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Article(id=1222466740894814381, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222466735333171928, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2019-0036, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1547136000000, receivedDateStr=2019-01-11, revisedDate=1549728000000, revisedDateStr=2019-02-10, acceptedDate=null, acceptedDateStr=null, onlineDate=1769388383363, onlineDateStr=2026-01-26, pubDate=1554998400000, pubDateStr=2019-04-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1769388383363, onlineIssueDateStr=2026-01-26, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1769388383363, creator=13701087609, updateTime=1769388383363, updator=13701087609, issue=Issue{id=1222466735333171928, tenantId=1146029695717560320, journalId=1189982191388893191, year='2019', volume='54', issue='4', pageStart='587', pageEnd='759', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1769388382037, creator=13701087609, updateTime=1769389323134, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1222470682642993456, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222466735333171928, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1222470682642993457, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222466735333171928, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=687, endPage=691, ext={EN=ArticleExt(id=1222466741834338532, articleId=1222466740894814381, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Synthesis and antitumor activity of fluoroquinolone C-3 arylidene thiazolone derivatives from ciprofloxacin, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

To expand an efficient strategy for the conversion of antibacterial activity of fluoroquinolones into an antitumor activity, sixteen new compounds, 1-cyclopropyl-6-fluoro-7-(4-methyl-piperazin-1-yl)-3-(5-arylidene-thiazol-4(5H)-one-2-yl)-quinolon-4(1H)-ones (7a-7p), were designed and synthesized with a thiazolone ring and an arylidene moiety as an isostere and modified group, respectively, from ciprofloxacin. Their structures were characterized by elemental analysis and spectral data. The in vitro antitumor activity of the synthesized compounds were measured using Hep-3B, Capan-1 and HL60 cell lines and were found to be more potent than ciprofloxacin. Meanwhile, the SAR revealed that the halogenated phenyl compounds such as fluorophenyl (7h, 7i), chlorophenyl (7j, 7k) or bromophenyl compounds (7l, 7m), and aromatic heterocyclic substitution such as furyl (6n) or pyridyl compounds (6o, 6p) displayed better activity than the control compounds, especially the IC50 values of pyridyl compounds 6o and 6p against Capan-1 cell growth was comparable to doxorubicin. Thus, an arylidene-modified thiazolone scaffold as the replacement of the C-3 carboxylic acid group appears to be an alternative route for an improved antitumor activity of fluoroquinolones.

, correspAuthors=Chao-ran CHEN, Guo-qiang HU, 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, authorCompany=null, fund=null, authors=null, authorsList=Na WANG, Hui-li ZHANG, Chao-ran CHEN, Wen-long HUANG, Guo-qiang HU), CN=ArticleExt(id=1222466742467678493, articleId=1222466740894814381, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=氟喹诺酮C-3芳苄叉基噻唑酮衍生物的合成与抗肿瘤活性, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

为扩展氟喹诺酮由抗菌活性向抗肿瘤活性转化的结构修饰策略，以噻唑酮为C-3羧基的生物电子排体，芳苄叉基为其功能修饰基，设计合成了1-环丙基-6-氟-7-（4-甲基哌嗪-1-基）-3-[5-芳苄叉基-噻唑-4（5H）-酮-2-基]-喹啉-4（1H）-酮（7a~7p）目标化合物，其结构经元素分析和光谱数据确证。体外抗肿瘤实验结果表明，16个目标化合物对Hep-3B、Capan-1和HL60三种实验癌细胞株的活性显著高于母体环丙沙星，其中，卤代苯苄叉基或芳香杂环苄叉基化合物的活性强于其他取代的活性，尤其是吡啶取代化合物（6o、6p）对Capan-1的IC50与对照药多柔比星相当。为此，芳叉苄基修饰的噻唑酮替代C-3羧基有利于提高氟喹诺酮的抗肿瘤活性。

