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Article(id=1196886678045508108, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1196886663541600644, articleNumber=1001-2494(2024)22-2116-10, orderNo=null, doi=10.11669/cpj.2024.22.003, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1697731200000, receivedDateStr=2023-10-20, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1763289621124, onlineDateStr=2025-11-16, pubDate=1732204800000, pubDateStr=2024-11-22, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763289621124, onlineIssueDateStr=2025-11-16, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763289621124, creator=13701087609, updateTime=1763289621124, updator=13701087609, issue=Issue{id=1196886663541600644, tenantId=1146029695717560320, journalId=1190317699101192196, year='2024', volume='59', issue='22', pageStart='2099', pageEnd='2196', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1763289617666, creator=13701087609, updateTime=1763292152892, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1196897297100488858, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1196886663541600644, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1196897297104683163, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1196886663541600644, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=2116, endPage=2125, ext={EN=ArticleExt(id=1196886678284583438, articleId=1196886678045508108, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Design, Synthesis and Evaluation of 3', 4'-Ethylendioxy Chalcone Derivatives as Potent Monoamine Oxidase B Inhibitors, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

OBJECTIVE To design, synthesize and evaluate a series of 3', 4'-ethylendioxy chalcone derivatives as monoamine oxidase B (MAO-B) inhibitors, and summarize the structure-activity relationship (SAR). METHODS The targeted compounds were synthesized via Claisen-Schmidt condensation reaction starting from 6-acetyl-1, 4-benzodioxan and corresponding benzaldehydes. The inhibition of these compounds on human MAO-B (hMAO-B) was determined, and the inhibiting selectivity, dynamics and reversibility were investigated as well. The binding mode between active compounds and hMAO-B was revealed by molecular docking study. Additionally, the inhibitory effect of active compounds on the proliferation of BV2 cell line was determined by MTT assay. RESULTS Sixteen targeted compounds were successfully prepared. Most compounds showed good inhibitory effects on hMAO-B. Representative compounds 9 and 13 exhibited IC50 values of 0.021 and 0.042 μmol·L-1, respectively, which showed high inhibiting selectivity towards hMAO-B. Both compounds acted as competitive and reversible hMAO-B inhibitors. The main interactions between active compounds and hMAO-B were hydrophobic interaction and hydrogen bond. The most active compound 9 exhibited low cytotoxicity in BV2 cells. CONCLUSION This class of 3', 4'-ethylendioxy chalcone derivatives represent potential novel inhibitors of hMAO-B, and compound 9 could be further investigated as a potent lead for future studies.

, correspAuthors=Yun HU, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, 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=Zhuo KONG, Demeng SUN, Yanmei JIANG, Yun HU), CN=ArticleExt(id=1196887006547592130, articleId=1196886678045508108, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=3',4'-亚乙二氧基查尔酮类MAO-B抑制剂的设计、合成及活性评价, columnId=1190352405612040510, journalTitle=中国药学杂志, columnName=论著, runingTitle=null, highlight=null, articleAbstract=

目的 设计合成一类3',4'-亚乙二氧基查尔酮类衍生物作为单胺氧化酶B(MAO-B)抑制剂。方法 通过Claisen-Schmidt缩合反应,合成目标化合物,测定其对人的单胺氧化酶(hMAO-B)的抑制作用。分析活性化合物抑制hMAO-B的选择性、作用类型和可逆性。探讨活性化合物与hMAO-B的结合模式。评价活性化合物对小鼠BV2细胞的增殖抑制作用。结果 成功合成16个化合物。多数化合物对hMAO-B具有良好的抑制活性和选择性,代表性化合物9和13的IC50值分别为0.021和0.042 μmol·L-1。二者均为MAO-B的竞争型可逆性抑制剂,与hMAO-B的结合作用力主要为疏水作用力和氢键。活性最好的化合物9对小鼠BV2小胶质细胞株表现出较低水平的细胞毒性。。结论 3',4'-亚乙二氧基查尔酮类化合物是一类高效的hMAO-B抑制剂,具有进一步研究价值。

, correspAuthors=胡云, authorNote=null, correspAuthorsNote=
* 胡云,男,博士,副教授 研究方向:药物化学 Tel: (0756)7623365
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孔卓,女,硕士研究生 研究方向:药物化学

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孔卓,女,硕士研究生 研究方向:药物化学

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DOI: 10.1016/j.bioorg.2012.08.003., articleTitle=Selected C7-substituted chromone derivatives as monoamine oxidase inhibitors, refAbstract=null)], funds=[Fund(id=1197125050911469817, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, awardId=81560562, language=CN, fundingSource=国家自然科学基金项目(81560562), fundOrder=null, country=null), Fund(id=1197125050978578682, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, awardId=21762055, language=CN, fundingSource=国家自然科学基金项目(21762055), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1197125047262425291, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, xref=null, ext=[AuthorCompanyExt(id=1197125047270813900, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, companyId=1197125047262425291, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=School of Bioengineering, Zunyi Medical University, Zhuhai 519041, China), AuthorCompanyExt(id=1197125047279202509, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, companyId=1197125047262425291, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=遵义医科大学生物工程学院, 广东 珠海 519041)])], figs=[ArticleFig(id=1197125048898203883, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, language=EN, label=Fig.1, caption=Common MAO inhibitors, chalcone and the design of 3', 4'-ethylendioxy chalcone derivatives

A-MAO inhibitors; B-chalcone and the design of 3', 4'-ethylendioxy chalcone derivatives.

, figureFileSmall=9vKi0l+2RhnIH3CKQl09Cg==, figureFileBig=BKH5GSnTa+IJSom4eIDXsA==, tableContent=null), ArticleFig(id=1197125048952729836, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, language=CN, label=图1, caption=常见的单胺氧化酶(MAO)抑制药物,查尔酮及其衍生物3',4'-亚乙二氧基查尔酮的设计

A-MAO抑制剂;B-查尔酮及3',4'-亚乙二氧基查尔酮类衍生物的设计。

, figureFileSmall=9vKi0l+2RhnIH3CKQl09Cg==, figureFileBig=BKH5GSnTa+IJSom4eIDXsA==, tableContent=null), ArticleFig(id=1197125049028227309, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, language=EN, label=Fig.2, caption=The synthetic routes of 3', 4'-ethylendioxy chalcone derivatives, figureFileSmall=1anhWYHP4q655pddfpHdrg==, figureFileBig=l3gCVKJ/wmWvs96C01poTw==, tableContent=null), ArticleFig(id=1197125049128890606, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, language=CN, label=图2, caption=3',4'-亚乙二氧基查尔酮类衍生物的合成路线, figureFileSmall=1anhWYHP4q655pddfpHdrg==, figureFileBig=l3gCVKJ/wmWvs96C01poTw==, tableContent=null), ArticleFig(id=1197125049183416559, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, language=EN, label=Fig.3, caption=Kinetic studies of enzymatic inhibition of compound 9 and 13 on hMAO-B

A-the kinetic result of enzymatic inhibition of compound 9 on hMAO-B; B-the kinetic result of enzymatic inhibition of compound 13 on hMAO-B; 1/V--the reciprocal of initial reaction velocity; 1/[S]-the reciprocal of concentrations of the substrate.

