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Article(id=1222466464175608810, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222466461742916318, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2018-0890, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1538236800000, receivedDateStr=2018-09-30, revisedDate=1540742400000, revisedDateStr=2018-10-29, acceptedDate=null, acceptedDateStr=null, onlineDate=1769388317387, onlineDateStr=2026-01-26, pubDate=1549900800000, pubDateStr=2019-02-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1769388317387, onlineIssueDateStr=2026-01-26, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1769388317387, creator=13701087609, updateTime=1769388317387, updator=13701087609, issue=Issue{id=1222466461742916318, tenantId=1146029695717560320, journalId=1189982191388893191, year='2019', volume='54', issue='2', pageStart='187', pageEnd='392', issueExtLink='null', onlineDate='null', pubDate='1549900800000', pubDateStr='2019-02-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1769388316807, creator='13701087609', updateTime=1769389248599, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1222470370016350509, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222466461742916318, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1222470370016350510, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222466461742916318, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=335, endPage=342, ext={EN=ArticleExt(id=1222466464729256947, articleId=1222466464175608810, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Design, synthesis and anticancer activity studies of oleanolic acid derivatives targeting mTOR, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Ten novel oleanolic acid (OA) derivatives containing urea or thiourea group were designed and synthesized, the chemical structures were confirmed by 1H NMR, 13C NMR and HR-MS. All of these compounds were evaluated for the inhibitory activity against growth of HepG2 and SGC7901 cells. The results showed that compounds I3 and Ⅱ3 exhibited significant antitumor activities with IC50 of 9.4 and 5.5 μmol·L-1, respectively. Molecular docking studies showed that all these compounds exhibit inhibitory ability against mTOR kinase. Compounds I3 and Ⅱ3 were further evaluated for the inhibitory activity against mTOR kinase. The results showed that I3 and Ⅱ3 exhibited strong inhibitory effect on mTOR kinase with IC50 values of 0.83 and 0.26 μmol·L-1.

, authors=null, authorsList=Yan-ling SONG, Ling LI, Zhong-yan LIU, Jie LI, Peng-bo ZHANG, authorCompany=null, correspAuthors=Yan-ling SONG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2019 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, fund=null), CN=ArticleExt(id=1222466466289537051, articleId=1222466464175608810, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=以mTOR激酶为靶点的齐墩果酸衍生物的设计、合成及抗肿瘤活性研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

本文以齐墩果酸（oleanolic acid，OA）为先导化合物进行结构优化，通过引入mTOR小分子抑制剂的重要药效基团脲基或硫脲基，同时拼合多种生物活性片段，设计并合成了10个新的衍生物，其结构经1H NMR、13C NMR和HR-MS确证。对所合成的目标化合物以人肝癌细胞（HepG2）和人胃癌细胞（SGC7901）进行体外抗肿瘤活性测试，结果表明目标化合物对两种肿瘤细胞的抑制活性均明显强于OA，其中I3和Ⅱ3对HepG2细胞显示出较强的活性（IC50=9.4和5.5 μmol·L-1）。分子模拟对接研究表明，目标化合物和mTOR激酶均具有较好的结合能力。对化合物I3和Ⅱ3进行mTOR激酶的抑制活性测试，结果表明化合物I3和Ⅱ3对mTOR激酶具有较强的抑制作用（IC50=0.83和0.26 μmol·L-1）。

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*宋艳玲, Tel:13840387750, E-mail:
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Reagent and conditions: (a) Jone's reagent, acetone, rt, 2 h; (b) (COCl)2, CH2Cl2, 40 ℃, 2 h; (c) Piperazine, CH2Cl2, Py, DMAP, rt, 3 h; (d) Substituted phenyl isocyanates, CH2Cl2, Et3N, rt, overnight; (e) Substituted phenyl isothiocyanates, CH2Cl2, Et3N, rt, overnight.