, correspAuthors=陈超然, 胡国强, authorNote=null, correspAuthorsNote=
*陈超然, Tel / Fax: 86-371-23885066, E-mail: ;
胡国强, Tel / Fax: 86-371-23885066, 23880680, E-mail: ;
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Acta Pharm Sin (药学学报), 2012, 47: 1017-1022., articleTitle=Design, synthesis and antitumor activity of fluoroquinolone C-3 heterocycles: bis-oxadiazole methylsulfide derivatives derived from ciprofloxacin, refAbstract=null)], funds=[Fund(id=1222466748104823487, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466740894814381, awardId=20872028, language=CN, fundingSource=国家自然科学基金资助项目(20872028), fundOrder=null, country=null), Fund(id=1222466748205486791, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466740894814381, awardId=21072045, language=CN, fundingSource=国家自然科学基金资助项目(21072045), fundOrder=null, country=null), Fund(id=1222466748306150095, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466740894814381, awardId=162102310392, language=CN, fundingSource=河南省科技发展计划项目(162102310392), fundOrder=null, country=null), Fund(id=1222466748402619093, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466740894814381, awardId=15A350004, language=CN, fundingSource=河南省教育厅科学技术研究重点项目(15A350004), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1222466742891303233, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466740894814381, xref=null, ext=[AuthorCompanyExt(id=1222466742895497538, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466740894814381, companyId=1222466742891303233, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1. 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Compd. Yield/% mp/℃ Elemental analysis (%, Calcd.) MS (m/z) [M+H]+(Calcd.)
C H N
4 45.6 234-236 63.02 (62.78) 5.92 (6.15) 16.53 (16.27) 345 (344.39)
5 73.8 186-188 60.24 (59.98) 5.63 (5.87) 15.78 (15.54) 361 (360.46)
6 64.7 218-220 60.20 (59.98) 5.06 (5.29) 14.23 (13.99) 401 (400.48)
7a 57.8 226-228 66.53 (66.38) 5.38 (5.16) 11.72 (11.47) 489 (488.59)
7b 62.3 231-233 64.03 (64.85) 5.04 (5.25) 11.04 (10.80) 519 (518.61)
7c 45.2 204-206 64.07 (64.85) 5.09 (5.25) 10.62 (10.80) 519 (518.61)
7d 55.6 194-196 67.13 (66.91) 5.65 (5.41) 11.38 (11.15) 503 (502.62)
7e 43.2 182-184 67.16 (66.91) 5.16 (5.41) 11.41 (11.15) 503 (502.62)
7f 72.6 246-248 63.38 (63.15) 4.48 (4.73) 10.76 (10.52) 533 (532.60)
7g 57.3 214-216 62.52 (62.27) 5.24 (5.40) 9.94 (9.68) 579 (578.67)
7h 57.2 243-245 64.26 (64.02) 4.64 (4.78) 11.28 (11.06) 507 (506.58)
7i 52.4 213-215 64.23 (64.02) 4.53 (4.78) 11.32 (11.06) 507 (506.58)
7j 73.2 216-218 62.25 (62.00) 4.42 (4.63) 10.52 (10.71) 523 (523.03)
7k 44.2 193-295 62.23 (62.00) 4.87 (4.63) 10.94 (10.71) 523 (523.03)
7l 65.7 212-214 57.42 (57.15) 4.05 (4.26) 10.15 (9.87) 567 (567.48)
7m 52.4 190-192 57.36 (57.15) 4.44 (4.26) 10.07 (9.87) 567 (567.48)
7n 67.6 226-228 62.58 (62.75) 4.73 (4.84) 11.56 (11.71) 479 (478.55)
7o 63.8 235-237 63.64 (63.79) 4.76 (4.94) 14.54 (14.30) 490 (489.58)
7p 70.3 241-243 64.03 (63.79) 4.78 (4.94) 14.56 (14.30) 490 (489.58)
), ArticleFig(id=1222466747500843667, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466740894814381, language=CN, label=Table 1, caption=

Physical constants and spectral data of intermediates 4, 5, 6 and target compounds (7a-7p)

, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. Yield/% mp/℃ Elemental analysis (%, Calcd.) MS (m/z) [M+H]+(Calcd.)
C H N
4 45.6 234-236 63.02 (62.78) 5.92 (6.15) 16.53 (16.27) 345 (344.39)
5 73.8 186-188 60.24 (59.98) 5.63 (5.87) 15.78 (15.54) 361 (360.46)
6 64.7 218-220 60.20 (59.98) 5.06 (5.29) 14.23 (13.99) 401 (400.48)
7a 57.8 226-228 66.53 (66.38) 5.38 (5.16) 11.72 (11.47) 489 (488.59)
7b 62.3 231-233 64.03 (64.85) 5.04 (5.25) 11.04 (10.80) 519 (518.61)
7c 45.2 204-206 64.07 (64.85) 5.09 (5.25) 10.62 (10.80) 519 (518.61)
7d 55.6 194-196 67.13 (66.91) 5.65 (5.41) 11.38 (11.15) 503 (502.62)
7e 43.2 182-184 67.16 (66.91) 5.16 (5.41) 11.41 (11.15) 503 (502.62)
7f 72.6 246-248 63.38 (63.15) 4.48 (4.73) 10.76 (10.52) 533 (532.60)
7g 57.3 214-216 62.52 (62.27) 5.24 (5.40) 9.94 (9.68) 579 (578.67)
7h 57.2 243-245 64.26 (64.02) 4.64 (4.78) 11.28 (11.06) 507 (506.58)
7i 52.4 213-215 64.23 (64.02) 4.53 (4.78) 11.32 (11.06) 507 (506.58)
7j 73.2 216-218 62.25 (62.00) 4.42 (4.63) 10.52 (10.71) 523 (523.03)
7k 44.2 193-295 62.23 (62.00) 4.87 (4.63) 10.94 (10.71) 523 (523.03)
7l 65.7 212-214 57.42 (57.15) 4.05 (4.26) 10.15 (9.87) 567 (567.48)
7m 52.4 190-192 57.36 (57.15) 4.44 (4.26) 10.07 (9.87) 567 (567.48)
7n 67.6 226-228 62.58 (62.75) 4.73 (4.84) 11.56 (11.71) 479 (478.55)
7o 63.8 235-237 63.64 (63.79) 4.76 (4.94) 14.54 (14.30) 490 (489.58)
7p 70.3 241-243 64.03 (63.79) 4.78 (4.94) 14.56 (14.30) 490 (489.58)
), ArticleFig(id=1222466747593118363, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466740894814381, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. 1H NMR (400MHz, DMSO-d6)
4 1.15-1.32 (m, 4H, c-Pr-H), 2.24 (s, 3H, N-CH3), 2.61-3.68 (m, 9H, piperazine-H and c-Pr-H), 7.23 (s, 1H, NH), 7.56 (d, J = 5.6 Hz, 1H, 8-H), 7.78 (d, J = 13.0 Hz, 1H, 5-H), 7.96, (s, 1H, NH), 8.86 (s, 1H, 2-H)
5 1.16-1.32 (m, 4H, c-Pr-H), 2.24 (s, 3H, N-CH3), 2.64-3.72 (m, 9H, piperazine-H and c-Pr-H), 7.62 (d, J = 5.6 Hz, 1H, 8-H), 7.82 (d, J = 13.2 Hz, 1H, 5-H), 8.88 (s, 1H, 2-H), 9.37, (s, 1H, NH), 9.58 (s, 1H, NH)
6 1.13-1.28 (m, 4H, c-Pr-H), 2.23 (s, 3H, N-CH3), 2.62-3.68 (m, 9H, piperazine-H and c-Pr-H), 4.27 (s, 2H, SCH2), 7.57 (d, J = 5.6 Hz, 1H, 8-H), 7.76 (d, J = 13.2 Hz, 1H, 5-H), 8.86 (s, 1H, 2-H)
7a 1.18-1.32 (m, 4H, c-Pr-H), 2.24 (s, 3H, CH3), 2.63-3.66 (m, 9H, piperazine-H and c-Pr-H), 7.36-7.74 (m, 6H, Ph-H and 8-H), 7.82 (d, J = 13.2 Hz, 1H, 5-H), 8.16 (s, 1H, CH=), 8.87 (s, 1H, 2-H)
7b 1.21-1.35 (m, 4H, c-Pr-H), 2.25 (s, 3H, CH3), 2.65-3.74 (m, 9H, piperazine-H and c-Pr-H), 3.87 (s, 3H, OCH3), 7.56-7.76 (m, 5H, Ph-H and 8-H), 7.86 (d, J = 13.2 Hz, 1H, 5-H), 8.18 (s, 1H, CH=), 8.89 (s, 1H, 2-H)
7c 1.23-1.37 (m, 4H, c-Pr-H), 2.25 (s, 3H, CH3), 2.65-3.72 (m, 9H, piperazine-H and c-Pr-H), 3.88 (s, 3H, OCH3), 7.46-7.78 (m, 5H, Ph-H and 8-H), 7.87 (d, J = 13.2 Hz, 1H, 5-H), 8.17 (s, 1H, CH=), 8.87 (s, 1H, 2-H)