, figureFileSmall=HgUvdtA+XlX/4M7hatZdAw==, figureFileBig=4+OYVPK/Gk0MShoCRzQUWA==, tableContent=null), ArticleFig(id=1197125049237942512, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, language=CN, label=图3, caption=化合物9和13对hMAO-B抑制的动力学研究

A-化合物9对hMAO-B抑制的动力学结果;B-化合物13对hMAO-B抑制的动力学结果;1/V-酶反应速率的倒数;1/[S]-底物浓度的倒数.。

, figureFileSmall=HgUvdtA+XlX/4M7hatZdAw==, figureFileBig=4+OYVPK/Gk0MShoCRzQUWA==, tableContent=null), ArticleFig(id=1197125049296662769, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, language=EN, label=Fig.4, caption=Studies of time-dependent inhibition of tested compounds on hMAO-B

A-selegiline, rasagiline and safinamide; B-compound 9 and 13.

, figureFileSmall=UwRlOXv9694VXYjd/Hq9QQ==, figureFileBig=+KooiuNqX8+L3yAsY+cp0w==, tableContent=null), ArticleFig(id=1197125049367965938, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, language=CN, label=图4, caption=化合物对hMAO-B的时间依赖性抑制研究

A-司来吉兰、雷沙吉兰和沙芬酰胺;B-化合物9和13。

, figureFileSmall=UwRlOXv9694VXYjd/Hq9QQ==, figureFileBig=+KooiuNqX8+L3yAsY+cp0w==, tableContent=null), ArticleFig(id=1197125049430880499, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, language=EN, label=Fig.5, caption=Diagrams of molecular docking results of chalcone, compounds 2,9,13 with hMAO-A/B

A-chalcone and compound 2 docking with hMAO-B; B-Compound 9 and 13 docking with hMAO-B; C-the side view of molecular docking result of compound 9 and 13 with hMAO-B; D-compound 9 and 13 docking with hMAO-A; Gray-chalcone; Yellow-compound 2; Cyan-compound 9; Purple-compound 13; Blue line-hydrogen bond.

, figureFileSmall=jiIkrtFfSTKMSOdEkiyK0A==, figureFileBig=02ft6XIeKV/qWfLMoLr1yg==, tableContent=null), ArticleFig(id=1197125049497989364, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, language=CN, label=图5, caption=查尔酮及活性化合物2、9、13与hMAO-A/B的分子对接示意图

A-查尔酮、活性化合物2与hMAO-B的分子对接结果;B-活性化合物9、13与hMAO-B的分子对接结果;C-活性化合物9、13与hMAO-B对接的侧面示意图;D-活性化合物9、13与hMAO-A的分子对接结果;灰色分子-查尔酮;黄色分子-化合物2;青色分子-化合物9;紫色分子-化合物13;蓝色虚线-氢键。

, figureFileSmall=jiIkrtFfSTKMSOdEkiyK0A==, figureFileBig=02ft6XIeKV/qWfLMoLr1yg==, tableContent=null), ArticleFig(id=1197125049560903925, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, language=EN, label=Fig.6, caption=The inhibitory effects of compound 9 on the proliferation of BV2 cell line. n=3,$\bar{x}±s$, figureFileSmall=lmpFOyRMzWVSwRroP+tGLw==, figureFileBig=m0D+546CsXBInBylBxR7lQ==, tableContent=null), ArticleFig(id=1197125049615429878, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, language=CN, label=图6, caption=化合物9对BV2细胞增殖抑制的影响。n=3,$\bar{x}±s$, figureFileSmall=lmpFOyRMzWVSwRroP+tGLw==, figureFileBig=m0D+546CsXBInBylBxR7lQ==, tableContent=null), ArticleFig(id=1197125049665761527, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, language=EN, label=Tab.1, caption=

The inhibitory activities on hMAO-A and hMAO-B of 3',4'-ethylendioxy chalcone derivatives. n=3,$\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Compound IC50 hMAO-A/μmol·L-1 Inhibition/%(IC50 hMAO-B/μmol·L-1) Selectivity Index(SI)2)
1 >40 41.6±0.0031)(13.04±0.06) >3.07
2 >40 86.2±2.83(0.13±0.02) >307.7
3 >40 37.9±0.07(-) -
4 >40 79.2±0.01(0.25±0.02) >160
5 >40 63.5±0.017(-) -
6 >40 2.6±0.02(-) -
7 >30 85.4±0.02(0.13±0.008) >230
8 >40 84.3±0.02(0.16±0.04) >250
9 >40 91.8±0.001(0.021±0.005) >1904
10 >40 84.3±1.3(0.15±0.003) >266
11 >30 83.7±0.02(0.15±0.009) >20
12 >40 51.6±0.04(-) -
13 >40 88.5±0.02(0.042±0.001) >952
14 >40 86±0.02(0.062±0.007) >645
15 >40 58.4±0.03(-) -
16 >40 48±0.01(-) -
17 >40 16.8±0.02(-) -
Selegiline3) - 92±0.7(-)3) -
Rasagiline - 90.1±0.9(0.096±0.01) -
Safinamide - 84±3.8(0.060±0.001) -
Clorgyline 79.9±0.5 - -
), ArticleFig(id=1197125049753841912, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1196886678045508108, language=CN, label=表1, caption=

3',4'-亚乙二氧基查尔酮化合物对人的单胺氧化酶A(hMAO-A)和人的单胺氧化酶B(hMAO-B)的抑制活性。n=3,$\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Compound IC50 hMAO-A/μmol·L-1 Inhibition/%(IC50 hMAO-B/μmol·L-1) Selectivity Index(SI)2)
1 >40 41.6±0.0031)(13.04±0.06) >3.07
2 >40 86.2±2.83(0.13±0.02) >307.7
3 >40 37.9±0.07(-) -
4 >40 79.2±0.01(0.25±0.02) >160
5 >40 63.5±0.017(-) -
6 >40 2.6±0.02(-) -
7 >30 85.4±0.02(0.13±0.008) >230
8 >40 84.3±0.02(0.16±0.04) >250
9 >40 91.8±0.001(0.021±0.005) >1904
10 >40 84.3±1.3(0.15±0.003) >266
11 >30 83.7±0.02(0.15±0.009) >20
12 >40 51.6±0.04(-) -
13 >40 88.5±0.02(0.042±0.001) >952
14 >40 86±0.02(0.062±0.007) >645
15 >40 58.4±0.03(-) -
16 >40 48±0.01(-) -
17 >40 16.8±0.02(-) -
Selegiline3) - 92±0.7(-)3) -
Rasagiline - 90.1±0.9(0.096±0.01) -
Safinamide - 84±3.8(0.060±0.001) -
Clorgyline 79.9±0.5 - -
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3',4'-亚乙二氧基查尔酮类MAO-B抑制剂的设计、合成及活性评价
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孔卓 , 孙德萌 , 江艳梅 , 胡云 *
中国药学杂志 | 论著 2024,59(22): 2116-2125
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中国药学杂志 | 论著 2024, 59(22): 2116-2125
3',4'-亚乙二氧基查尔酮类MAO-B抑制剂的设计、合成及活性评价
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孔卓, 孙德萌, 江艳梅, 胡云*
作者信息
  • 遵义医科大学生物工程学院, 广东 珠海 519041

