 509.129 9
5d 39 256-258 1H NMR (500 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.05 (s, 1H), 8.28 (s, 2H), 8.20-8.17 (m, 1H), 8.14 (d, J= 7.8 Hz, 1H), 7.84 (s, 1H), 7.76-7.72 (m, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.10 (s, 1H), 6.19 (s, 2H), 4.96 (t, J = 6.4 Hz, 2H), 4.90 (s, 2H), 4.04 (s, 3H), 3.20 (t, J = 6.4 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 166.2, 155.3, 150.2, 148.2, 146.4, 138.5, 138.1, 134.4, 133.7, 132.9, 131.2, 129.3, 129.2, 128.6, 128.3, 125.7, 124.9, 122.2, 121.3, 121.0, 108.9, 106.0, 102.6, 57.4, 55.6, 46.2, 26.7. C27H22Cl2N2O4 [M-Cl]+: 473.126 4, found: 473.124 8
5e 28 243-245 1H NMR (500 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.80 (s, 1H), 9.06 (s, 1H), 8.27 (s, 2H), 7.84 (s, 1H), 7.11 (s, 1H), 6.19 (s, 2H), 4.98 (t, J = 6.4 Hz, 2H), 4.07 (s, 3H), 3.21 (t, J = 6.4 Hz, 2H), 2.71 (s, 3H), 2.45 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 171.4, 161.9, 159.3, 155.0, 150.3, 148.1, 146.4, 138.0, 133.6, 131.2, 128.3, 125.6, 124.5, 121.6, 121.2, 120.9, 113.1, 108.9, 106.0, 102.5, 57.5, 55.7, 26.7, 13.1, 11.3. C25H22ClN3O5 [M-Cl]+: 444.155 4, found: 444.153 8
5f 36 205-207 1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.84 (s, 1H), 9.23 (s, 1H), 9.06 (s, 1H), 9.01 (d, J = 2.2 Hz, 1H), 8.72 (s, 1H), 8.29 (s, 2H), 7.84 (s, 1H), 7.11 (s, 1H), 6.19 (s, 2H), 4.95 (t, J = 6.3 Hz, 2H), 4.06 (s, 3H), 3.21 (t, J = 6.3 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 172.5, 164.1, 155.3, 153.6, 150.4, 148.3, 148.2, 146.3, 138.7, 138.3, 133.7, 131.2, 128.7, 125.7, 124.7, 121.3, 121.1, 120.9, 120.5, 108.9, 106.0, 102.6, 57.5, 56.5, 26.7. C25H19BrClN3O4 [M-Cl]+: 504.055 4, found: 504.053 5
7 30 102-104 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 10.06 (s, 1H), 8.79 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.89 (s, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.51-6.46 (m, 1H), 6.39 (dd, J = 8.3, 2.4 Hz, 1H), 4.80 (t, J = 6.5 Hz, 2H), 4.65 (d, J = 6.5 Hz, 2H), 3.93 (s, 3H), 3.84 (s, 3H), 3.77 (s, 3H), 3.70 (s, 3H), 3.15 (t, J = 6.3 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 160.4, 158.5, 150.4, 148.4, 147.7, 146.8, 137.3, 137.0, 133.9, 130.2, 129.0, 125.0, 120.4, 119.6, 118.4, 118.0, 117.4, 115.6, 109.9, 104.7, 98.9, 57.5, 56.8, 56.0, 55.8 (2), 46.9, 26.7. C28H29ClN2O5 [M-Cl]+: 473.207 1, found: 473.205 4
8 80 207-209 1H NMR (600 MHz, DMSO-d6) δ 10.20 (d, J = 5.7 Hz, 1H), 9.92 (s, 1H), 8.65 (s, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.62 (s, 1H), 7.31 (d, J = 8.6 Hz, 1H), 6.82 (s, 1H), 6.81 (s, 2H), 4.67 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.11 (t, J = 6.3 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 150.1, 148.4, 147.0, 143.7, 138.1, 136.3, 132.6, 128.8, 123.3, 119.2, 118.6, 115.6, 113.9, 113.2, 109.8, 57.1, 56.8, 55.5, 26.8. C19H19ClN2O3 [M-Cl]+: 323.139 0, found: 323.138 0
9 38 153-155 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.97 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.22 (s, 1H), 7.15 (d, J = 8.3 Hz, 1H), 6.58 (t, J = 6.5 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.41 (dd, J = 8.3, 2.4 Hz, 1H), 4.85 (t, J = 6.2 Hz, 2H), 4.68 (d, J = 6.4 Hz, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.77 (s, 3H), 3.71 (s, 3H), 3.23 (t, J = 6.3 Hz, 2H), 2.09-2.04 (m, 3H), 2.03-1.99 (m, 6H), 1.78-1.71 (m, 6H). 13C NMR (126 MHz, DMSO-d6) δ 175.2, 160.5, 158.5, 151.4, 148.3, 147.5, 142.2, 137.7, 135.6, 133.2, 130.2, 128.2, 126.1, 124.7, 123.4, 121.6, 120.3, 118.2, 117.7, 110.4, 104.8, 98.9, 57.5, 57.3, 55.8, 55.8, 55.7, 46.9, 41.1, 39.0 (3), 36.5 (3), 27.9 (3), 26.4. C39H43ClN2O6 [M-Cl]+: 635.308 7, found: 635.311 7