7d 1.20-1.35 (m, 4H, c-Pr-H), 2.23, 2.26 (2s, 6H, 2×CH3), 2.62-3.70 (m, 9H, piperazine-H and c-Pr-H), 7.36-7.76 (m, 5H, Ph-H and 8-H), 7.86 (d, J = 13.2 Hz, 1H, 5-H), 8.16 (s, 1H, CH=), 8.86 (s, 1H, 2-H)
7e 1.23-1.32 (m, 4H, c-Pr-H), 2.24, 2.27 (2s, 6H, 2×CH3), 2.64-3.68 (m, 9H, piperazine-H and c-Pr-H), 7.46-7.78 (m, 5H, Ph-H and 8-H), 7.84 (d, J = 13.2 Hz, 1H, 5-H), 8.17 (s, 1H, CH=), 8.86 (s, 1H, 2-H)
7f 1.25-1.37 (m, 4H, c-Pr-H), 2.26 (s, 3H, CH3), 2.66-3.74 (m, 9H, piperazine-H and c-Pr-H), 6.26 (s, 2H, OCH2O), 7.58-7.82 (m, 4H, Ph-H and 8-H), 7.94 (d, J = 13.2 Hz, 1H, 5-H), 8.18 (s, 1H, CH=), 8.92 (s, 1H, 2-H)
7g 1.26-1.38 (m, 4H, c-Pr-H), 2.26 (s, 3H, CH3), 2.68-3.77 (m, 9H, piperazine-H and c-Pr-H), 3.87, 3.92 (s, 9H, 3×OCH3), 7.68-7.85 (m, 3H, Ph-H and 8-H), 7.93 (d, J = 13.2 Hz, 1H, 5-H), 8.17 (s, 1H, CH=), 8.89 (s, 1H, 2-H)
7h 1.27-1.38 (m, 4H, c-Pr-H), 2.28 (s, 3H, CH3), 2.72-3.78 (m, 9H, piperazine-H and c-Pr-H), 7.72-8.03 (m, 5H, Ph-H and 8-H), 8.06 (d, J = 13.2 Hz, 1H, 5-H), 8.21 (s, 1H, CH=), 8.94 (s, 1H, 2-H)
7i 1.26-1.37 (m, 4H, c-Pr-H), 2.27 (s, 3H, CH3), 2.73-3.76 (m, 9H, piperazine-H and c-Pr-H), 7.68-8.02 (m, 5H, Ph-H and 8-H), 8.05 (d, J = 13.2 Hz, 1H, 5-H), 8.20 (s, 1H, CH=), 8.93 (s, 1H, 2-H)
7j 1.25-1.36 (m, 4H, c-Pr-H), 2.25 (s, 3H, CH3), 2.68-3.76 (m, 9H, piperazine-H and c-Pr-H), 7.74-7.85 (m, 5H, Ph-H and 8-H), 8.03 (d, J = 13.2 Hz, 1H, 5-H), 8.18 (s, 1H, CH=), 8.91 (s, 1H, 2-H)
7k 1.25-1.37 (m, 4H, c-Pr-H), 2.26 (s, 3H, CH3), 2.66-3.77 (m, 9H, piperazine-H and c-Pr-H), 7.72-7.83 (m, 5H, Ph-H and 8-H), 8.05 (d, J = 13.2 Hz, 1H, 5-H), 8.17 (s, 1H, CH=), 8.89 (s, 1H, 2-H)
7l 1.24-1.37 (m, 4H, c-Pr-H), 2.25 (s, 3H, CH3), 2.73-3.78 (m, 9H, piperazine-H and c-Pr-H), 7.76-7.87 (m, 5H, Ph-H and 8-H), 7.96 (d, J = 13.2 Hz, 1H, 5-H), 8.18 (s, 1H, CH=), 8.93 (s, 1H, 2-H)
7m 1.25-1.37 (m, 4H, c-Pr-H), 2.26 (s, 3H, CH3), 2.68-3.75 (m, 9H, piperazine-H and c-Pr-H), 7.73-7.84 (m, 5H, Ph-H and 8-H), 7.93 (d, J = 13.2 Hz, 1H, 5-H), 8.16 (s, 1H, CH=), 8.95 (s, 1H, 2-H)
7n 1.28-1.40 (m, 4H, 2'- and 3'-H), 2.28 (s, 3H, CH3), 2.75-3.82 (m, 9H, piperazine-H and 1'-H), 7.12-8.07 (m, 4H, furyl-H, 8- and 5-H), 8.23 (s, CH=), 8.46 (d, J = 6.5 Hz, 1H, furyl-H), 9.14 (s, 1H, 2-H)
7o 1.31-1.42 (m, 4H, 2'- and 3'-H), 2.33 (s, 3H, CH3), 2.76-3.85 (m, 9H, piperazine-H and 1'-H), 7.62-8.16 (m, 3H, pyridyl-H, 8- and 5-H), 8.26-8.67 (m, 2H, pyridyl-H and CH=), 8.86-9.17 (m, 3H, pyridyl-H and 2-H)
7p 1.33-1.45 (m, 4H, 2'- and 3'-H), 2.36 (s, 3H, CH3), 2.78-3.86 (m, 9H, piperazine-H and 1'-H), 7.68 (d, J = 5.6 Hz, 1H, 8-H), 8.27-8.84 (m, 3H, CH= and pyridyl-H), 8.95-9.24 (m, 3H, pyridyl-H and 2-H)
), ArticleFig(id=1222466747718947494, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466740894814381, language=CN, label=Table 2, caption=