    • 孔卓,女,硕士研究生 研究方向:药物化学

通讯作者:

* 胡云,男,博士,副教授 研究方向:药物化学 Tel: (0756)7623365
Design, Synthesis and Evaluation of 3', 4'-Ethylendioxy Chalcone Derivatives as Potent Monoamine Oxidase B Inhibitors
Zhuo KONG, Demeng SUN, Yanmei JIANG, Yun HU*
Affiliations
  • School of Bioengineering, Zunyi Medical University, Zhuhai 519041, China
出版时间: 2024-11-22 doi: 10.11669/cpj.2024.22.003
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摘要
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目的 设计合成一类3',4'-亚乙二氧基查尔酮类衍生物作为单胺氧化酶B(MAO-B)抑制剂。方法 通过Claisen-Schmidt缩合反应,合成目标化合物,测定其对人的单胺氧化酶(hMAO-B)的抑制作用。分析活性化合物抑制hMAO-B的选择性、作用类型和可逆性。探讨活性化合物与hMAO-B的结合模式。评价活性化合物对小鼠BV2细胞的增殖抑制作用。结果 成功合成16个化合物。多数化合物对hMAO-B具有良好的抑制活性和选择性,代表性化合物9和13的IC50值分别为0.021和0.042 μmol·L-1。二者均为MAO-B的竞争型可逆性抑制剂,与hMAO-B的结合作用力主要为疏水作用力和氢键。活性最好的化合物9对小鼠BV2小胶质细胞株表现出较低水平的细胞毒性。。结论 3',4'-亚乙二氧基查尔酮类化合物是一类高效的hMAO-B抑制剂,具有进一步研究价值。

神经退行性疾病  /  单胺氧化酶B抑制剂  /  查尔酮  /  构效关系

OBJECTIVE To design, synthesize and evaluate a series of 3', 4'-ethylendioxy chalcone derivatives as monoamine oxidase B (MAO-B) inhibitors, and summarize the structure-activity relationship (SAR). METHODS The targeted compounds were synthesized via Claisen-Schmidt condensation reaction starting from 6-acetyl-1, 4-benzodioxan and corresponding benzaldehydes. The inhibition of these compounds on human MAO-B (hMAO-B) was determined, and the inhibiting selectivity, dynamics and reversibility were investigated as well. The binding mode between active compounds and hMAO-B was revealed by molecular docking study. Additionally, the inhibitory effect of active compounds on the proliferation of BV2 cell line was determined by MTT assay. RESULTS Sixteen targeted compounds were successfully prepared. Most compounds showed good inhibitory effects on hMAO-B. Representative compounds 9 and 13 exhibited IC50 values of 0.021 and 0.042 μmol·L-1, respectively, which showed high inhibiting selectivity towards hMAO-B. Both compounds acted as competitive and reversible hMAO-B inhibitors. The main interactions between active compounds and hMAO-B were hydrophobic interaction and hydrogen bond. The most active compound 9 exhibited low cytotoxicity in BV2 cells. CONCLUSION This class of 3', 4'-ethylendioxy chalcone derivatives represent potential novel inhibitors of hMAO-B, and compound 9 could be further investigated as a potent lead for future studies.