10 76 215-217 1H NMR (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 10.45 (s, 1H), 8.87 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.84 (s, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.20 (s, 1H), 7.02 (s, 2H), 4.76 (t, J = 6.3 Hz, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 3.22 (t, J = 6.2 Hz, 2H), 2.10-2.04 (m, 3H), 2.04-1.96 (m, 6H), 1.81-1.67 (m, 6H). 13C NMR (126 MHz, DMSO-d6) δ 175.4, 151.4 (2), 147.6, 144.4, 142.1, 138.5, 132.0, 128.1, 126.2, 123.4, 123.1, 121.1, 114.0, 113.7, 110.3, 57.3, 57.1, 55.5, 41.1, 39.0 (3), 36.5 (3), 27.9 (3), 26.44. C30H33ClN2O4 [M-Cl]+: 485.243 5, found: 485.241 8
11 35 186-188 1H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.21 (s, 1H), 8.27 (d, J = 9.1 Hz, 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.91 (s, 1H), 7.24 (s, 1H), 4.99 (t, J = 6.3 Hz, 2H), 4.12 (s, 3H), 4.10 (s, 3H), 3.95 (s, 3H), 3.24 (t, J = 6.3 Hz, 2H), 2.08-2.04 (m, 3H), 2.04-2.00 (m, 6H), 1.78–1.71 (m, 6H). 13C NMR (126 MHz, DMSO-d6) δ 175.2, 151.5, 151.4, 146.6, 144.4, 142.5, 137.5, 133.3, 128.6, 127.4, 125.9, 124.4, 123.5, 122.4, 121.9, 110.7, 62.6, 57.7, 57.3, 56.0, 41.2, 39.0 (3), 36.5 (3), 27.9 (3), 26.1. C31H34ClNO5 [M-Cl]+: 500.243 2, found: 500.243 4
), ArticleFig(id=1218968409358909558, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263398471618896, language=CN, label=Table 1, caption=

Physical properties and spectra data of all newly synthesized compounds

, figureFileSmall=null, figureFileBig=null, tableContent=
No. Yield /% mp/℃ (Dec.) 1H NMR 13C NMR HR-ESI-MS (m/z)
2a 35 190-192 1H NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.08 (s, 1H), 8.29 (d, J = 9.2 Hz, 1H), 8.21 (d, J = 9.2 Hz, 1H), 7.82 (s, 1H), 7.10 (s, 1H), 6.18 (s, 2H), 4.98 (t, J = 6.4 Hz, 2H), 4.03 (s, 3H), 3.23 (t, J = 6.4 Hz, 2H), 2.88 (t, J = 7.3 Hz, 2H), 1.77 (h, J = 7.3 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 171.2, 151.0, 150.6, 148.3, 145.1, 138.7, 134.2, 133.5, 131.5, 127.3, 126.5, 121.8, 121.2, 121.0, 109.1, 106.2, 102.8, 57.8, 55.8, 35.7, 26.8, 18.5, 14.0. C23H22ClNO5 [M-Cl]+: 392.148 0, found: 392.149 2
2b 37 204-206 1H NMR (500 MHz, DMSO-d6) δ 9.52 (s, 1H), 9.08 (s, 1H), 8.29 (d, J = 9.2 Hz, 1H), 8.21 (d, J = 9.2 Hz, 1H), 7.84 (s, 1H), 7.12 (s, 1H), 6.19 (s, 2H), 4.98 (t, J = 6.3 Hz, 2H), 4.02 (s, 3H), 3.22 (t, J = 6.3 Hz, 2H), 2.18 (d, J = 3.0 Hz, 6H), 2.14-2.10 (m, 3H), 1.79 (t, J = 3.0 Hz, 6H). 13C NMR (126 MHz, DMSO-d6) δ 174.8, 150.8, 150.6, 148.4, 144.5, 138.7, 134.6, 133.6, 131.5, 127.2, 126.5, 121.6, 121.4, 121.0, 109.1, 106.2, 102.8, 57.9, 56.2, 41.6, 38.8 (3), 36.5 (3), 27.9 (3), 26.8. C30H30ClNO5 [M-Cl]+: 484.211 9, found: 484.212 3
2c 41 176-178 1H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.11 (s, 1H), 8.37 (d, J = 9.3 Hz, 1H), 8.34-8.31 (m, 1H), 8.29 (d, J = 9.2 Hz, 1H), 8.15 (d, J = 2.9 Hz, 1H), 7.95-7.86 (m, 2H), 7.85 (s, 1H), 7.11 (s, 1H), 6.20 (s, 2H), 4.90 (t, J = 6.5 Hz, 2H), 4.05 (s, 3H), 3.21 (t, J = 6.4 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 162.8, 151.0, 150.7, 149.2, 148.4, 145.2, 138.9, 133.7, 133.6, 132.2, 131.6, 130.8, 130.2, 128.0, 127.9, 126.5, 123.2, 121.7, 121.3, 121.0, 120.7, 109.1, 106.2, 102.8, 58.0, 55.9, 26.8. C27H19ClF3NO6 [M-Cl]+: 510.115 9, found: 510.114 0