1H NMR data of intermediates 4, 5, 6 and target compounds (7a-7p)

, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. 1H NMR (400MHz, DMSO-d6)
4 1.15-1.32 (m, 4H, c-Pr-H), 2.24 (s, 3H, N-CH3), 2.61-3.68 (m, 9H, piperazine-H and c-Pr-H), 7.23 (s, 1H, NH), 7.56 (d, J = 5.6 Hz, 1H, 8-H), 7.78 (d, J = 13.0 Hz, 1H, 5-H), 7.96, (s, 1H, NH), 8.86 (s, 1H, 2-H)
5 1.16-1.32 (m, 4H, c-Pr-H), 2.24 (s, 3H, N-CH3), 2.64-3.72 (m, 9H, piperazine-H and c-Pr-H), 7.62 (d, J = 5.6 Hz, 1H, 8-H), 7.82 (d, J = 13.2 Hz, 1H, 5-H), 8.88 (s, 1H, 2-H), 9.37, (s, 1H, NH), 9.58 (s, 1H, NH)
6 1.13-1.28 (m, 4H, c-Pr-H), 2.23 (s, 3H, N-CH3), 2.62-3.68 (m, 9H, piperazine-H and c-Pr-H), 4.27 (s, 2H, SCH2), 7.57 (d, J = 5.6 Hz, 1H, 8-H), 7.76 (d, J = 13.2 Hz, 1H, 5-H), 8.86 (s, 1H, 2-H)
7a 1.18-1.32 (m, 4H, c-Pr-H), 2.24 (s, 3H, CH3), 2.63-3.66 (m, 9H, piperazine-H and c-Pr-H), 7.36-7.74 (m, 6H, Ph-H and 8-H), 7.82 (d, J = 13.2 Hz, 1H, 5-H), 8.16 (s, 1H, CH=), 8.87 (s, 1H, 2-H)
7b 1.21-1.35 (m, 4H, c-Pr-H), 2.25 (s, 3H, CH3), 2.65-3.74 (m, 9H, piperazine-H and c-Pr-H), 3.87 (s, 3H, OCH3), 7.56-7.76 (m, 5H, Ph-H and 8-H), 7.86 (d, J = 13.2 Hz, 1H, 5-H), 8.18 (s, 1H, CH=), 8.89 (s, 1H, 2-H)
7c 1.23-1.37 (m, 4H, c-Pr-H), 2.25 (s, 3H, CH3), 2.65-3.72 (m, 9H, piperazine-H and c-Pr-H), 3.88 (s, 3H, OCH3), 7.46-7.78 (m, 5H, Ph-H and 8-H), 7.87 (d, J = 13.2 Hz, 1H, 5-H), 8.17 (s, 1H, CH=), 8.87 (s, 1H, 2-H)
7d 1.20-1.35 (m, 4H, c-Pr-H), 2.23, 2.26 (2s, 6H, 2×CH3), 2.62-3.70 (m, 9H, piperazine-H and c-Pr-H), 7.36-7.76 (m, 5H, Ph-H and 8-H), 7.86 (d, J = 13.2 Hz, 1H, 5-H), 8.16 (s, 1H, CH=), 8.86 (s, 1H, 2-H)
7e 1.23-1.32 (m, 4H, c-Pr-H), 2.24, 2.27 (2s, 6H, 2×CH3), 2.64-3.68 (m, 9H, piperazine-H and c-Pr-H), 7.46-7.78 (m, 5H, Ph-H and 8-H), 7.84 (d, J = 13.2 Hz, 1H, 5-H), 8.17 (s, 1H, CH=), 8.86 (s, 1H, 2-H)
7f 1.25-1.37 (m, 4H, c-Pr-H), 2.26 (s, 3H, CH3), 2.66-3.74 (m, 9H, piperazine-H and c-Pr-H), 6.26 (s, 2H, OCH2O), 7.58-7.82 (m, 4H, Ph-H and 8-H), 7.94 (d, J = 13.2 Hz, 1H, 5-H), 8.18 (s, 1H, CH=), 8.92 (s, 1H, 2-H)
7g 1.26-1.38 (m, 4H, c-Pr-H), 2.26 (s, 3H, CH3), 2.68-3.77 (m, 9H, piperazine-H and c-Pr-H), 3.87, 3.92 (s, 9H, 3×OCH3), 7.68-7.85 (m, 3H, Ph-H and 8-H), 7.93 (d, J = 13.2 Hz, 1H, 5-H), 8.17 (s, 1H, CH=), 8.89 (s, 1H, 2-H)
7h 1.27-1.38 (m, 4H, c-Pr-H), 2.28 (s, 3H, CH3), 2.72-3.78 (m, 9H, piperazine-H and c-Pr-H), 7.72-8.03 (m, 5H, Ph-H and 8-H), 8.06 (d, J = 13.2 Hz, 1H, 5-H), 8.21 (s, 1H, CH=), 8.94 (s, 1H, 2-H)
7i 1.26-1.37 (m, 4H, c-Pr-H), 2.27 (s, 3H, CH3), 2.73-3.76 (m, 9H, piperazine-H and c-Pr-H), 7.68-8.02 (m, 5H, Ph-H and 8-H), 8.05 (d, J = 13.2 Hz, 1H, 5-H), 8.20 (s, 1H, CH=), 8.93 (s, 1H, 2-H)