neurodegenerative disease  /  monoamine oxidase B inhibitor  /  chalcone  /  structure-activity relationship
孔卓, 孙德萌, 江艳梅, 胡云. 3',4'-亚乙二氧基查尔酮类MAO-B抑制剂的设计、合成及活性评价. 中国药学杂志, 2024 , 59 (22) : 2116 -2125 . DOI: 10.11669/cpj.2024.22.003
Zhuo KONG, Demeng SUN, Yanmei JIANG, Yun HU. Design, Synthesis and Evaluation of 3', 4'-Ethylendioxy Chalcone Derivatives as Potent Monoamine Oxidase B Inhibitors[J]. Chinese Pharmaceutical Journal, 2024 , 59 (22) : 2116 -2125 . DOI: 10.11669/cpj.2024.22.003
正文
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单胺氧化酶(monoamine oxidase,MAO)是一种存在于细胞线粒体膜上的黄素蛋白酶,以二聚体的形式存在。在中枢和周围神经系统中,MAO介导内源性和异源性单胺物质的催化氧化,在维持神经递质的代谢平衡中发挥重要的调节作用[1]。Edmondson等[2]通过研究MAO晶体结构发现,MAO分为MAO-A和MAO-B两种亚型。二者对底物识别的差异性主要取决于MAO-A中的Phe208和MAO-B中的Ile199[3]。与MAO-A底物空腔相比,MAO-B底物空腔更大,能容纳体积更大的分子[4]。尽管MAO两种亚型都有共同的底物,但相比较而言,MAO-A优先催化5-羟色胺的氧化脱氨反应,而MAO-B则更多催化苄胺和多巴胺的氧化[5]。多巴胺是由多巴胺能神经元合成的重要神经递质,而各种病理变化引起脑部MAO-B的过量表达或活性的异常升高,将会加速多巴胺的氧化代谢,降低其在脑部的正常水平。同时在此过程中,还会伴随着过量H2O2的产生,导致氧化应激,引起神经元细胞的死亡等,这与多种神经退行性疾病如帕金森病(Parkinson's disease, PD)和阿尔茨海默病(Alzheimers' disease, AD)密切相关[6]。因此,抑制MAO-B的活性,被认为是治疗PD及AD的有效策略[7-8]。
目前,MAO-B抑制剂在临床上主要用于PD的治疗,常见的药物包括司来吉兰(selegiline)、雷沙吉兰(rasagiline)和沙芬酰胺(safinamide)等(图1A)。司来吉兰和雷沙吉兰属于不可逆抑制剂,而沙芬酰胺属于近期研发的可逆性抑制剂[9]。由于PD患者多以耐受能力差的老年人为主,MAO-B不可逆抑制剂生物利用度不高,长期疗效较差,且存在一定的不良反应如失眠、眩晕、头痛等[10-11],而沙芬酰胺抑制活性较高,选择性好,毒性较小,但是依然表现出运动障碍等不良反应[12]。因此研发新一代高活性、高选择性和安全性好的MAO-B可逆性抑制剂具有重要研究价值和现实意义。
研究发现,天然查尔酮类化合物如异甘草素是一类良好的MAO-B抑制剂,其分子骨架查尔酮(1,3-二苯基-2-丙烯-1-酮,1,图1B)可作为活性骨架进一步展开结构优化修饰,以期发现新的MAO-B抑制剂[13]。本课题组前期的研究发现,用3,4-亚乙二氧基取代异甘草素分子骨架的B环得到的衍生物对人的MAO-B(hMAO-B)具有高效的抑制活性[14-15]。而对查尔酮的A环能否同样用3,4-亚乙二氧基进行取代则有待阐明。有研究显示,用3,4-亚乙二氧基取代查尔酮母核A环产生的3',4'-亚乙二氧基查尔酮类衍生物具有抗炎及抗肿瘤等方面的活性[16-17],但其对hMAO-B的抑制作用则罕有研究。因此,本研究设计、合成一系列3',4'-亚乙二氧基查尔酮类衍生物,评价其对hMAO-B的抑制活性,并对构效关系进行总结。同时,对活性化合物抑制hMAO-B的选择性、作用类型和可逆性也作了探讨和验证。
1 材料与方法
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1.1 仪器与试剂
精密度分析天平(METTLER TOLEDO仪器有限公司);ZF暗箱式紫外分析仪(巩义市予华仪器有限责任公司);旋转蒸发仪(德国 IKA 公司);DLSB-10L/20 低温冷却液循环泵(巩义市予华仪器有限责任公司);DF集热式恒温加热磁力搅拌器(巩义市予华仪器有限责任公司);79-2 型双向磁力搅拌器(江苏省金坛市荣华仪器制造有限公司);Spectra Max M5 多功能酶标仪[美谷分子仪器(上海)有限公司];Agilent 1290 型高分辨串级飞行时间液质联用仪(美国安捷伦科技公司)。
实验所用主要药品:2-氯苯甲醛、3-氯苯甲醛、3,4-二氯苯甲醛、2-溴苯甲醛、苯甲醛、4-溴苯甲醛、2-氟苯甲醛、3-氟苯甲醛、3-溴-4-氟苯甲醛、3,4-二氟苯甲醛、3-甲氧基苯甲醛、3-羟基-4-甲氧基苯甲醛、水杨醛、3-羟基苯甲醛、6-乙酰基-1,4-苯并二 烷、氢氧化钠、硫酸氢钠、苄胺、噻唑蓝(MTT),以上试剂均为分析纯;人的MAO-A(hMAO-A)和MAO-B(hMAO-B)、辣根过氧化物酶(SIGMA-ALDRICH公司);DMEM basic(1X)[赛默飞世尔(苏州)仪器有限公司];其他化学试剂均为分析纯。
1.2 合成方法
称取1 mmol的6-乙酰基-1,4-苯并二 烷与1 mmol不同取代的苯甲醛放入圆底烧瓶中,滴入适量乙醇溶解后,室温下加入质量分数60% NaOH溶液,搅拌,用薄层层析色谱法检测反应进程。待反应结束后取出反应液,缓慢加入冰水中,冷却后过滤,将滤渣放入水中调节pH值至2~3,静置。析出沉淀后,过滤,收集滤渣,使用柱层析分离纯化,得到目标化合物。
(E)-1-(2,3-二氢-苯并[1, 4]二氧杂环己烯-6-基)-3-苯基丙-2-烯-1-酮(2):收率38.97%;UPLC纯度95.32%, tR=1.763 min。1H-NMR(400 MHz, DMSO-d6)δ: 7.95~7.89(m, 3H), 7.76~7.70(m, 3H), 7.46(dd, J=5.1, 2.0 Hz, 3H), 7.03(d, J=8.4 Hz, 1H), 4.34(dd, J=13.6, 4.9 Hz, 4H)。13C-NMR(101 MHz, DMSO-d6) δ: 187.7, 148.5, 143.8, 143.8, 135.2, 131.6, 130.9, 129.3, 123.1, 122.3, 118.0, 117.7, 65.0, 64.4。
(E)-1-(2, 3-二氢-苯并[1, 4]二氧杂环己烯-6-基)-3-(2-羟基苯基)丙-2-烯-1-酮(3) :收率53.47%; UPLC 纯度 97.74%, tR=6.472 min。1H-NMR(400 MHz, DMSO-d6) δ: 10.25(s, 1H), 8.03(d, J=15.7 Hz, 1H), 7.89(d, J=7.8 Hz, 1H), 7.83(d, J=15.8 Hz, 1H), 7.68(dd, J=8.5, 2.1 Hz, 1H), 7.64(d, J=2.1 Hz, 1H), 7.27(t, J=7.7 Hz, 1H), 7.02(d, J=8.4 Hz, 1H), 6.94(d, J=8.2 Hz, 1H), 6.87(t, J=7.5 Hz, 1H), 4.36~4.31(m, 4H)。13C-NMR(101 MHz, DMSO-d6)δ: 187.9, 157.6, 148.2, 143.8, 139.2, 132.3, 131.9, 129.1, 122.9, 122.0, 121.1, 119.83, 117.8, 117.6, 116.6, 65.0, 64.4。HRMS: m/z [M-H]+计算得出C17H14O4: 281.081 9, 理论值: 281.078 6。