2d 33 180-182 1H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.12 (s, 1H), 8.36 (d, J = 9.3 Hz, 1H), 8.34 (t, J = 1.9 Hz, 1H), 8.29 (d, J = 9.2 Hz, 1H), 8.25 (dt, J = 7.8, 1.5 Hz, 1H), 7.93 (dt, J = 7.8, 1.5 Hz, 1H), 7.85 (s, 1H), 7.73 (t, J = 7.8 Hz, 1H), 6.19 (s, 2H), 4.98 (s, 2H), 4.91 (t, J = 6.4 Hz, 2H), 4.04 (s, 3H), 3.21 (t, J = 6.4 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 163.7, 151.0, 150.6, 148.4, 145.2, 139.5, 138.8, 135.6, 134.1, 133.6, 131.5, 131.2, 131.0, 130.3, 129.0, 127.7, 126.5, 121.8, 121.3, 121.0, 109.1, 106.2, 102.8, 57.9, 55.9, 45.9, 26.8. C27H21Cl2NO5 [M-Cl]+: 474.110 3, found: 474.108 6
2e 27 193-195 1H NMR (500 MHz, methanol-d4) δ 9.82 (s, 1H), 8.88 (s, 1H), 8.32 (d, J = 9.2 Hz, 1H), 8.28 (d, J = 9.2 Hz, 1H), 7.73 (s, 1H), 6.99 (s, 1H), 6.14 (s, 2H), 5.01-4.93 (m, 2H), 4.12 (s, 3H), 3.28 (t, J = 6.3 Hz, 2H), 2.84 (s, 3H), 2.56 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 177.9, 160.5, 159.6, 151.2, 150.7, 148.4, 145.1, 138.9, 133.6, 133.2, 131.6, 127.8, 126.5, 121.9, 121.3, 121.0, 109.1, 108.1, 106.2, 102.8, 58.0, 55.9, 26.8, 14.2, 12.3. C25H21ClN2O6 [M-Cl]+: 445.139 4, found: 445.137 7
2f 34 180-182 1H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.38 (d, J = 1.8 Hz, 1H), 9.19 (d, J = 2.3 Hz, 1H), 9.09 (s, 1H), 8.82 (t, J = 2.1 Hz, 1H), 8.37 (d, J = 9.2 Hz, 1H), 8.29 (d, J = 9.1 Hz, 1H), 7.84 (s, 1H), 7.12 (s, 1H), 6.20 (s, 2H), 4.89 (t, J = 6.3 Hz, 2H), 4.06 (s, 3H), 3.22 (t, J = 6.5 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 172.7, 161.8, 156.2, 151.0, 150.7, 150.0, 148.4, 145.2, 140.7, 139.0, 133.6, 133.3, 131.6, 128.0, 126.6, 121.5, 121.3, 121.2, 121.0, 109.1, 106.2, 102.8, 58.0, 56.0, 26.8. C25H18BrClN2O5 [M-Cl]+: 505.039 4, found: 505.037 5
5a 30 225-227 1H NMR (500 MHz, methanol-d4) δ 9.47 (s, 1H), 8.79 (s, 1H), 8.26 (d, J = 9.2 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.69 (s, 1H), 6.99 (s, 1H), 6.13 (s, 2H), 5.02-4.93 (m, 2H), 4.12 (s, 3H), 3.32-3.23 (m, 3H), 2.65 (t, J = 7.4 Hz, 2H), 1.86 (h, J = 7.4 Hz, 2H), 1.13 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 173.2, 154.9, 150.5, 148.3, 146.8, 138.0, 133.8, 131.3, 127.9, 125.8, 124.6, 122.5, 121.4, 121.1, 109.1, 106.1, 102.8, 57.6, 55.9, 38.1, 26.9, 19.1, 14.4. C23H23ClN2O4 [M-Cl]+: 391.164 0, found: 391.165 2
5b 43 242-244 1H NMR (500 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.29 (d, J = 4.6 Hz, 1H), 8.21 (s, 2H), 7.82 (s, 1H), 7.11 (s, 1H), 6.18 (s, 2H), 5.00 (t, J = 6.3 Hz, 2H), 4.07-3.96 (m, 3H), 3.21 (t, J = 6.3 Hz, 2H), 2.07 (s, 9H), 1.76 (s, 6H). 13C NMR (126 MHz, DMSO-d6) δ 177.9, 155.2, 150.3, 148.1, 146.0, 137.8, 133.6, 131.2, 127.9, 125.7, 124.9, 122.9, 121.3, 120.9, 108.9, 106.0, 102.5, 57.5, 56.0, 41.3, 38.9, 36.6 (3), 28.2 (3), 26.8 (3). C30H31ClN2O4Cl [M-Cl]+: 483.227 8, found: 483.228 0
5c 37 245-247 1H NMR (500 MHz, DMSO-d6) δ 10.69 (s, 1H), 9.82 (s, 1H), 9.06 (s, 1H), 8.29 (s, 2H), 8.20 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.82-7.68 (m, 2H), 7.10 (s, 1H), 6.19 (s, 2H), 4.96 (t, J = 6.1 Hz, 2H), 4.05 (s, 3H), 3.20 (t, J = 6.2 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 165.1, 155.3, 150.3, 148.8, 148.1, 146.4, 138.1, 136.2, 133.7, 131.2, 131.1, 128.5, 127.8, 125.7, 120.6, 125.0, 124.8, 121.7, 121.3, 121.2, 120.9, 108.8, 106.0, 102.5, 57.5, 55.6, 26.7. C27H20F3N2 O5 [M-Cl]+: 509.131 9, found: 509.129 9