, figureFileSmall=tGlsfLhpOYLi4tzmf1RRZw==, figureFileBig=UmvCfSds++DiwoNLUSfnVg==, tableContent=null), ArticleFig(id=1222513647809713078, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466464175608810, language=EN, label=null, caption=null, figureFileSmall=BPQF11Rz7h+m9BftMYBlfw==, figureFileBig=eHoGZQber8U/mfflLdZ+Cg==, tableContent=null), ArticleFig(id=1222513647973290946, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466464175608810, language=CN, label=Figure 4, caption= Binding of compounds <strong>Ⅰ<sub>3</sub></strong> and <strong>Ⅱ<sub>3</sub></strong> to the active site of mTOR , figureFileSmall=BPQF11Rz7h+m9BftMYBlfw==, figureFileBig=eHoGZQber8U/mfflLdZ+Cg==, tableContent=null), ArticleFig(id=1222513648111702993, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466464175608810, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. MolDock Score
/kcal·mol-1
Ⅰ1 -141.137
Ⅰ2 -145.932
Ⅰ3 -155.361
Ⅰ4 -140.963
Ⅰ5 -147.076
L64 -140.016
Ⅱ1 -133.509
Ⅱ2 -148.026
Ⅱ3 -157.754
Ⅱ4 -154.117
Ⅱ5 -141.312
OA -108.186
), ArticleFig(id=1222513648229143516, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466464175608810, language=CN, label=Table 1, caption=

Comparison of energy scores for different compounds with mTOR

, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. MolDock Score
/kcal·mol-1
Ⅰ1 -141.137
Ⅰ2 -145.932
Ⅰ3 -155.361
Ⅰ4 -140.963
Ⅰ5 -147.076
L64 -140.016
Ⅱ1 -133.509
Ⅱ2 -148.026
Ⅱ3 -157.754
Ⅱ4 -154.117
Ⅱ5 -141.312
OA -108.186
), ArticleFig(id=1222513648350778348, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466464175608810, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. Inhibition rate/% IC50/μmol·L-1
HepG2 SGC7901 HepG2 SGC7901
OA 19.7 15.3 > 50 > 50
Ⅰ1 38.6 39.1 32.8 35.2
Ⅰ2 43.3 40.0 30.1 36.6
Ⅰ3 59.5 50.4 9.4 12.6
Ⅰ4 38.1 41.2 37.5 30.4
Ⅰ5 41.6 40.2 35.5 39.1
Ⅱ1 40.4 38.5 34.9 41.7
Ⅱ2 31.5 36.9 31.5 45.8
Ⅱ3 63.5 53.2 5.5 10.6
Ⅱ4 50.4 45.5 19.3 25.2
Ⅱ5 42.5 36.9 29.5 45.5
AZD8055 60.3 52.8 10.7 13.5
), ArticleFig(id=1222513648464024569, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466464175608810, language=CN, label=Table 2, caption=

Inhibitory activity of the target compounds on HepG2 and SGC7901 cell lines

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Compd. Inhibition rate/% IC50/μmol·L-1
HepG2 SGC7901 HepG2 SGC7901
OA 19.7 15.3 > 50 > 50
Ⅰ1 38.6 39.1 32.8 35.2
Ⅰ2 43.3 40.0 30.1 36.6
Ⅰ3 59.5 50.4 9.4 12.6
Ⅰ4 38.1 41.2 37.5 30.4
Ⅰ5 41.6 40.2 35.5 39.1
Ⅱ1 40.4 38.5 34.9 41.7
Ⅱ2 31.5 36.9 31.5 45.8
Ⅱ3 63.5 53.2 5.5 10.6
Ⅱ4 50.4 45.5 19.3 25.2
Ⅱ5 42.5 36.9 29.5 45.5
AZD8055 60.3 52.8 10.7 13.5
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以mTOR激酶为靶点的齐墩果酸衍生物的设计、合成及抗肿瘤活性研究
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宋艳玲 * , 李玲 , 刘忠岩 , 李杰 , 张蓬勃
药学学报 | 研究论文 2019,54(2): 335-342
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药学学报 |研究论文 2019 , 54 (2) : 335 -342
以mTOR激酶为靶点的齐墩果酸衍生物的设计、合成及抗肿瘤活性研究
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宋艳玲* , 李玲, 刘忠岩, 李杰, 张蓬勃
作者信息
  • 沈阳化工大学制药与生物工程学院, 辽宁 沈阳 110142
通讯作者:
*宋艳玲, Tel:13840387750, E-mail:
Design, synthesis and anticancer activity studies of oleanolic acid derivatives targeting mTOR
Yan-ling SONG* , Ling LI, Zhong-yan LIU, Jie LI, Peng-bo ZHANG
Affiliations
  • Institute of Pharmaceutical and Biological Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China
出版时间: 2019-02-12 doi: 10.16438/j.0513-4870.2018-0890
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摘要
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本文以齐墩果酸（oleanolic acid，OA）为先导化合物进行结构优化，通过引入mTOR小分子抑制剂的重要药效基团脲基或硫脲基，同时拼合多种生物活性片段，设计并合成了10个新的衍生物，其结构经1H NMR、13C NMR和HR-MS确证。对所合成的目标化合物以人肝癌细胞（HepG2）和人胃癌细胞（SGC7901）进行体外抗肿瘤活性测试，结果表明目标化合物对两种肿瘤细胞的抑制活性均明显强于OA，其中I3和Ⅱ3对HepG2细胞显示出较强的活性（IC50=9.4和5.5 μmol·L-1）。分子模拟对接研究表明，目标化合物和mTOR激酶均具有较好的结合能力。对化合物I3和Ⅱ3进行mTOR激酶的抑制活性测试，结果表明化合物I3和Ⅱ3对mTOR激酶具有较强的抑制作用（IC50=0.83和0.26 μmol·L-1）。

齐墩果酸衍生物  /  合成  /  分子对接  /  抗肿瘤活性

Ten novel oleanolic acid (OA) derivatives containing urea or thiourea group were designed and synthesized, the chemical structures were confirmed by 1H NMR, 13C NMR and HR-MS. All of these compounds were evaluated for the inhibitory activity against growth of HepG2 and SGC7901 cells. The results showed that compounds I3 and Ⅱ3 exhibited significant antitumor activities with IC50 of 9.4 and 5.5 μmol·L-1, respectively. Molecular docking studies showed that all these compounds exhibit inhibitory ability against mTOR kinase. Compounds I3 and Ⅱ3 were further evaluated for the inhibitory activity against mTOR kinase. The results showed that I3 and Ⅱ3 exhibited strong inhibitory effect on mTOR kinase with IC50 values of 0.83 and 0.26 μmol·L-1.