(E)-1-(2, 3-二氢-苯并[1, 4]二氧杂环己烯-6-基)-3-(3-羟基苯基)丙-2-烯-1-酮(4):收率22.74%;UPLC纯度97.69%, tR=5.965 min。1H-NMR(400 MHz, DMSO-d6) δ: 9.62(s, 1H), 7.82(d, J=15.6 Hz, 1H), 7.75~7.66(m, 2H), 7.61(d, J=15.5 Hz, 1H), 7.32(d, J=7.7 Hz, 1H), 7.29~7.19(m, 2H), 7.02(d, J=8.4 Hz, 1H), 6.88(d, J=7.9 Hz, 1H), 4.39~4.29(m, 4H)。13C-NMR(101 MHz, DMSO-d6)δ: 187.7, 158.2, 148.4, 144.0, 143.8, 136.5, 131.6, 130.3, 123.1, 122.2, 120.3, 118.1, 118.0, 117.6, 115.8, 65.0, 64.4。 HRMS: m/z [M+H]+计算得出 C17H14O4: 283.096 5, 理论值: 283.098 7。
(E)-1-(2, 3-二氢-苯并[1, 4]二氧杂环己烯-6-基)-3-(3-甲氧基苯基)丙-2-烯-1-酮(5):收率21.11%; UPLC 纯度 97.35%, tR=7.637 min。1H-NMR(400 MHz, DMSO-d6)δ:7.94(d, J=15.6 Hz, 1H), 7.77~7.73(m, 2H), 7.68(d, J=15.5 Hz, 1H), 7.50(s, 1H), 7.44(d, J=7.6 Hz, 1H), 7.37(t, J=7.8 Hz, 1H), 7.03(d, J=8.3 Hz, 2H), 4.34(dd, J=13.8, 4.6 Hz, 4H), 3.84(s, 3H)。13C-NMR(101 MHz, DMSO-d6)δ: 187.6, 160.1, 148.5, 143.8, 136.6, 131.6, 130.3, 123.2, 122.5, 122.2, 118.1, 117.6, 117.0, 113.7, 65.0, 64.4, 55.7。HRMS: m/z [M+H]+计算得出C18H16O4: 297.112 1, 理论值: 297.114 8。
(E)-1-(2, 3-二氢-苯并[1, 4]二氧杂环己烯-6-基)-3-(3-羟基-4-甲氧基苯基)丙-2-烯-1-酮 (6):收率45.31%; UPLC 纯度 99.19%, tR=6.217 min。1H-NMR(400 MHz, DMSO-d6)δ: 9.17(s, 1H), 7.72~7.67(m, 3H), 7.59(d, J=15.4 Hz, 1H), 7.34(s, 1H), 7.30(d, J=8.2 Hz, 1H), 7.02~6.98(m, 2H), 4.36~4.31(m, 4H), 3.85(s, 3H)。13C-NMR(101 MHz, DMSO-d6)δ: 187.5, 150.6, 148.2, 147.1, 144.3, 143.8, 131.9, 128.20 122.9, 122.4, 119.7, 117.9, 117.6, 115.4, 112.3, 65.0, 64.4, 56.1。HRMS: m/z [M+H]+计算得出 C18H16O5: 313.107 1, 理论值: 313.109 2。
(E)-1-(2, 3-二氢-苯并[1, 4]二氧杂环己烯-6-基)-3-(2-氟苯基)丙-2-烯-1-酮(7):收率73.87%; UPLC 纯度 95.98%, tR=8.351 min。1H-NMR(400 MHz, DMSO-d6) δ: 8.11(s, 1H), 8.03(d, J=15.6 Hz, 1H), 7.83(d, J=6.4 Hz, 1H), 7.77(d, J=7.7 Hz, 2H), 7.68(d, J=15.6 Hz, 1H), 7.51~7.45(m, 2H), 7.03(d, J=8.3 Hz, 1H), 4.35(dd, J=13.9, 4.3 Hz, 4H)。13C-NMR(101 MHz, DMSO-d6) δ: 187.5, 148.6, 143.8, 142.1, 137.5, 134.2, 131.4, 131.1, 130.4, 128.4, 128.4, 123.8, 123.3, 118.2, 117.7, 65.1, 64.4。
(E)-1-(2, 3-二氢-苯并[1, 4]二氧杂环己烯-6-基)-3-(2-氯苯基)丙-2-烯-1-酮(8):收率30.14%; UPLC 纯度 97.07%, tR=9.649 min。1H-NMR(400 MHz, DMSO-d6) δ: 8.01(d, J=15.6 Hz, 1H), 7.88(d, J=10.0 Hz, 1H), 7.81~7.64(m, 4H), 7.50(q, J=7.2, 6.6 Hz, 1H), 7.28(t, J=8.1 Hz, 1H), 7.03(d, J=8.3 Hz, 1H), 4.35(d, J=10.5 Hz, 4H)。13C-NMR(101 MHz, DMSO-d6) δ: 187.5, 164.2, 161.8, 148.6, 143.8, 142.3, 142.3, 137.9, 137.8, 131.4, 131.3, 131.2, 126.1, 123.8, 123.2, 118.2, 117.7, 117.4, 115.2, 114.9, 65.1, 64.4。HRMS: m/z [M+H]+计算得出 C17H13ClO3: 301.063 1, 理论值: 301.064 5。
(E)-1-(2, 3-二氢-苯并[1, 4]二氧杂环己烯-6-基)-3-(2-溴苯基)丙-2-烯-1-酮(9):收率38.42%; UPLC 纯度 97.20%, tR=8.281 min。1H-NMR(400 MHz, DMSO-d6) δ: 8.27~8.22(m, 1H), 8.01~7.96(m, 2H), 7.78~7.73(m, 3H), 7.53~7.47(m, 1H), 7.44~7.37(m, 1H), 7.11~7.03(m, 1H), 4.40~4.34(m, 4H)。13C-NMR(101 MHz, DMSO-d6) δ: 187.4, 148.7, 143.9, 141.1, 134.5, 133.7, 132.5, 131.3, 129.3, 128.6, 125.8, 125.2, 123.3, 118.2, 117.7, 65.1, 64.4。HRMS: m/z [M+H]+计算得出 C17H13BrO3: 345.012 6, 理论值: 345.011 8。