5d 39 256-258 1H NMR (500 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.05 (s, 1H), 8.28 (s, 2H), 8.20-8.17 (m, 1H), 8.14 (d, J= 7.8 Hz, 1H), 7.84 (s, 1H), 7.76-7.72 (m, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.10 (s, 1H), 6.19 (s, 2H), 4.96 (t, J = 6.4 Hz, 2H), 4.90 (s, 2H), 4.04 (s, 3H), 3.20 (t, J = 6.4 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 166.2, 155.3, 150.2, 148.2, 146.4, 138.5, 138.1, 134.4, 133.7, 132.9, 131.2, 129.3, 129.2, 128.6, 128.3, 125.7, 124.9, 122.2, 121.3, 121.0, 108.9, 106.0, 102.6, 57.4, 55.6, 46.2, 26.7. C27H22Cl2N2O4 [M-Cl]+: 473.126 4, found: 473.124 8
5e 28 243-245 1H NMR (500 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.80 (s, 1H), 9.06 (s, 1H), 8.27 (s, 2H), 7.84 (s, 1H), 7.11 (s, 1H), 6.19 (s, 2H), 4.98 (t, J = 6.4 Hz, 2H), 4.07 (s, 3H), 3.21 (t, J = 6.4 Hz, 2H), 2.71 (s, 3H), 2.45 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 171.4, 161.9, 159.3, 155.0, 150.3, 148.1, 146.4, 138.0, 133.6, 131.2, 128.3, 125.6, 124.5, 121.6, 121.2, 120.9, 113.1, 108.9, 106.0, 102.5, 57.5, 55.7, 26.7, 13.1, 11.3. C25H22ClN3O5 [M-Cl]+: 444.155 4, found: 444.153 8
5f 36 205-207 1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.84 (s, 1H), 9.23 (s, 1H), 9.06 (s, 1H), 9.01 (d, J = 2.2 Hz, 1H), 8.72 (s, 1H), 8.29 (s, 2H), 7.84 (s, 1H), 7.11 (s, 1H), 6.19 (s, 2H), 4.95 (t, J = 6.3 Hz, 2H), 4.06 (s, 3H), 3.21 (t, J = 6.3 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 172.5, 164.1, 155.3, 153.6, 150.4, 148.3, 148.2, 146.3, 138.7, 138.3, 133.7, 131.2, 128.7, 125.7, 124.7, 121.3, 121.1, 120.9, 120.5, 108.9, 106.0, 102.6, 57.5, 56.5, 26.7. C25H19BrClN3O4 [M-Cl]+: 504.055 4, found: 504.053 5
7 30 102-104 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 10.06 (s, 1H), 8.79 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.89 (s, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.51-6.46 (m, 1H), 6.39 (dd, J = 8.3, 2.4 Hz, 1H), 4.80 (t, J = 6.5 Hz, 2H), 4.65 (d, J = 6.5 Hz, 2H), 3.93 (s, 3H), 3.84 (s, 3H), 3.77 (s, 3H), 3.70 (s, 3H), 3.15 (t, J = 6.3 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 160.4, 158.5, 150.4, 148.4, 147.7, 146.8, 137.3, 137.0, 133.9, 130.2, 129.0, 125.0, 120.4, 119.6, 118.4, 118.0, 117.4, 115.6, 109.9, 104.7, 98.9, 57.5, 56.8, 56.0, 55.8 (2), 46.9, 26.7. C28H29ClN2O5 [M-Cl]+: 473.207 1, found: 473.205 4
8 80 207-209 1H NMR (600 MHz, DMSO-d6) δ 10.20 (d, J = 5.7 Hz, 1H), 9.92 (s, 1H), 8.65 (s, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.62 (s, 1H), 7.31 (d, J = 8.6 Hz, 1H), 6.82 (s, 1H), 6.81 (s, 2H), 4.67 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.11 (t, J = 6.3 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 150.1, 148.4, 147.0, 143.7, 138.1, 136.3, 132.6, 128.8, 123.3, 119.2, 118.6, 115.6, 113.9, 113.2, 109.8, 57.1, 56.8, 55.5, 26.8. C19H19ClN2O3 [M-Cl]+: 323.139 0, found: 323.138 0
9 38 153-155 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.97 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.22 (s, 1H), 7.15 (d, J = 8.3 Hz, 1H), 6.58 (t, J = 6.5 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.41 (dd, J = 8.3, 2.4 Hz, 1H), 4.85 (t, J = 6.2 Hz, 2H), 4.68 (d, J = 6.4 Hz, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.77 (s, 3H), 3.71 (s, 3H), 3.23 (t, J = 6.3 Hz, 2H), 2.09-2.04 (m, 3H), 2.03-1.99 (m, 6H), 1.78-1.71 (m, 6H). 13C NMR (126 MHz, DMSO-d6) δ 175.2, 160.5, 158.5, 151.4, 148.3, 147.5, 142.2, 137.7, 135.6, 133.2, 130.2, 128.2, 126.1, 124.7, 123.4, 121.6, 120.3, 118.2, 117.7, 110.4, 104.8, 98.9, 57.5, 57.3, 55.8, 55.8, 55.7, 46.9, 41.1, 39.0 (3), 36.5 (3), 27.9 (3), 26.4. C39H43ClN2O6 [M-Cl]+: 635.308 7, found: 635.311 7