oleanolic acid derivative  /  synthesis  /  molecular docking  /  anti-tumor activity
宋艳玲, 李玲, 刘忠岩, 李杰, 张蓬勃. 以mTOR激酶为靶点的齐墩果酸衍生物的设计、合成及抗肿瘤活性研究. 药学学报, 2019 , 54 (2) : 335 -342 . DOI: 10.16438/j.0513-4870.2018-0890
Yan-ling SONG, Ling LI, Zhong-yan LIU, Jie LI, Peng-bo ZHANG. Design, synthesis and anticancer activity studies of oleanolic acid derivatives targeting mTOR[J]. Acta Pharmaceutica Sinica, 2019 , 54 (2) : 335 -342 . DOI: 10.16438/j.0513-4870.2018-0890
正文
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哺乳动物雷帕霉素靶蛋白(mTOR)是一种丝氨酸/苏氨酸激酶, 其介导的PI3K-Akt-mTOR信号通路在肿瘤细胞增殖、分化、凋亡及蛋白质合成、血管生成过程中发挥重要作用[1, 2]。目前, 通过与ATP竞争mTOR的催化靶位从而抑制mTOR激酶的小分子抑制剂已成为抗肿瘤药物的研究热点[3-5]。齐墩果酸(oleanolic acid, OA)是一种五环三萜类天然产物, 具有独特的手性刚性骨架及良好的生物活性和生物相容性[6-9]。近年来的研究发现, OA具有诱导肿瘤细胞分化、诱导肿瘤细胞凋亡、抑制肿瘤血管生成和肿瘤转移等作用[10-12], 但分子作用机制尚未明确。也有研究表明OA能够抑制人前列腺癌细胞PC-3和乳腺癌细胞MCF-7中激活状态的mTOR[13], 并且OA对人白血病HL-60细胞的PI3K表达也具有抑制作用[14]。因此, mTOR信号通路可能是齐墩果酸抗肿瘤作用的重要靶点。
通过对mTOR小分子抑制剂构效关系研究发现, PKI587、PKI179、PF-05139962、L64和NVP-BEZ235等结构中的脲基是重要的药效基团, 结构式见图 1[15]。PDB数据库中L64与mTOR激酶(PDB: 3IBE)的共晶结构分析表明, L64可插入靶蛋白活性口袋并与周围的氨基酸残基紧密结合, 其结构中脲基上的氧原子和氢原子分别与LYS83、ASP964和ASP841各形成一个牢固的氢键, 进一步说明脲基是其抗肿瘤作用的重要药效基团(图 2)。已有的OA构效关系研究表明C-3位羰基和C-28位酰胺化能显著提高抗肿瘤活性[16]; C-28位引入哌嗪基团, 其水溶性和生物活性也会明显增强[17]。本研究以C-3位羰基OA为先导化合物, 通过C-28引入哌嗪基团作为连接臂, 再利用拼合原理引入脲基及疏水性芳环基团, 设计并合成5个衍生物Ⅰ1~Ⅰ5, 通过将脲基置换成硫脲基设计并合成5个衍生物Ⅱ1~Ⅱ5, 见图 3。同时对目标化合物进行体外抗肿瘤活性测试和分子模拟对接研究。
结果与讨论
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1 化学部分
以OA为起始原料, 经过C-3位氧化、C-28位酰氯化反应和取代反应得到重要中间体化合物3, 化合物3进一步和取代的异氰酸酯或异硫氰酸酯反应, 合成了10个齐墩果酸衍生物, 见合成路线1。目标化合物结构经1H NMR、1C NMR和HR-MS确证, 数据见实验部分。
2 分子对接
以PDB数据库中mTOR为靶点(PDB编号: 3IBE), 作为分子对接受体模型。将3IBE导入计算机辅助药物设计软件Molegro Virtual Docker (MVD 6.0), 根据cavity的探测选择最佳对接区域(center x: 42.33 y: 15.87 z: 32.79, radius: 15)。将受体蛋白中原有配体替换为目标化合物, 利用Docking wizard向导设定配体的对接运算次数后, 选择打分函数MolDock Score[GRID]与构象搜寻MolDock SE[18], 分别对化合物(Ⅰ1~Ⅰ5和Ⅱ1~Ⅱ5)与受体对接的结合能进行评分, 评分结果见表 1。结果表明, 目标化合物的结合能均明显高于OA, 其中化合物Ⅰ3、Ⅱ3和Ⅱ4高于L64。选取MD score绝对值最高的分子构象作为与靶点的模拟对接模型, 利用Discovery studio 4.0分析配体与氨基酸残基作用的图像。目标化合物均能较好的插入到mTOR-ATP催化区域, 并与周围多个氨基酸紧密连接。对比化合物Ⅰ3、Ⅱ3和L64与靶蛋白的分子对接图(图 4), 结果表明化合物Ⅰ3、Ⅱ3和L64与靶蛋白具有相同的氢键结合位点, 分子结构中的脲基或硫脲基能与靶蛋白氨基酸残基LYS833\ASP841和ASP964形成氢键。
3 生物活性评价
3.1 目标化合物对人癌细胞株的体外增殖抑制实验
选取HepG2和SGC7901细胞, 采用MTT法, 以AZD8055作为阳性对照药物, 测试目标化合物Ⅰ1~Ⅰ5和Ⅱ1~Ⅱ5的体外抗肿瘤活性, 测试结果见表 2。结果表明目标化合物对两种肿瘤细胞的抑制活性均明显强于OA, 其中Ⅰ3和Ⅱ3对HepG2细胞显示出较强的活性, IC50值分别是9.4和5.5 μmol·L-1。
3.2 mTOR激酶抑制实验
选取化合物Ⅰ3和Ⅱ3进行mTOR激酶抑制实验, 实验由Invitrogen公司完成。结果表明化合物Ⅰ3和Ⅱ3对mTOR激酶具有较好的抑制作用, IC50值分别为0.83和0.26 μmol·L-1。
4 小结