(E)-1-(2, 3-二氢-苯并[1, 4]二氧杂环己烯-6-基)-3-(3-氟苯基)丙-2-烯-1-酮(10) :收率67.57%; UPLC 纯度 95.98%, tR=7.531 min。1H-NMR(400 MHz, DMSO-d6) δ:8.01(d, J=15.6 Hz, 1H), 7.88(d, J=10.0 Hz, 1H), 7.81~7.64(m, 4H), 7.50(q, J=7.2, 6.6 Hz, 1H), 7.28(t, J=8.1 Hz, 1H), 7.03(d, J=8.3 Hz, 1H), 4.35(d, J=10.5 Hz, 4H)。13C-NMR(101 MHz, DMSO-d6) δ: 187.5, 164.2, 161.8, 148.6, 143.8, 142.3, 142.3, 137.9, 137.8, 131.4, 131.3, 131.2, 126.1, 123.8, 123.2, 118.2, 117.7, 117.4, 115.2, 114.9, 65.1, 64.4. HRMS: m/z [M+Na]+计算得出 C17H13FO3: 307.074 1, 理论值: 307.099 4。
(E)-1-(2, 3-二氢-苯并[1, 4]二氧杂环己烯-6-基)-3-(3-氯苯基)丙-2-烯-1-酮(11):收率49.25%; UPLC 纯度 96.18%, tR=8.808 min. 1H-NMR(400 MHz, DMSO-d6) δ: 8.10(s, 1H), 8.02(d, J=15.6 Hz, 1H), 7.85~7.72(m, 3H), 7.67(d, J=15.5 Hz, 1H), 7.48~7.44(m, 2H), 7.02(d, J=8.3 Hz, 1H), 4.33(d, J=10.1 Hz, 4H)。13C-NMR(101 MHz, DMSO-d6) δ: 187.5, 148.6, 143.8, 142.1, 137.5, 134.2, 131.4, 131.1, 130.4, 128.4, 128.4, 123.7, 123.3, 118.2, 117.7, 65.0, 64.4。HRMS: m/z [M+H]+计算得出 C17H13ClO3: 301.062 6, 理论值:301.062 7。
(E)-1-(2, 3-二氢-苯并[1, 4]二氧杂环己烯-6-基)-3-(4-溴苯基)丙-2-烯-1-酮(12):收率53.03%; UPLC 纯度 96.59%, tR=8.561 min。1H-NMR(400 MHz, DMSO-d6) δ: 7.99(dd, J=15.6, 2.4 Hz, 1H), 7.88(dd, J=8.5, 2.4 Hz, 2H), 7.76~7.66(m, 5H), 7.03(dd, J=8.4, 2.4 Hz, 1H), 4.35(d, J=11.1 Hz, 4H)。13C-NMR(101 MHz, DMSO-d6) δ: 187.5, 148.5, 143.8, 142.4, 134.5, 132.3, 131.5, 131.2, 124.3, 123.2, 123.0, 118.1, 117.7, 65.0, 64.4。HRMS:m/z [M+H]+计算得出 C17H13BrO3: 345.012 1, 理论值:345.012 9。
(E)-1-(2, 3-二氢-苯并[1, 4]二氧杂环己烯-6-基)-3-(3-溴-4-氟苯基)丙-2-烯-1-酮(13):收率62.15%; UPLC 纯度 96.24%, tR=8.488 min。1H-NMR(400 MHz, DMSO-d6) δ: 8.41(d, J=6.7 Hz, 1H), 8.01~7.93(m, 2H), 7.76(d, J=7.4 Hz, 2H), 7.67(d, J=15.6 Hz, 1H), 7.47(t, J=8.6 Hz, 1H), 7.03(d, J=8.8 Hz, 1H), 4.35(dd, J=14.0, 4.6 Hz, 4H)。13C-NMR(101 MHz, DMSO-d6) δ: 187.4, 160.8, 158.4, 148.6, 143.8, 141.2, 133.8, 133.7, 131.4, 131.3, 131.3, 123.4, 123.2, 118.2, 117.7, 117.4, 109.4, 109.2, 65.1, 64.4。
(E)-1-(2, 3-二氢-苯并[1, 4]二氧杂环己烯-6-基)-3-(3, 4-二氟苯基)丙-2-烯-1-酮(14):收率39.67%; UPLC 纯度 98.42%, tR=7.908 min。1H-NMR(400 MHz, DMSO-d6) δ: 8.16(t, J=10.1 Hz, 1H), 7.96(d, J=15.5 Hz, 1H), 7.75-7.65(m, 4H), 7.52(q, J=8.8 Hz, 1H), 7.03(d, J=8.8 Hz, 1H), 4.35(dd, J=14.2, 4.7 Hz, 4H)。 13C-NMR(101 MHz, DMSO-d6) δ: 187.4, 152.2(d, J=11.1 Hz), 151.4(d, J=12.6 Hz), 149.8(d, J=12.7 Hz), 149.0(d, J=12.9 Hz), 148.6, 143.8, 141.5, 133.2(dd, J=6.6, 3.9 Hz), 131.4, 127.3(d, J=3.5 Hz), 123.5, 123.2, 118.4, 118.2, 118.2, 117.7 117.4, 117.3, 65.0, 64.4. HRMS: m/z [M+H]+计算得出 C17H12F2O3: 303.082 7, 理论值:303.083 6。
(E)-1-(2, 3-二氢-苯并[1, 4]二氧杂环己烯-6-基)-3-(3, 4-二氯苯基)丙-2-烯-1-酮(15):收率54.45%; UPLC 纯度 95.44%, tR=9.106 min。1H-NMR(400 MHz, DMSO-d6) δ: 8.28(s, 1H), 8.02(d, J=15.4 Hz, 1H), 7.85(d, J=7.7 Hz, 1H), 7.73~7.62(m, 4H), 7.00(d, J=8.0 Hz, 1H), 4.32(d, J=11.2 Hz, 4H。13C-NMR(101 MHz, DMSO-d6) δ: 187.4, 148.6, 143.8, 141.0, 136.1, 133.0, 132.2, 131.4, 130.5, 129.6, 124.3, 123.3, 118.2, 117.7, 65.1, 64.4。HRMS: m/z [M+H]+计算得出 C17H12Cl2O3: 335.023 6, 理论值:335.024 2。
(E)-1-(2, 3-二氢-苯并[1, 4]二氧杂环己烯-6-基)-3-(2, 3-二氢-苯并[1, 4]二氧杂环己烯-6-基)丙-2-烯-1-酮 (16):收率46.46%;UPLC 纯度96.15%, tR=6.732 min。1H-NMR(400 MHz, DMSO-d6) δ: 7.78(d, J=15.5 Hz, 1H), 7.80~7.70(m, 2H), 7.60(d, J=15.5 Hz, 1H), 7.51(d, J=2.0 Hz, 1H), 7.36(dd, J=8.4, 2.0 Hz, 1H), 7.00(d, J=8.3 Hz, 1H), 6.92(d, J=8.3 Hz, 1H), 4.36~4.29(m, 8H)。13C-NMR(101 MHz, DMSO-d6) δ: 187.5, 148.3, 146.2, 144.0, 143.8, 143.7, 131.8, 128.8, 123.5, 123.0, 120.4, 118.0, 117.8, 117.6, 117.6, 65.0, 64.9, 64.4。HRMS: m/z [M+H]+计算得出 C19H16O5: 325.107 1, 理论值:325.115 4。