7j 1.25-1.36 (m, 4H, c-Pr-H), 2.25 (s, 3H, CH3), 2.68-3.76 (m, 9H, piperazine-H and c-Pr-H), 7.74-7.85 (m, 5H, Ph-H and 8-H), 8.03 (d, J = 13.2 Hz, 1H, 5-H), 8.18 (s, 1H, CH=), 8.91 (s, 1H, 2-H)
7k 1.25-1.37 (m, 4H, c-Pr-H), 2.26 (s, 3H, CH3), 2.66-3.77 (m, 9H, piperazine-H and c-Pr-H), 7.72-7.83 (m, 5H, Ph-H and 8-H), 8.05 (d, J = 13.2 Hz, 1H, 5-H), 8.17 (s, 1H, CH=), 8.89 (s, 1H, 2-H)
7l 1.24-1.37 (m, 4H, c-Pr-H), 2.25 (s, 3H, CH3), 2.73-3.78 (m, 9H, piperazine-H and c-Pr-H), 7.76-7.87 (m, 5H, Ph-H and 8-H), 7.96 (d, J = 13.2 Hz, 1H, 5-H), 8.18 (s, 1H, CH=), 8.93 (s, 1H, 2-H)
7m 1.25-1.37 (m, 4H, c-Pr-H), 2.26 (s, 3H, CH3), 2.68-3.75 (m, 9H, piperazine-H and c-Pr-H), 7.73-7.84 (m, 5H, Ph-H and 8-H), 7.93 (d, J = 13.2 Hz, 1H, 5-H), 8.16 (s, 1H, CH=), 8.95 (s, 1H, 2-H)
7n 1.28-1.40 (m, 4H, 2'- and 3'-H), 2.28 (s, 3H, CH3), 2.75-3.82 (m, 9H, piperazine-H and 1'-H), 7.12-8.07 (m, 4H, furyl-H, 8- and 5-H), 8.23 (s, CH=), 8.46 (d, J = 6.5 Hz, 1H, furyl-H), 9.14 (s, 1H, 2-H)
7o 1.31-1.42 (m, 4H, 2'- and 3'-H), 2.33 (s, 3H, CH3), 2.76-3.85 (m, 9H, piperazine-H and 1'-H), 7.62-8.16 (m, 3H, pyridyl-H, 8- and 5-H), 8.26-8.67 (m, 2H, pyridyl-H and CH=), 8.86-9.17 (m, 3H, pyridyl-H and 2-H)
7p 1.33-1.45 (m, 4H, 2'- and 3'-H), 2.36 (s, 3H, CH3), 2.78-3.86 (m, 9H, piperazine-H and 1'-H), 7.68 (d, J = 5.6 Hz, 1H, 8-H), 8.27-8.84 (m, 3H, CH= and pyridyl-H), 8.95-9.24 (m, 3H, pyridyl-H and 2-H)
), ArticleFig(id=1222466747802833582, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466740894814381, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. Ar IC50/μmol·L-1
Hep-3B Capan-1 HL60
7a C6H5 10.7 ± 1.2 6.7 ± 0.6 18.6 ± 1.6
7b 4-CH3O-C6H4 15.2 ± 1.4 11.6 ± 1.2 21.8 ± 1.7
7c 2-CH3O-C6H4 8.4 ± 1.0 5.6 ± 0.6 12.6 ± 1.0
7d 4-CH3C6H4 16.5 ± 1.6 12.6 ± 1.5 24.6 ± 2.3
7e 3-CH3-C6H4 13.6 ± 1.4 10.7 ± 0.8 18.7 ± 1.6
7f 3, 4-OCH2O-C6H3 13.8 ± 1.5 6.4 ± 0.8 20.4 ± 1.7
7g 3, 4, 5-(CH3O)3-C6H2 14.5 ± 1.4 12.8 ± 1.3 24.5 ± 2.6
7h 4-F-C6H4 3.5 ± 0.4 2.5 ± 0.3 8.7 ± 1.0
7i 3-F-C6H4 2.8 ± 0.5 1.7 ± 0.3 7.3 ± 0.8
7j 4-Cl-C6H4 3.2 ± 0.4 3.2 ± 0.4 10.5 ± 1.2
7k 3-Cl-C6H4 3.6 ± 0.5 2.8 ± 0.3 8.6 ± 1.1
7l 4-Br-C6H4 2.7 ± 0.3 3.6 ± 0.5 8.6 ± 1.2
7m 3-Br-C6H4 3.6 ± 0.6 3.1 ± 0.4 7.8 ± 1.0
7n 2-Furyl 4.0 ± 0.6 3.7 ± 0.5 5.3 ± 0.7
7o 3-Pyridyl 1.5 ± 0.2 0.6 ± 0.1 1.8 ± 0.3
7p 4-Pyridyl 1.7 ± 0.3 0.8 ± 0.06 2.5 ± 0.4
4 > 100 > 100 > 100
5 > 100 > 100 > 100
6 > 70 > 50 > 70
DOX 2.8 ± 0.4 2.0 ± 0.3 3.6 ± 0.5
1 > 100 > 100 > 100
), ArticleFig(id=1222466747928662705, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466740894814381, language=CN, label=Table 3, caption=