本文以OA为起始原料, 通过在OA-28位引入哌嗪基团, 并以此为连接臂, 引入mTOR小分子抑制剂的药效基团脲基, 再用硫脲基替换脲基, 设计并合成了10个新的OA衍生物, 目标化合物结构经1H NMR、1C NMR和HR-MS确证。通过计算机辅助药物设计分子对接方法预测目标化合物和mTOR激酶的结合能, 结果表明目标化合物的结合能均明显高于OA, 其中化合物Ⅰ3、Ⅱ3和Ⅱ4的结合能高于化合物L64, 且化合物Ⅰ3、Ⅱ3和L64与mTOR激酶具有相同的氢键结合位点。采用MTT法考察目标化合物的体外抗肿瘤活性, 结果表明目标化合物对人肝癌细胞(HepG2)和人胃癌细胞(SGC7901)的抑制活性明显高于OA, 说明以哌嗪作为连接臂, 连入脲基或硫脲基, 其抗肿瘤活性显著增强。mTOR激酶抑制活性测试结果表明化合物Ⅰ3和Ⅱ3具有较强的mTOR激酶抑制活性。实测活性与分子模拟对接预测的结果相关性较好, 本研究结果对进一步优化设计齐墩果酸衍生物作为mTOR激酶抑制剂的研究具有参考价值。
实验部分
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Büchi B-540熔点测定仪; BrukerARX-600型核磁共振分析仪(DMSO-d6为溶剂, TMS为内标); Autospec Ultima-TOF质谱测定仪; WZZ-1S (2s)自动旋光仪; 齐墩果酸(质量分数 > 98%)购于陕西慈缘生物技术有限公司; 柱色谱200~300目硅胶、薄层色谱硅胶GF254, 购于青岛海洋化工厂; 显色剂为10%硫酸-乙醇溶液; 体外抗肿瘤活性测试所用的RPMI-1640培养基(含10%胎牛血清、100 μg·mL-1青霉素、100 μg·mL-1链霉素)、溴化四氮唑盐(MTT)、胰蛋白酶(Trypsin)和标准胎牛血清(FBS)、活性测试所用HepG2和SGC7901细胞由沈阳药科大学药理教研室提供。所有试剂均为市售分析纯或化学纯。
1 化合物的合成
1.1 3-氧代-齐墩果烷型-12-烯-28-羧酸(1)的制备
将齐墩果酸(0.500 g, 1.095 mmol)溶解于30 mL丙酮中, 冰盐浴下缓慢滴加30滴新配置的Jones试剂, 室温反应2 h, TLC监测反应终点。加入异丙醇15 mL淬灭, 继续反应30 min。乙酸乙酯萃取3次, 合并有机相, 饱和食盐水洗涤3次, 无水硫酸钠干燥, 抽滤, 蒸干溶剂, 得到白色固体0.483 g, 产率为96%, mp 218.7~221.3 ℃ (文献值mp 220.3~222.1 ℃[19])。
1.2 3-氧代-齐墩果烷型-12-烯-28-酰氯(2)的制备
将化合物1 (0.500 g, 1.020 mmol)溶解于30 mL无水二氯甲烷中, 加热至40 ℃, 搅拌下缓慢滴加草酰氯(0.698 g, 5.499 mmol), 回流反应2 h, TLC监测反应终点。减压蒸干溶剂, 加入环己烷(10 mL×2)洗涤, 蒸干溶剂, 得到白色固体0.488 g, 产率为97%, 密闭备用。
1.3 化合物(3)的制备
在25 mL茄形瓶中加入哌嗪(1.455 g, 16.889 mmol), 冰盐浴冷却。将化合物2 (1.000 g, 2.114 mmol)溶解于10 mL无水二氯甲烷中, 缓慢滴加到降至0 ℃的哌嗪溶液中, 再依次加入无水DMAP (0.013 g, 0.106 mmol)和无水吡啶(0.248 g, 3.135 mmol), 室温反应3 h, TLC监测反应终点。二氯甲烷萃取3次, 合并有机相, 饱和食盐水洗涤3次, 无水硫酸钠干燥, 抽滤, 减压蒸干溶剂, 得到淡黄色固体。经硅胶柱色谱分离纯化[洗脱剂:甲醇-二氯甲烷=1:150 (V/V)]得到白色固体0.864 g, 产率为86%, mp 149.9~151.2 ℃。HR-MS (m/z): 523.402 8 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 5.21 (t, J = 3.7 Hz, 1H, H-12), 3.38~3.30 (m, 4H, piperazinyl-H-2', 6'), 2.86~2.78 (m, 4H, piperazinyl-H-3', 5'), 1.15 (s, 3H, CH3), 1.13~1.11 (m, 1H, piperazinyl-H-4'), 1.09 (s, 3H, CH3), 1.04 (s, 6H, 2CH3), 0.93 (d, J = 3.2 Hz, 3H, CH3), 0.90 (s, 3H, CH3), 0.78 (s, 3H, CH3); 13C NMR (101MHz, CDCl3) δ 127.62, 174.55, 151.61, 144.45, 139.87, 129.34, 129.26, 128.58, 123.49, 121.92, 121.85, 55.26, 51.86, 51.67, 49.71, 49.38, 47.60, 47.45, 46.32, 43.85, 43.33, 41.96, 40.15, 39.42, 37.68, 34.29, 33.97, 33.08, 31.15, 30.73, 28.84, 28.45, 27.32, 27.08, 26.12, 23.94, 22.07, 20.86, 20.75, 17.46, 16.22。
1.4 化合物Ⅰ1~Ⅰ5的制备
1.4.1 化合物Ⅰ1的制备