10 76 215-217 1H NMR (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 10.45 (s, 1H), 8.87 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.84 (s, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.20 (s, 1H), 7.02 (s, 2H), 4.76 (t, J = 6.3 Hz, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 3.22 (t, J = 6.2 Hz, 2H), 2.10-2.04 (m, 3H), 2.04-1.96 (m, 6H), 1.81-1.67 (m, 6H). 13C NMR (126 MHz, DMSO-d6) δ 175.4, 151.4 (2), 147.6, 144.4, 142.1, 138.5, 132.0, 128.1, 126.2, 123.4, 123.1, 121.1, 114.0, 113.7, 110.3, 57.3, 57.1, 55.5, 41.1, 39.0 (3), 36.5 (3), 27.9 (3), 26.44. C30H33ClN2O4 [M-Cl]+: 485.243 5, found: 485.241 8
11 35 186-188 1H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.21 (s, 1H), 8.27 (d, J = 9.1 Hz, 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.91 (s, 1H), 7.24 (s, 1H), 4.99 (t, J = 6.3 Hz, 2H), 4.12 (s, 3H), 4.10 (s, 3H), 3.95 (s, 3H), 3.24 (t, J = 6.3 Hz, 2H), 2.08-2.04 (m, 3H), 2.04-2.00 (m, 6H), 1.78–1.71 (m, 6H). 13C NMR (126 MHz, DMSO-d6) δ 175.2, 151.5, 151.4, 146.6, 144.4, 142.5, 137.5, 133.3, 128.6, 127.4, 125.9, 124.4, 123.5, 122.4, 121.9, 110.7, 62.6, 57.7, 57.3, 56.0, 41.2, 39.0 (3), 36.5 (3), 27.9 (3), 26.1. C31H34ClNO5 [M-Cl]+: 500.243 2, found: 500.243 4
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基于阻断IL-6/STAT信号通路的全新小檗碱衍生物的设计、合成及其抗炎作用评价
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曾庆轩 , 张娜 , 邓洪斌 , 宋丹青 , 蒋建东 , 汪燕翔 *
药学学报 | 研究论文 2017,52(12): 1895-1902
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药学学报 | 研究论文 2017, 52(12): 1895-1902
基于阻断IL-6/STAT信号通路的全新小檗碱衍生物的设计、合成及其抗炎作用评价
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曾庆轩, 张娜, 邓洪斌, 宋丹青, 蒋建东, 汪燕翔*
作者信息
  • 中国医学科学院、北京协和医学院医药生物技术研究所, 北京 100050

通讯作者:

* 汪燕翔, Tel:86-10-63033012, E-mail:
Design, synthesis and evaluation of anti-inflammatory effect of novel berberine derivatives on IL-6/STAT signaling pathway
Qing-xuan ZENG, Na ZHANG, Hong-bin DENG, Dan-qing SONG, Jian-dong JIANG, Yan-xiang WANG*
Affiliations
  • Institute of Medicinal Biotechnology, China Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
出版时间: 2017-12-12 doi: 10.16438/j.0513-4870.2017-0835
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白介素-6（IL-6）/转录激活因子（STAT）信号通路的活化与动脉粥样硬化（AS）的发生发展密切相关。本研究以我国天然产物单体盐酸小檗碱（BBR）为先导物，通过在其3-位或/和9-位引入不同类型的侧链基团，设计合成了一系列全新结构BBR衍生物，并对其抑制IL-6诱导的STAT1/3的磷酸化进行了评价。构效关系表明，3-位或9-位引入刚性结构有利于活性提高，其中，化合物2b和9显示出最优的抑制活性。进一步研究提示，化合物2b和9通过激活HUVEC细胞中AMPK活性，抑制IL-6诱导的STAT1和STAT3磷酸化。研究结果显示，BBR衍生物通过AMPK途径抑制IL-6/STAT信号通路介导的炎症反应，为此类化合物发展成为抗AS候选物提供了有益的科学数据。

小檗碱  /  动脉粥样硬化  /  构效关系  /  IL-6  /  STAT-1/3

Interleukin-6 (IL-6)/signal transducers and activators of transcription (STAT) signaling pathway is closely related to the development and progression of atherosclerosis (AS). Taking Chinese natural product berberine (BBR) as the leading compound, a series of novel BBR analogues defined on different types of substituents on position 3 or/and 9 were designed, synthesized and evaluated for their inhibitory activities on phosphorylation of STAT-1 and STAT-3 induced by IL-6. The structure-activity relationship indicated that introduction of rigid fragment on position 3 or 9 was beneficial for enhancing their activities. Among them, compounds 2b and 9 exhibited the most satisfactory potency. The study revealed that the compounds 2b and 9 exhibit anti-inflammatory potencies via activating AMPK, and down-regulation of phosphorylation of STAT1 and STAT3 induced by IL-6 in HUVEC cells. These results suggest that BBR derivatives may inhibit the inflammatory response mediated by the IL-6/STAT signaling pathway through regulation of AMPK, which provides useful insight into the development of BBR derivatives for treatment of atherosclerosis.