(E)-1-(2, 3-二氢-苯并[1, 4]二氧杂环己烯-6-基)-3-(6-甲氧基萘-2-基)丙-2-烯-1-酮 (17):收率61.47%; UPLC 纯度 95.64%, tR=8.484 min。1H-NMR(400 MHz, DMSO-d6) δ: 8.26(s, 1H), 8.09(d, J=8.6 Hz, 1H), 8.00(d, J=15.5 Hz, 1H), 7.90~7.74(m, 5H), 7.38(s, 1H), 7.23(dd, J=9.0, 2.6 Hz, 1H), 7.04(d, J=8.4 Hz, 1H), 4.47~4.33(m, 4H), 3.91(s, 3H)。13C-NMR(101 MHz, DMSO-d6) δ: 187.5, 158.9, 148.4, 144.1, 143.8, 136.0, 131.8, 130.9, 130.7, 130.6, 128.8, 127.8, 125.6, 123.1, 121.4, 119.6, 118.0, 117.6, 106.7, 65.0, 64.4, 55.8. HRMS: m/z [M+Na]+计算得出 C22H18O4: 369.109 7,理论值:369.115 6。
1.3 hMAO抑制活性测试
1.3.1 化合物抑制hMAO活性筛选实验
待测化合物对MAO-A/B的抑制活性筛选根据Lu等[18]报道的测试方法进行。实验分为空白组、阴性对照组、阳性对照组、待测化合物组。其中空白组和阴性对照组中,用20 μL缓冲液和体积分数0.1%二甲基亚砜(DMSO)溶液代替待测化合物。将hMAO-A/B用缓冲溶液稀释至12.5,75 μg·mL-1备用。将1 μmol·L-1的待测化合物(每孔20 μL)和hMAO-A/B(每孔80 μL)先后加入96孔黑板中,在37 ℃孵育15 min后,立即加入总体积为100 μL底物工作液(工作浓度为200 μmol·L-1的Ampliflu Red,2 mmol·L-1的酪胺和苄胺,2 U·mL-1的HRP),再次放置于37 ℃孵育15 min后,立即多功能酶标仪上(EX=545 nm,EM=590 nm)检测,并记录荧光值。在该浓度下对hMAO-B的抑制率大于70%的化合物进一步测定其IC50值。
1.3.2 酶抑制动力学实验
在抑制动力学实验中,选择抑制活性较好的化合物作为代表,在0、IC50、3/2 IC50、2 IC50、5/2 IC50 5个作用浓度下,加入4个不同浓度的底物,测试化合物对hMAO-B的抑制活性随时间的变化,整理作Lineweaver-Burk图,即分别作出酶的反应速率倒数对底物浓度倒数的双倒数直线,测定活性化合物的对hMAO-B的抑制类型[19]。
1.3.3 hMAO-B可逆性实验
依据Reis等[20]报道的测试方法,将实验组设置阴性对照组(体积分数0.1% DMSO)、阳性对照组(沙芬酰胺、雷沙吉兰、司来吉兰)及待测药物组(终浓度IC80值的药物)。用50 mmol·L-1,pH=7.4磷酸二氢钾缓冲溶液将hMAO-B,稀释至8 μg·mL-1的工作浓度,备用;将Ampliflu Red、苄胺、HRP、待测活性化合物分别稀释至终浓度为200 、1 mmol·L-1、1 U·mL-1、IC80值的溶液,备用。测试方法与“1.3.1”项下方法相同,在EX=545 nm,EM=590 nm的波长下,持续检测120 min,每4 min记录一次荧光值。
1.4 分子对接研究
选用抑制活性较好的化合物为代表作为对接底物,用hMAO-B晶体(PDB code: 2V61)和hMAO-A(PDB code: 2Z5X)晶体作为对接受体,对接过程按照 Molecular Operating Environment 2022的分子对接模块标准操作进行。除特别介绍外,所有参数均采用默认值。
1.5 MTT实验
将体积分数0.1% DMSO作为对照,利用MTT法测出目标化合物的体外抑制活性。取用对数生长期的小胶质细胞BV2,以每孔5×10 3个细胞接种于96孔板,培养过夜后,设置1,5,25,50 μmol·L-1 4个不同浓度梯度,每个浓度设3个复孔。作用24 h后,每孔加20 μL 5.0 g·L-1的MTT后,再孵育4 h,吸去细胞培养液,每孔加入150 μL DMSO。用多功能酶标仪在 570 nm下测定吸光度,计算细胞存活率。
2 结果与讨论
收起
2.1 化合物合成
本系列化合物通过无机碱催化Claisen-Schmidt缩合反应进行制备,其合成路线见图2。所合成化合物的纯度和结构,均已通过超高效液相色谱(ultra performance liquid chromatography,UPLC),核磁共振氢谱(1H nuclear magnetic resonance,1H-NMR), 核磁共振碳谱(13C nuclear magnetic resonance,13C-NMR)及高分辨质谱(high resolution mass spectrum,HR-MS)等方法得到确证。
2.2 化合物对hMAO-A/B的抑制活性及构效关系讨论
对于所合成的目标化合物,大部分都对hMAO-B表现出了较强的抑制活性,其中有13个化合物在1 μmol·L-1作用浓度下对hMAO-B的抑制率超过50%(以下所讨论化合物对hMAO-B的抑制率,无特殊说明,均为在1 μmol·L-1作用浓度下测得)。
由表1可知,阳性对照药物司来吉兰、雷沙吉兰和沙芬酰胺在测试浓度下能明显抑制hMAO-B的活性,对hMAO-B的抑制率分别为92%、90.1%和84%。雷沙吉兰和沙芬酰胺对hMAO-B的抑制IC50值分别为0.096和0.06 μmol·L-1。查尔酮(化合物1)对hMAO-B表现出一定的抑制活性,在10 μmol·L-1浓度下对hMAO-B的抑制率为41%,其IC50为13.04 μmol·L-1。用3,4-亚乙二氧基对查尔酮A环的间位和对位进行取代得到3',4'-亚乙二氧基查尔酮(化合物2),其对hMAO-B的抑制率达到86.2%,IC50值为0.13 μmol·L-1,只有化合物1 IC50值的百分之一。这表明了,用3,4-亚乙二氧基对查尔酮骨架A环的间位和对位进行取代能显著提高其对hMAO-B的抑制活性。化合物2可作为新的活性分子骨架进行更进一步的构效关系探究。
在化合物2的B环引入给电子基-OH或-OCH3后,无论是2-OH(化合物3)、3-OH(化合物4)、3-OCH3(化合物5)或同时引入3-OH,4-OCH3(化合物6),所得化合物的活性均比化合物2有明显下降,只有化合物4表现出相对较好的抑制活性,IC50值为0.25 μmol·L-1。这表明在3',4'-亚乙二氧基查尔酮活性骨架的B环苯环上引入给电子取代基将使化合物的抑制活性下降。
在其B环苯环上的不同位置引入2-F(化合物7)、2-Cl(化合物8)、2-Br(化合物9)、3-F(化合物10),3-Cl(化合物11)或4-Br(化合物12)等吸电子取代基,所得的化合物7~8,10~11表现出与化合物2相当或相对较弱的抑制活性,IC50值分别为0.13,0.16和0.15 μmol·L-1。而化合物9则表现出了在该系列化合物中最高的抑制活性,IC50值为0.021 μmol·L-1,比化合物2的活性高出约6倍,明显优于阳性对照药物雷沙吉兰和沙芬酰胺。故此,在B环邻位引入Br原子可显著提高化合物对hMAO-B的抑制活性。另外,在化合物2的B环同时引入了3-Br,4-F(化合物13)或3,4-二氟(化合物14)同样有利于提高化合物的抑制活性,所得化合物12和13的IC50值为0.042和0.062 μmol·L-1。然而,同时引入3,4-二氯后所得的化合物15的活性却出现明显下降,其抑制率只有58.4%。
此外,用1,4-苯并二氧六环基或萘环基替换B环后得到的化合物16和17,其抑制率均比化合物2显著降低,分别为48%和16.8%,这说明了对于该系列化合物,增大B端芳环的体积和疏水性将导致化合物的抑制活性下降。