将苯基异氰酸酯(0.054 g, 0.453 mmol)溶于10 mL无水1, 2-二氯乙烷中, 置于常温下搅拌; 将溶于5 mL无水1, 2-二氯乙烷的化合物3 (0.158 g, 0.302 mmol)加入三乙胺(0.183 g, 1.808 mmol), 混合均匀后, 缓慢滴入苯基异氰酸酯中, 常温, 过夜反应, TLC跟踪监测反应终点。二氯甲烷萃取3次, 合并有机相, 饱和食盐水洗涤3次, 无水硫酸钠干燥, 抽滤, 减压蒸干溶剂, 得到淡黄色固体。粗品经硅胶色谱纯化分离[洗脱剂:甲醇-二氯甲烷=1:80 (V/V)]得到白色固体0.118 g, 产率为75%, mp 159.6~160.8 ℃; [α]D25+40.5 (c 0.50, CHCl3); HR-MS (m/z): 642.455 2 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 7.54~7.50 (m, 2H, ph-H-2', 6'), 7.39~7.35 (m, 2H, ph-H-3', 5'), 7.06~7.04 (m, 1H, ph-H-4'), 5.24 (t, J = 3.7 Hz, 1H, H-12), 3.62~3.54 (m, 4H, piperazinyl-H-3', 5'), 3.50~3.42 (m, 4H, piperazinyl-H-2', 6'), 1.08 (s, 3H, CH3), 0.97 (s, 3H, CH3), 0.91 (s, 6H, 2CH3), 0.86 (s, 6H, 2CH3), 0.70 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 217.62, 174.55, 151.61, 144.45, 139.87, 129.34, 129.26, 128.58, 123.49, 121.92, 121.85, 55.26, 51.86, 51.67, 49.71, 49.38, 47.60, 47.45, 46.32, 43.85, 43.33, 41.96, 40.15, 39.42, 37.68, 34.29, 33.97, 33.08, 31.15, 30.73, 28.84, 28.45, 27.32, 27.08, 26.12, 23.94, 22.07, 20.86, 20.75, 17.46, 16.22。
1.4.2 化合物Ⅰ2的制备
按照Ⅰ1的制备方法, 由化合物3 (0.158 g, 0.302 mmol)与邻甲苯异氰酸酯(0.060 g, 0.453 mmol)反应。粗品经硅胶色谱纯化分离[洗脱剂:甲醇-二氯甲烷=1:80 (V/V)]得到白色固体0.114 g, 产率为72%, mp 170.5~171.8 ℃; [α]D25+48.6 (c 0.55, CHCl3); HR-MS (m/z): 656.471 4 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 7.30 (d, J = 6.2 Hz, 1H, ph-H-3'), 7.28~7.24 (m, 2H, ph-H-5', 6'), 7.06~7.04 (m, 1H, ph-H-4'), 3.59~3.51 (m, 4H, piperazinyl-H-3', 5'), 3.47~3.39 (m, 4H, piperazinyl-H-2', 6'), 2.23 (s, 3H, ph-CH3), 1.14 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.03 (s, 3H, CH3), 1.00 (s, 3H, CH3), 0.88 (s, 3H, CH3), 0.84 (s, 3H, CH3), 0.78 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 217.65, 174.57, 151.66, 144.42, 134.97, 131.85, 130.98, 129.54, 126.13, 123.26, 114.79, 55.24, 51.88, 51.67, 49.73, 49.40, 47.58, 47.47, 46.32, 43.82, 43.33, 41.95, 40.13, 39.40, 37.64, 34.32, 33.97, 33.04, 31.15, 30.78, 28.79, 28.35, 26.88, 26.80, 26.24, 23.93, 21.91, 21.78, 20.65, 17.47, 17.08, 16.17。
1.4.3 化合物Ⅰ3的制备
按照Ⅰ1的制备方法, 由化合物3 (0.158 g, 0.302 mmol)与2-氟-4-甲基苯基异氰酸酯(0.068 g, 0.453 mmol)反应。粗品经硅胶色谱纯化分离[洗脱剂:甲醇-二氯甲烷=1:80 (V/V)]得到白色固体0.118 g, 产率为75%, mp 171.3~173.1 ℃; [α]D25 +58.9 (c 0.90, CHCl3); HR-MS (m/z): 674.461 9 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 7.46 (d, J = 6.1 Hz, 1H, ph-H-6'), 7.05 (d, J = 7.2 Hz, 1H, ph-H-5'), 6.95 (s, 1H, ph-H-3'), 5.24 (t, J = 3.7 Hz, 1H, H-12), 3.60~3.52 (m, 4H, piperazinyl-H-3', 5'), 3.48~3.40 (m, 4H, piperazinyl-H-2', 6'), 2.29 (s, 3H, ph-CH3), 1.15 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.03 (s, 3H, CH3), 1.00 (s, 3H, CH3), 0.88 (s, 3H, CH3), 0.84 (s, 3H, CH3), 0.79 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 217.58, 174.84, 163.16, 155.63, 144.47, 134.54, 125.38, 123.35, 123.18, 116.54, 116.29, 55.26, 51.67, 51.42, 49.79, 49.64, 47.81, 47.65, 46.28, 43.84, 43.35, 41.94, 39.88, 39.27, 37.62, 34.03, 33.93, 32.75, 31.24, 30.81, 28.79, 28.53, 27.08, 26.64, 26.27, 23.99, 21.91, 21.77, 21.54, 20.82, 17.41, 16.15。