berberine  /  atherosclerosis  /  structure-activity relationship  /  IL-6  /  STAT-1/3
曾庆轩, 张娜, 邓洪斌, 宋丹青, 蒋建东, 汪燕翔. 基于阻断IL-6/STAT信号通路的全新小檗碱衍生物的设计、合成及其抗炎作用评价. 药学学报, 2017 , 52 (12) : 1895 -1902 . DOI: 10.16438/j.0513-4870.2017-0835
Qing-xuan ZENG, Na ZHANG, Hong-bin DENG, Dan-qing SONG, Jian-dong JIANG, Yan-xiang WANG. Design, synthesis and evaluation of anti-inflammatory effect of novel berberine derivatives on IL-6/STAT signaling pathway[J]. Acta Pharmaceutica Sinica, 2017 , 52 (12) : 1895 -1902 . DOI: 10.16438/j.0513-4870.2017-0835
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动脉粥样硬化(atherosclerosis, AS)作为一种慢性炎症性疾病, 是多种心脑血管疾病的共同病理基础, 严重威胁人类的生命健康[1-3]。白细胞介素6 (interleukin-6, IL-6)作为一种前炎症因子, 在斑块形成和发展中起着重要的作用, 被认为是AS发生和发展的主要致病因子之一[1, 4, 5]。IL-6与受体结合后活化细胞膜表面的糖蛋白130 (gp130), 可以诱导下游信号转导和转录激活因子(STAT)活化, 进而引发炎症反应[6]。研究表明STAT在AS病变中可被激活, 活化的STAT在人类AS的炎症区域增多, 提示IL-6/ STAT信号转导通路在AS的发生、发展中的重要作用[7, 8], 通过抑制IL-6/STAT信号通路介导的炎症反应, 可能为寻找新型抗AS候选物提供一种新的思路和策略。
盐酸小檗碱(berberine, BBR, 图 1)作为我国传统中药单体, 安全性良好, 具有抗菌、抗炎、降血脂等广泛的药理活性[9-13]。研究表明, 在150 mg·kg-1剂量下, BBR可以减少ApoE基因敲除小鼠动脉粥样硬化斑块, 显示出中度的抗AS活性[14]。鉴于本课题组长期致力于从我国生物碱天然产物中寻找创新药物[15-18], 本研究以BBR为先导物, 主要在其3-位或/和9-位(图 1)引入不同类型的侧链基团, 包括短链烷基、刚性大基团、杂环和芳香性基团等, 由此设计合成了17个全新的BBR酯类、酰胺以及胺类衍生物。通过并测定其对IL-6诱导的STAT1和STAT3磷酸化的抑制活性, 总结构效关系。并进一步证实此类化合物是通过抑制AMPK磷酸化水平抑制炎症反应。
首先, 以市售BBR为原料, 在高温真空条件下, 选择性脱除9-位甲基, 而后在碱性条件下与相应的酰氯反应得到9-位酯类化合物2a~2f (合成路线1)。以BBR为原料, 在高温条件下加入2, 4-二甲氧基苄胺, 获得重要中间体3。强酸条件下裸露出9-氨基后, 以吡啶为缚酸剂, 制得9-位酰胺类衍生物5a~5f。另外, 以市售药根碱(6)为起始原料, 在高温条件下获得9-位取代氨基衍生物7, 酸性条件下裸露出氨基制备出化合物8。在化合物7的3-位进行酯化反应, 得金刚烷甲酯衍生物9, 盐酸脱苄后得氨基化合物10。最后, 以乙腈为溶剂, 在三乙胺催化下转化为对应的3-位酯类目标物11 (合成路线2)。
结果与讨论
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1 化合物的合成
所有目标化合物结构经1H NMR、13C NMR以及HR-MS分析确证。化合物的理化性质及图谱数据见表 1。
2 体外活性筛选
磷酸化的STAT (p-STAT)是STAT的活化形式, 其中STAT1络氨酸701 (Tyr701)位点和STAT3络氨酸705 (Tyr705)位点的磷酸化分别是两者活化的标志。使用Western blotting的方法, 在人血管内皮细胞(HUVEC)中对新合成的化合物(2a~2f、5a~5f以及7~11)抑制IL-6诱导的p-STAT1 (Tyr701)和p-STAT3 (Tyr705)的磷酸化进行了筛选, 结果如图 2所示。首先, 在6个9-位取代BBR酯型衍生物2a~2f中, 金刚烷甲酯衍生物2b可以明显抑制IL-6/ STAT1和IL-6/STAT3磷酸化; 而脂肪链(化合物2a)、芳香环(化合物2c和2d)以及杂环取代(化合物2e和2f)衍生物的活性则明显下降或完全丧失。随后, 将BBR的9-位氧原子替换为氮原子, 得到了6个与酯类衍生物对应的酰胺类衍生物5a~5f。结果显示, 所有酰胺衍生物的抗炎活性均在不同程度上有所下降, 说明9-位酯键连接刚性片段时有利于活性提高。
据此, 将BBR的A环亚甲二氧基打开, 在3-位引入金刚烷活性片段; 同时在其9-位分别引入氨基或者2, 4-二甲氧基苄胺等基团, 共设计合成了5个全新衍生物。结果显示, 当3-位缺少金刚烷片段(化合物7和8), 或9-位没有芳香体系存在(化合物10和11)时, 所得衍生物的抗炎活性均有不同程度的降低。而当3-位引入金刚烷片段, 同时9-位为2, 4-二甲氧基苄胺取代时, 化合物9对STAT1和STAT3的活化显示出良好的抑制活性, 提示3-位存在刚性片段的同时, 在9-位引入芳香体系有利于抗炎活性的提高。
鉴于AMPK激活后可抑制STAT信号途径从而发挥其抑制炎症反应[19, 20], 进一步探讨了此类衍生物抑制STAT通路的初步机制。通过Western blotting方法, 在HUVEC细胞中检测了目标化合物对AMPK磷酸化水平的影响, 结果如图 3所示。结果显示, 代表性化合物2b和9能显著增加AMPK和下游因子ACC磷酸化水平, 表明化合物2b和9可以激活AMPK。此结果与STAT1/3磷酸化的抑制活性相对应, 提示化合物2b和9可以通过激活AMPK从而抑制IL-6诱导的STAT1/3的磷酸化。
结论
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本研究以酯键、酰胺键等作为连接臂, 在BBR的9-位或/和3-位引入短链烷基、刚性基团、杂环以及取代芳环等不同类型取代基, 共设计合成了17个全新的BBR酯类、酰胺和胺类衍生物, 并对其抑制由IL-6诱导的STAT1和STAT3磷酸化进行了评价。构效关系显示, 3-位或9-位刚性结构的引入有利于活性的提高。其中, 化合物2b和9表现出最优的抑制活性, 进一步研究提示, 两者可以通过激活AMPK抑制IL-6诱导的STAT1和STAT3磷酸化, 进而抑制IL-6/STAT信号通路介导的炎症反应。研究结果为BBR衍生物发展成为一类新型抗AS候选物提供了良好的构效关系与科学数据。