由表1还可得知,该系列化合物对hMAO-B具有较好的抑制专一性。所合成的目标化合物除化合物7和11对hMAO-A的抑制IC50值大于30 μmol·L-1外,其余化合物均大于40 μmol·L-1。活性化合物9对hMAO-B的选择性指数SI(selectie index,等于化合物对hMAO-A的IC50与对hMAO-B的IC50的比值)大于1 904,优于阳性对照药物雷沙吉兰[20]。这些结果表明了本研究所合成的化合物,尤其是活性化合物,对hMAO-B的抑制作用具有高度的选择专一性。
综上所述,以上实验结果基本阐明了3',4'-亚乙二氧基查尔酮化合物抑制hMAO-B的构效关系,为下一步开发活性更优、选择性更高的MAO-抑制剂提供了重要参考。
2.3 活性化合物hMAO-B抑制动力学研究
为探讨活性化合物对hMAO-B的抑制作用类型,本实验选用抑制活性较好的化合物9和13为代表性化合物进行抑制动力学研究。在化合物不同的作用浓度下,作出Linearweaver-Burk图,即以酶浓度倒数(1/[S])为横坐标,酶反应速率倒数(1/V)为纵坐标作图进行分析。所测试的两个化合物Linearweaver-Burk图中几组直线均相交于Y轴,而且这些直线的斜率随着抑制剂浓度的增大而变大。由此可知,活性化合物9和13对hMAO-B的抑制类型为均为竞争型抑制(图3)。
2.4 活性化合物抑制hMAO-B的可逆性分析
本研究采用时间依赖抑制的测试方法,分析活性化合物9和13对hMAO-B的抑制可逆性。实验选用不可逆抑制剂司来吉兰和雷沙吉兰,可逆性抑制剂沙芬酰胺作为阳性对照,在相同的时间范围内考察化合物在与底物共存的情况下对hMAO-B抑制作用的变化情况。
由图4A可见,司来吉兰和雷沙吉兰与hMAO-B孵育12 min后,hMAO-B的活性随着孵育时间的延长而持续下降,这表明了二者对酶的抑制作用是不可逆的。而沙芬酰胺与hMAO-B开始孵育后,酶活性呈持续下降,24 min后,酶活性开始恢复,并持续增强,这表明该抑制剂对酶的抑制作用是可逆的。对于活性化合物9和13,与hMAO-B开始孵育后,酶活性在开始阶段迅速下降,之后下降趋势逐渐减缓,在40 min后酶活性持续恢复和增强(图4B)。由上可知,活性化合物9和13对hMAO-B活性的抑制作用随时间变化曲线与沙芬酰胺相似,而不同于司来吉兰和雷沙吉兰。由上可知,活性化合物9和13为hMAO-B的可逆性抑制剂。
2.5 分子对接研究
为从分子水平上探讨活性化合物抑制hMAO-B的作用方式,本部分研究利用分子对接的方法研究二者的结合模式。首先,分析查尔酮与hMAO-B的结合情况(图5A),可知查尔酮的A环占据着由Trp119、Phe168、Pro102及Leu164等氨基酸残基组成的疏水腔,B环则伸向FAD一端区域,其结合力主要是疏水作用力。而对于化合物2,其以伸展的构象占据活性口袋,苯环占据的区域与查尔酮的A环相近,1,4-苯并二氧六环伸向FAD一侧,更加靠近相对亲水的催化中心区,其结构上的α,β-不饱和酮羰基与活性口袋的Cys172残基巯基形成了氢键(相距约3.11 Å,图5A)。对于活性化合物13,骨架结构上的苯环和1,4-苯并二氧六环在活性口袋的空间取向与化合物2相似,α,β-不饱和酮的羰基与残基Cys172的巯基形成了氢键(相距约3.13 Å)。另外,其苯环上的3-Br和4-F分别嵌入了由Trp119、Leu164和Phe168及Phe103、Phe104和Trp119等氨基酸残基组成的局部空腔,进一步增强了与酶的结合力(图5B)。对于活性最好的化合物9,其在活性口袋的伸展取向与化合物13相似,苯环上的2-Br嵌入了由Trp119、Leu164和Phe168等残基形成的局部空腔,而α,β-不饱和酮的羰基则更靠近Cys172,与其巯基形成了较强的氢键(3.05 Å)。因为与Cys172以氢键结合是很多抑制剂与 MAO-B作用的重要模式[19,21],由此推测,这种作用模式能明显增强活性化合物与hMAO-B的结合,从而使其表现出高效的抑制活性。
由抑制活性筛选结果可知,活性化合物对hMAO-B的抑制还具有良好的选择专一性,对hMAO-A表现出很弱的抑制作用。为阐明活性化合物对hMAO-A/B抑制产生活性差异的原因,本部分研究以活性化合物9和13为研究对象,同样利用分子对接的方法,对化合物与酶的结合模式进行分析。结果显示,与活性化合物占据hMAO-B活性口袋时充分伸展的分子构象(图5C)不同,活性化合物9和13以相对折叠的分子构象占据hMAO-A大半个活性口袋,存在的相互作用力为疏水作用力(图5D)。采用这种折叠的分子结合构象主要因为hMAO-A的活性口袋是单腔结构,总体积要小于hMAO-B的活性口袋[21],这样可以避免化合物分子本身与周围氨基酸残基相冲突。然而,这种作用模式存在较大位阻斥力,并不利于稳定结合[22]。由此可推测,空间位阻效应是活性化合物无法对hMAO-A产生较好抑制活性的主要原因。
2.6 细胞增殖抑制实验
本实验采用MTT法评价活性化合物对神经细胞的毒性。选用抑制hMAO-B活性最好的化合物9作为研究对象,小鼠小胶质细胞BV2细胞作为测试细胞株,以体积分数0.1% DMSO作为阴性对照,分别在化合物1、5和25 μmol·L-1的作用浓度下,考察其对细胞的增殖抑制影响。由图6可知,在所测试的浓度范围内,化合物9对于BV2细胞未表现明显的增殖抑制作用。这说明了化合物9具有较低水平的神经毒性。
3 结论
收起
本实验从查尔酮母核结构出发,设计和合成了一系列3',4'-亚乙二氧基查尔酮衍生物,评价其抑制hMAO-B的活性,从中筛选得到了抑制活性高效的化合物9和13,并总结了该类化合物的构效关系。结果显示,化合物9和13对hMAO-B的抑制IC50值分别为0.021和0.042 μmol·L-1,优于阳性药物雷沙吉兰和沙芬酰胺,二者对hMAO-B的抑制作用表现出高度的选择专一性。酶抑制动力学研究表明,化合物9和13是hMAO-B的可逆性竞争型抑制剂。分子对接研究表明,活性化合物主要是通过疏水作用力和氢键增强了与hMAO-B的结合。另外,体外细胞增殖抑制实验显示,活性化合物9对小鼠BV2小胶质细胞未表现出明显的神经毒性,具备一定的安全性。综上所述,本实验发现的3',4'-亚乙二氧基查尔酮类MAO-B抑制剂具备较好的研究和开发潜力,可为发展新型抑制MAO-B的先导化合物提供借鉴和参考。
基金
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  • 国家自然科学基金项目(81560562)
  • 国家自然科学基金项目(21762055)
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2024年第59卷第22期
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doi: 10.11669/cpj.2024.22.003
  • 接收时间：2023-10-20
  • 首发时间：2025-11-16
  • 出版时间：2024-11-22
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  • 收稿日期：2023-10-20
基金
国家自然科学基金项目(81560562)
国家自然科学基金项目(21762055)
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    遵义医科大学生物工程学院, 广东 珠海 519041

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* 胡云,男,博士,副教授 研究方向:药物化学 Tel: (0756)7623365
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