1.4.4 化合物Ⅰ4的制备
按照Ⅰ1的制备方法, 由化合物3 (0.158 g, 0.302 mmol)与对甲氧基苯异氰酸酯(0.062 g, 0.453 mmol)反应。粗品经硅胶色谱纯化分离[洗脱剂:甲醇-二氯甲烷=1:80 (V/V)]得到白色固体0.120 g, 产率为76%, mp 165.0~166.4 ℃; [α]D25+46.5 (c 0.55, CHCl3); HR-MS (m/z): 672.466 2 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 7.32~7.28 (m, 2H, ph-H-2', 6'), 6.95~6.91 (m, 2H, ph-H-3'), 5.25 (t, J = 3.7 Hz, 1H, H-12), 3.78 (s, 3H, ph-OCH3), 3.61~3.53 (m, 4H, piperazinyl-H-3', 5'), 3.51~3.43 (m, 4H, piperazinyl-H-2', 6'), 1.00 (s, 3H, CH3), 0.99 (s, 3H, CH3), 0.96 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.87 (s, 6H, 2CH3), 0.70 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 217.61, 174.87, 159.34, 155.65, 144.45, 131.98, 123.38, 120.34, 120.17, 114.82, 114.73, 56.03, 55.24, 51.79, 51.68, 49.86, 49.73, 47.51, 47.46, 46.34, 43.76, 43.34, 41.95, 39.81, 39.38, 37.65, 34.42, 33.93, 32.76, 31.28, 30.75, 28.80, 28.39, 26.72, 26.70, 26.29, 23.97, 21.77, 21.65, 20.96, 17.48, 16.13。
1.4.5 化合物Ⅰ5的制备
按照Ⅰ1的制备方法, 由化合物3 (0.158 g, 0.302 mmol)与3-氟苯基异氰酸酯(0.062 g, 0.453 mmol)反应。粗品经硅胶色谱纯化分离[洗脱剂:甲醇-二氯甲烷=1:80 (V/V)]得到白色固体0.099 g, 产率为63%, mp 158.6~159.2 ℃; [α]D25 +47.6 (c 0.55, CHCl3); HR-MS (m/z): 660.446 2 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 7.79 (s, 1H, ph-H-2'), 7.41~7.39 (m, 1H, ph-H-5'), 7.35 (d, J = 5.0 Hz, 1H, ph-H-6'), 7.03 (d, J = 7.3 Hz, 1H, ph-H-4'), 5.23 (t, J = 3.7 Hz, 1H, H-12), 3.60~3.52 (m, 4H, piperazinyl-H-3', 5'), 3.50~3.42 (m, 4H, piperazinyl-H-2', 6'), 1.05 (s, 3H, CH3), 0.97 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.85 (s, 6H, 2CH3), 0.70 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 217.60, 174.58, 163.73, 155.67, 144.64, 137.91, 130.84, 123.51, 117.67, 116.83, 116.44, 55.27, 51.73, 51.68, 49.85, 49.62, 47.69, 47.51, 46.28, 43.79, 43.33, 41.94, 40.15, 39.34, 37.57, 34.26, 33.96, 32.86, 30.72, 30.81, 28.63, 28.35, 26.74, 26.79, 26.28, 23.90, 21.96, 21.72, 20.93, 17.39, 16.17。
1.5 化合物Ⅱ1~Ⅱ5的制备
1.5.1 化合物Ⅱ1的制备
将苯基异硫氰酸酯(0.061 g, 0.453 mmol)溶于10 mL无水1, 2-二氯乙烷中, 置于常温下搅拌; 将溶于5 mL无水1, 2-二氯乙烷的化合物3 (0.158 g, 0.302 mmol)加入三乙胺(0.183 g, 1.808 mmol), 混合均匀后, 缓慢滴入苯基异硫氰酸酯中, 常温, 过夜反应, TLC跟踪监测反应终点。二氯甲烷萃取3次, 合并有机相, 饱和食盐水洗涤3次, 无水硫酸钠干燥, 抽滤, 减压蒸干溶剂, 得到淡黄色固体。