实验部分
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熔点用CXM-300型精密熔点仪测定, 温度未校正; 1H NMR和13C NMR用Bruker Avance Ⅲ 500和600核磁共振仪测定(500/600 MHz), 溶剂为DMSO-d6或methanol-d4; HR-MS用Autospec Ultima-TOF质谱测定仪测定; Flash柱分离纯化用Combiflash Rf 200快速制备液相; 荧光检测用ZF-20D暗箱式紫外分析仪; 薄层色谱(TLC)采用E-Merck公司预铺硅胶铝箔卷; 试剂均为分析纯。
Medium 200培养基、低血清生长添加剂(LSGS)和胎牛血清购自美国Gibco公司。丙烯酰胺、甲叉双丙烯酰胺、十二烷基磺酸钠(SDS)、Tris碱、过硫酸铵及Tween-20均购自美国Amresco公司。蛋白酶抑制剂(Cocktail)购自美国Sigma公司。磷酸化STAT3 (p-STAT3 Tyr705)抗体、磷酸化STAT1 (p-STAT1 Tyr701)抗体、磷酸化ACC (p-ACC Ser79)抗体、磷酸化AMPK (p-AMPK Tyr172)抗体、STAT3抗体、STAT1抗体、ACC抗体和AMPK抗体购自美国Cell Signaling公司。β-Actin抗体和羊抗兔或小鼠二抗均购自美国Santa Cruz公司。白介素6刺激因子sIL-6Ra和IL-6均购自美国Invivogen公司。PVDF膜购自美国Millipore公司。ECL Plus超敏免疫印迹检测试剂盒购自美国Bio-RAD公司。其他试剂均为国产分析纯。
1 化学合成
1.1 化合物2a~2f的合成
BBR (3.71 g, 10 mmol)在195~210 ℃减压(30~40 mmHg)加热30 min得紫黑色油状物。产物经5%盐酸/甲醇酸化, 减压除去溶剂, 以二氯甲烷/甲醇为流动相, 经硅胶柱分离纯化得橙红色固体1 (2.85 g, 80%)。
化合物1 (100 mg, 0.28 mmol)溶于5 mL无水乙腈中, 加入三乙胺(175 μL, 1.26 mmol)和相应酰氯(1.1~1.2 eq), 70 ℃反应5~6 h。冷却至固体完全析出, 抽滤, 沉淀以大量二氯甲烷洗, 得目标化合物2a~2f。
1.2 化合物5a~5f的合成
BBR (7.4 g, 20 mmol)加于2, 4-二甲氧基苄胺15 mL (78 mmol)中, 120 ℃加热反应6~8 h。冷却至室温, 加入丙酮50 mL, 搅拌, 抽滤, 丙酮2×50 mL洗涤。固体经硅胶柱, 以二氯甲烷/甲醇为流动相分离纯化得红色化合物3 (3.5 g, 37%)。
化合物3 (3 g, 6.4 mmol)溶于甲醇中, 加入浓盐酸3 mL, 室温搅拌5~6 h, 抽滤, 沉淀以80%乙醇洗涤, 得红色化合物4 (1.8 g, 80 %)。
化合物4 (100 mg, 0.28 mmol)于5 mL无水二氯甲烷中, 加入吡啶(100 μL, 1.24 mmol)和相应酰氯(2~3 eq), 回流反应10~12 h。减压除去溶剂, 以二氯甲烷/甲醇为流动相, 经硅胶柱分离纯化得。目标化合物5a~5f。
1.3 化合物7~10的合成
药根碱(6, 2 g, 5.8 mmol)于2, 4-二甲氧基苄胺5 mL (23 mmol)中, 120 ℃加热反应6~8 h。冷却至室温, 加入乙醚20 mL, 抽滤, 以乙醚2×20 mL洗涤, 除去未反应的胺。沉淀以二氯甲烷/甲醇为流动相, 经硅胶柱分离纯化得红色化合物7 (0.8 g, 30%)。
化合物7 (100 mg, 0.21 mmol), 加入2 mol·L-1盐酸乙醚2 mL, 室温搅拌5~6 h, 抽滤, 沉淀以80%乙醇洗涤, 得红色化合物8 (54 mg, 80%)。
化合物7 (0.5 g, 1.05 mmol)溶于5 mL无水乙腈中, 加入三乙胺(175 μL, 1.26 mmol)、金刚烷甲酰氯(235 mg, 1.2 mmol), 70 ℃反应5~6 h。减压除去溶剂, 加入二氯甲烷50 mL, 以0.5%盐酸20 mL、饱和食盐水2×20 mL洗涤, 无水硫酸钠干燥, 浓缩。产物以二氯甲烷/甲醇为流动相, 经硅胶柱分离纯化得红色化合物9 (0.38 g, 38%)。
化合物9 (100 mg, 0.16 mmol), 加入盐酸乙醚2 mL, 室温搅拌5~6 h, 抽滤, 沉淀以80%乙醇洗涤, 得红色化合物10 (58 mg, 76%)。
1.4 化合物11的合成
药根碱(100 mg, 0.29 mmol)溶于5 mL无水乙腈中, 加入三乙胺(175 μL, 1.26 mmol)和金刚烷甲酰氯(62 mg, 0.32 mmol), 70 ℃反应5~6 h。冷却至固体完全析出, 抽滤, 沉淀以大量二氯甲烷洗, 得黄色化合物11 (51 mg, 35%)。
2 生物学实验
2.1 细胞培养及化合物处理
人血管内皮细胞HUVEC购自美国ATCC。使用含有10%胎牛血清、2% LSGS、100 u·mL-1青霉素、100 μg·mL-1硫酸链霉素的M200完全培养基, 在饱和湿度、37 ℃、5% CO2条件下进行细胞培养。当细胞生长至约80%~90%汇合时, 将细胞按1：3进行传代培养。实验中合成的化合物均溶于DMSO中, IL-6和IL-6Ra溶于PBS缓冲液中。使用10 μmol·L-1的化合物作用细胞2 h后, 再加入sIL-6Ra (25 ng·mL-1)和IL-6 (5 ng·mL-1)处理30 min, 而后收集细胞进行蛋白免疫印迹分析。
2.2 Western blotting
将处理后的细胞用细胞刮刀刮下, 1 200×g离心收集细胞。加入适量裂解液(50 mmol·L-1 Tris-HCl pH 7.5, 1% Triton-100, 150 mmol·L-1NaCl, 2 mmol·L-1 EDTA, 1×Cocktail), 冰上放置30 min, 然后14 000×g离心15 min, 收集上清液即为蛋白提取液。用标准Bradford方法测定样品的蛋白浓度。于12% SDS聚丙烯酰胺凝胶电泳分离蛋白, 半干法将蛋白转至PVDF膜。转膜结束后, 将其放入含5%脱脂奶粉的TBS-T (20 mmol·L-1 Tris-HCl、150 mmol·L-1 NaCl、0.1% Tween-20, pH 7.6)中振荡封闭1 h。封闭后的膜装入杂交袋与一抗溶液(1：1 000稀释) 4 ℃孵育过夜, 用TBS-T洗膜3次, 以洗去未结合的一抗。与辣根过氧化物酶标记的二抗溶液(抗兔二抗1：2 000稀释、抗鼠二抗1：5 000稀释)在室温孵育1~2 h后, TBS-T洗膜3次, 按照ECL Plus免疫试剂盒说明书进行显色, 通过Tanon-5100凝胶成像系统(上海天能科技有限公司)捕获并分析图像。
基金
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  • 中国医学科学院医学与健康科技创新工程资助(2016-12M-1-011)
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参考文献 引证文献
排序方式：
[1]
van Diepen JA, Berbee JF, Havekes LM, et al. Interactions between inflammation and lipid metabolism:relevance for efficacy of anti-inflammatory drugs in the treatment of atherosclerosis[J]. Atherosclerosis, 2013, 228:306-315.