The in vitro antitumor activity of the title compounds 7a-7p against the tested cancer cells (n = 3). DOX: Doxorubicin

, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. Ar IC50/μmol·L-1
Hep-3B Capan-1 HL60
7a C6H5 10.7 ± 1.2 6.7 ± 0.6 18.6 ± 1.6
7b 4-CH3O-C6H4 15.2 ± 1.4 11.6 ± 1.2 21.8 ± 1.7
7c 2-CH3O-C6H4 8.4 ± 1.0 5.6 ± 0.6 12.6 ± 1.0
7d 4-CH3C6H4 16.5 ± 1.6 12.6 ± 1.5 24.6 ± 2.3
7e 3-CH3-C6H4 13.6 ± 1.4 10.7 ± 0.8 18.7 ± 1.6
7f 3, 4-OCH2O-C6H3 13.8 ± 1.5 6.4 ± 0.8 20.4 ± 1.7
7g 3, 4, 5-(CH3O)3-C6H2 14.5 ± 1.4 12.8 ± 1.3 24.5 ± 2.6
7h 4-F-C6H4 3.5 ± 0.4 2.5 ± 0.3 8.7 ± 1.0
7i 3-F-C6H4 2.8 ± 0.5 1.7 ± 0.3 7.3 ± 0.8
7j 4-Cl-C6H4 3.2 ± 0.4 3.2 ± 0.4 10.5 ± 1.2
7k 3-Cl-C6H4 3.6 ± 0.5 2.8 ± 0.3 8.6 ± 1.1
7l 4-Br-C6H4 2.7 ± 0.3 3.6 ± 0.5 8.6 ± 1.2
7m 3-Br-C6H4 3.6 ± 0.6 3.1 ± 0.4 7.8 ± 1.0
7n 2-Furyl 4.0 ± 0.6 3.7 ± 0.5 5.3 ± 0.7
7o 3-Pyridyl 1.5 ± 0.2 0.6 ± 0.1 1.8 ± 0.3
7p 4-Pyridyl 1.7 ± 0.3 0.8 ± 0.06 2.5 ± 0.4
4 > 100 > 100 > 100
5 > 100 > 100 > 100
6 > 70 > 50 > 70
DOX 2.8 ± 0.4 2.0 ± 0.3 3.6 ± 0.5
1 > 100 > 100 > 100
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氟喹诺酮C-3芳苄叉基噻唑酮衍生物的合成与抗肿瘤活性
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王娜 1 , 张会丽 2 , 陈超然 3, * , 黄文龙 4 , 胡国强 1, *
药学学报 | 研究论文 2019,54(4): 687-691
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药学学报 | 研究论文 2019, 54(4): 687-691
氟喹诺酮C-3芳苄叉基噻唑酮衍生物的合成与抗肿瘤活性
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王娜1, 张会丽2, 陈超然3, * , 黄文龙4, 胡国强1, *
作者信息
  • 1.河南大学药物研究所, 河南 开封 475001
  • 2.郑州工业应用技术学院药学院, 河南 郑州 451150
  • 3.河南大学护理与健康研究所, 河南 开封 475004
  • 4.中国药科大学新药研究中心, 江苏 南京 210009