粗品经硅胶色谱纯化分离[洗脱剂:甲醇-二氯甲烷=1:80 (V/V)]得到白色固体0.118 g, 产率为75%, mp 134.6~136.4 ℃; [α]D25+42.3 (c 0.55, CHCl3); HR-MS (m/z): 658.432 8 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 7.42~7.38 (m, 2H, ph-H-3', 5'), 7.33~7.29 (m, 2H, ph-H-2', 6'), 7.10~7.08 (m, 1H, ph-H-4'), 5.24 (t, J = 3.7 Hz, 1H, H-12), 3.90~3.82 (m, 4H, piperazinyl-H-3', 5'), 3.52~3.44 (m, 4H, piperazinyl-H-2', 6'), 1.08 (s, 3H, CH3), 0.97 (s, 3H, CH3), 0.91 (s, 6H, 2CH3), 0.86 (s, 6H, 2CH3), 0.70 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 217.57, 182.15, 174.84, 144.68, 138.91, 129.68, 129.54, 128.63, 126.84, 126.65, 56.94, 56.58, 55.67, 50.71, 50.52, 47.86, 47.72, 46.43, 43.84, 43.58, 41.93, 40.18, 39.56, 37.64, 34.33, 33.72, 32.97, 31.20, 30.68, 28.97, 28.43, 27.05, 26.87, 26.19, 23.71, 22.07, 21.83, 20.84, 17.27, 16.11。
1.5.2 化合物Ⅱ2的制备
按照Ⅱ1的制备方法, 由化合物3 (0.158 g, 0.302 mmol)与邻甲苯异硫氰酸酯(0.068 g, 0.453 mmol)反应。粗品经硅胶色谱纯化分离[洗脱剂:甲醇-二氯甲烷=1:80 (V/V)]得到白色固体0.114 g, 产率为72%, mp 142.5~143.9 ℃; [α]D25 +49.8 (c 0.58, CHCl3); HR-MS (m/z): 672.446 8 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 7.23 (d, J = 6.2 Hz, 1H, ph-H-3'), 7.18~7.16 (m, 1H, ph-H-5'), 7.16 (d, J = 6.5 Hz, 1H, ph-H-6'), 7.12~7.10 (m, 1H, ph-H-4'), 5.24 (t, J = 3.7 Hz, 1H, H-12), 3.87~3.79 (m, 4H, piperazinyl-H-3', 5'), 3.48~3.40 (m, 4H, piperazinyl-H-2', 6'), 2.25 (s, 3H, ph-CH3), 1.15 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.03 (s, 3H, CH3), 0.93 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.75 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 217.58, 182.26, 174.94, 144.48, 137.02, 136.27, 131.33, 130.18, 127.49, 126.56, 56.92, 56.88, 55.56, 50.81, 50.63, 47.79, 47.60, 46.52, 43.93, 43.58, 42.05, 40.21, 39.36, 37.67, 34.34, 33.92, 32.76, 30.83, 30.68, 28.84, 28.51, 27.09, 26.86, 26.23, 23.97, 21.84, 21.65, 20.63, 18.19, 17.51, 16.18。
5.3 化合物Ⅱ3的制备
按照Ⅱ1的制备方法, 由化合物3 (0.158 g, 0.302 mmol)与2-氟-4-甲基苯基异硫氰酸酯(0.076 g, 0.453 mmol)反应。粗品经硅胶色谱纯化分离[洗脱剂:甲醇-二氯甲烷=1:80 (V/V)]得到白色固体0.117 g, 产率为75%, mp 144.2~145.4 ℃; [α]D25+60.5 (c 0.95, CHCl3); HR-MS (m/z): 690.438 6 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 7.41~7.39 (m, 1H, ph-H-6'), 7.05 (d, J = 7.1 Hz, 1H, ph-H-5'), 6.96 (s, 1H, ph-H-3'), 5.20 (t, J = 3.7 Hz, 1H, H-12), 3.88~3.80 (m, 4H, piperazinyl-H-3', 5'), 3.46~3.38 (m, 4H, piperazinyl-H-2', 6'), 2.31 (s, 3H, ph-CH3), 1.11 (s, 3H, CH3), 1.00 (s, 3H, CH3), 0.97 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.89 (s, 6H, 2CH3), 0.72 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 217.60, 182.36, 174.95, 167.89, 144.70, 134.88, 128.34, 125.26, 123.35, 117.62, 116.56, 56.93, 56.78, 55.65, 50.69, 50.41, 47.88, 47.64, 46.52, 43.95, 43.35, 41.94, 40.27, 39.33, 37.78, 34.36, 34.17, 32.92, 31.26, 30.76, 28.84, 28.46, 27.18, 26.76, 26.54, 24.25, 21.97, 21.62, 21.44, 20.85, 17.46, 16.14。
1.5.4 化合物Ⅱ4的制备