[2]
Taleb S. Inflammation in atherosclerosis[J]. Arch Cardiovasc Dis, 2016, 109:708-715.
[3]
Viola J, Soehnlein O. Atherosclerosis-a matter of unresolved inflammation[J]. Semin Immunol, 2015, 27:184-193.
[4]
Marciniak A, Nawrocka Rutkowska J, Brodowska A, et al. Cardiovascular system diseases in patients with polycystic ovary syndrome-the role of inflammation process in this pathology and possibility of early diagnosis and prevention[J]. Ann Agric Environ Med, 2016, 23:537-541.
[5]
Hartman J, Frishman WH. Inflammation and atherosclerosis:a review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy[J]. Cardiol Rev, 2014, 22:147-151.
[6]
Rutherford C, Speirs C, Williams JJ, et al. Phosphorylation of Janus kinase 1(JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling[J]. Sci Signal, 2016, 9:ra109.
[7]
Voloshyna I, Littlefield MJ, Reiss AB. Atherosclerosis and interferon-gamma:new insights and therapeutic targets[J]. Trends Cardiovasc Med, 2014, 24:45-51.
[8]
Szelag M, Piaszyk-Borychowska A, Plens-Galaska M, et al. Targeted inhibition of STATs and IRFs as a potential treatment strategy in cardiovascular disease[J]. Oncotarget, 2016, 7:48788-48812.
[9]
Yao J, Kong W, Jiang JD. Learning from berberine:treating chronic diseases through multiple targets[J]. Sci China Life Sci, 2015, 58:854-859.
[10]
Heidarian E, Rafieian-Kopaei M, Khoshdel A, et al. Metabolic effects of berberine on liver phosphatidate phosphohydrolase in rats fed on high lipogenic diet:an additional mechanism for the hypolipidemic effects of berberine[J]. Asian Pac J Trop Biomed, 2014, 4:S429-S435.
[11]
Bi CW, Zhang CX, Li YB, et al. Synthesis and structure-activity relationship of cycloberberine as anti-cancer agent[J]. Acta Pharm Sin (药学学报), 2013, 48:1800-1806.
[12]
Li YH, liu YX, Wang YX, et al. Synthesis and biological evaluation of new 13-n-nonylprotoberberine derivatives as antitubercular agents[J]. Acta Pharm Sin B, 2013, 3:38-45.
[13]
Wang YX, Fu HG, Li YH, et al. Synthesis and biological evaluation of 8-substituted berberine derivatives as novel anti-mycobacterial agents[J]. Acta Pharm Sin B, 2012, 2:581-587.
[14]
Feng M, Zou Z, Zhou X, et al. Comparative effect of berberine and its derivative 8-cetylberberine on attenuating atherosclerosis in ApoE-/- mice[J]. Int Immunopharmacol, 2017, 43:195-202.
[15]
Wang YX, Kong WJ, Li YH, et al. Synthesis and structure-activity relationship of berberine analogues in LDLR up-regulation and AMPK activation[J]. Bioorg Med Chem, 2012, 20:6552-6558.
[16]
Ma Y, Ou TM, Tan JH, et al. Quinolino-benzo-[5, 6]-dihydroisoquindolium compounds derived from berberine:a new class of highly selective ligands for G-quadruplex DNA in c-myc oncogene[J]. Eur J Med Chem, 2011, 46:1906-1913.
[17]
Li YH, Wang L, Hong B, et al. Synthesis and structure-activity relationship of 13-hexylberberine analogues as CD36 antagonists[J]. Acta Pharm Sin (药学学报), 2010, 45:1128-1133.
[18]
Ren G, Zhang MR, Song DQ, et al. Study on hypoglycemic activity of 9-substituted berberine derivatives in vitro[J]. Acta Pharm Sin (药学学报), 2017, 52:1282-1286.
[19]
Mancini SJ, White AD, Bijland S, et al. Activation of AMP-activated protein kinase rapidly suppresses multiple pro-inflammatory pathways in adipocytes including IL-1 receptor-associated kinase-4 phosphorylation[J]. Mol Cell Endocrinol, 2017, 440:44-56.
[20]
Kelly M, Keller C, Avilucea PR, et al. AMPK activity is diminished in tissues of IL-6 knockout mice:the effect of exercise[J]. Biochem Biophys Res Commun, 2004, 320:449-454.
2017年第52卷第12期
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doi: 10.16438/j.0513-4870.2017-0835
  • 接收时间：2017-08-28
  • 首发时间：2026-01-14
  • 出版时间：2017-12-12
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  • 收稿日期：2017-08-28
  • 修回日期：2017-09-27
基金
中国医学科学院医学与健康科技创新工程资助(2016-12M-1-011)
作者信息
    中国医学科学院、北京协和医学院医药生物技术研究所, 北京 100050

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* 汪燕翔, Tel:86-10-63033012, E-mail:
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
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红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
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红菇属 Russula 17 8.13
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