按照Ⅱ1的制备方法, 由化合物3 (0.158 g, 0.302 mmol)与对甲氧基苯异硫氰酸酯(0.075 g, 0.453 mmol)反应。粗品经硅胶色谱纯化分离[洗脱剂:甲醇-二氯甲烷=1:80 (V/V)]得到白色固体0.119 g, 产率为76%, mp 135.8~137.4 ℃; [α]D25 +48.5 (c 0.55, CHCl3); HR-MS (m/z): 688.443 6 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 7.44~7.40 (m, 2H, ph-H-2', 6'), 6.92~6.88 (m, 2H, ph-H-3', 5'), 5.25 (t, J = 3.7 Hz, 1H, H-12), 3.88~3.80 (m, 4H, piperazinyl-H-3', 5'), 3.75 (s, 3H, ph-OCH3), 3.45~3.37 (m, 4H, piperazinyl-H-2', 6'), 1.01 (s, 3H, CH3), 0.99 (s, 3H, CH3), 0.96 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.87 (s, 6H, 2CH3), 0.70 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 217.56, 182.49, 174.68, 159.65, 144.59, 127.84, 127.67, 123.40, 114.91, 114.65, 113.54, 56.97, 56.75, 55.98, 55.64, 50.46, 50.18, 47.86, 47.62, 46.43, 43.98, 43.52, 42.05, 40.26, 39.57, 37.88, 34.64, 33.98, 32.61, 31.16, 30.92, 28.89, 28.67, 27.16, 26.78, 26.42, 23.63, 21.64, 21.58, 20.96, 17.44, 16.10。
1.5.5 化合物Ⅱ5的制备
按照Ⅱ1的制备方法, 由化合物3 (0.158 g, 0.302 mmol)与3-氟苯基异硫氰酸酯(0.069 g, 0.453 mmol)反应。粗品经硅胶色谱纯化分离[洗脱剂:甲醇-二氯甲烷=1:80 (V/V)]得到白色固体0.098 g, 产率为63%, mp 136.6~138.2 ℃; [α]D25 +51.5 (c 0.60, CHCl3); HR-MS (m/z): 676.423 6 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 7.66 (s, 1H, ph-H-2'), 7.38~7.36 (m, 1H, ph-H-5'), 7.21 (d, J = 6.1 Hz, 1H, ph-H-6'), 6.95 (d, J = 8.1 Hz, 1H, ph-H-4'), 5.23 (t, J = 3.7 Hz, 1H, H-12), 3.87~3.79 (m, 4H, piperazinyl-H-3', 5'), 3.46~3.38 (m, 4H, piperazinyl-H-2', 6'), 1.08 (s, 3H, CH3), 0.97 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.85 (s, 6H, 2CH3), 0.69 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 217.52, 182.26, 174.85, 163.57, 144.53, 139.02, 130.95, 123.41, 122.56, 121.85, 116.76, 56.97, 56.65, 55.64, 50.68, 50.49, 47.88, 47.63, 46.25, 43.84, 43.67, 41.94, 40.22, 39.54, 37.61, 34.32, 33.98, 32.67, 31.22, 30.74, 28.91, 28.34, 26.75, 26.65, 26.54, 23.60, 21.97, 21.62, 20.95, 17.55, 16.09。
2 生物活性测试
以AZD8055为阳性对照药, 采用MTT法对合成的目标化合物进行体外抗肿瘤活性测试, 所选用的肿瘤细胞为人肝癌细胞HepG2和人胃癌细胞SGC7901。将对数生长期肿瘤细胞培养在96孔培养板中, 各细胞株每孔接种5×103个, 每组3个复孔, 置于CO2恒温培养箱中, 培养24 h备用。给药组药品浓度为10 μmol·L−1, CO2恒温培养箱中继续培养72 h。每孔20 µL (1 mg·mL-1) MTT溶液加入, 在37 ℃下孵育4 h, 弃上清液, 加入二甲基亚砜200 µL, 振荡溶解。在酶标仪波长570 nm条件下测定各孔光密度(OD)值, 计算所测化合物对细胞的抑制率和IC50。实验重复3次, 结果取平均值, 计算各组细胞的抑制率, 抑制率= (对照组OD值-药物组OD值)/对照组OD值×100%。
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doi: 10.16438/j.0513-4870.2018-0890
  • 接收时间：2018-09-30
  • 首发时间：2026-01-26
  • 出版时间：2019-02-12
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  • 收稿日期：2018-09-30
  • 修回日期：2018-10-29
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辽宁省自然科学基金资助项目(2015020687)
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    沈阳化工大学制药与生物工程学院, 辽宁 沈阳 110142

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