通讯作者:

*陈超然, Tel / Fax: 86-371-23885066, E-mail: ;
胡国强, Tel / Fax: 86-371-23885066, 23880680, E-mail: ;
Synthesis and antitumor activity of fluoroquinolone C-3 arylidene thiazolone derivatives from ciprofloxacin
Na WANG1, Hui-li ZHANG2, Chao-ran CHEN3, * , Wen-long HUANG4, Guo-qiang HU1, *
Affiliations
  • 1. Institute of Drugs, Henan University, Kaifeng 475001, China
  • 2. School of Pharmacy, Zhengzhou University of Industrial Technology, Zhengzhou 451150, China
  • 3. Institute of Nursing and Health, Henan University, Kaifeng 475004, China
  • 4. Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
出版时间: 2019-04-12 doi: 10.16438/j.0513-4870.2019-0036
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摘要
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为扩展氟喹诺酮由抗菌活性向抗肿瘤活性转化的结构修饰策略，以噻唑酮为C-3羧基的生物电子排体，芳苄叉基为其功能修饰基，设计合成了1-环丙基-6-氟-7-（4-甲基哌嗪-1-基）-3-[5-芳苄叉基-噻唑-4（5H）-酮-2-基]-喹啉-4（1H）-酮（7a~7p）目标化合物，其结构经元素分析和光谱数据确证。体外抗肿瘤实验结果表明，16个目标化合物对Hep-3B、Capan-1和HL60三种实验癌细胞株的活性显著高于母体环丙沙星，其中，卤代苯苄叉基或芳香杂环苄叉基化合物的活性强于其他取代的活性，尤其是吡啶取代化合物（6o、6p）对Capan-1的IC50与对照药多柔比星相当。为此，芳叉苄基修饰的噻唑酮替代C-3羧基有利于提高氟喹诺酮的抗肿瘤活性。

氟喹诺酮  /  噻唑  /  不饱和酮  /  生物电子等排体  /  抗肿瘤活性

To expand an efficient strategy for the conversion of antibacterial activity of fluoroquinolones into an antitumor activity, sixteen new compounds, 1-cyclopropyl-6-fluoro-7-(4-methyl-piperazin-1-yl)-3-(5-arylidene-thiazol-4(5H)-one-2-yl)-quinolon-4(1H)-ones (7a-7p), were designed and synthesized with a thiazolone ring and an arylidene moiety as an isostere and modified group, respectively, from ciprofloxacin. Their structures were characterized by elemental analysis and spectral data. The in vitro antitumor activity of the synthesized compounds were measured using Hep-3B, Capan-1 and HL60 cell lines and were found to be more potent than ciprofloxacin. Meanwhile, the SAR revealed that the halogenated phenyl compounds such as fluorophenyl (7h, 7i), chlorophenyl (7j, 7k) or bromophenyl compounds (7l, 7m), and aromatic heterocyclic substitution such as furyl (6n) or pyridyl compounds (6o, 6p) displayed better activity than the control compounds, especially the IC50 values of pyridyl compounds 6o and 6p against Capan-1 cell growth was comparable to doxorubicin. Thus, an arylidene-modified thiazolone scaffold as the replacement of the C-3 carboxylic acid group appears to be an alternative route for an improved antitumor activity of fluoroquinolones.

fluoroquinolone  /  thiazole  /  unsaturated ketone  /  bioisostere  /  antitumor activity
王娜, 张会丽, 陈超然, 黄文龙, 胡国强. 氟喹诺酮C-3芳苄叉基噻唑酮衍生物的合成与抗肿瘤活性. 药学学报, 2019 , 54 (4) : 687 -691 . DOI: 10.16438/j.0513-4870.2019-0036
Na WANG, Hui-li ZHANG, Chao-ran CHEN, Wen-long HUANG, Guo-qiang HU. Synthesis and antitumor activity of fluoroquinolone C-3 arylidene thiazolone derivatives from ciprofloxacin[J]. Acta Pharmaceutica Sinica, 2019 , 54 (4) : 687 -691 . DOI: 10.16438/j.0513-4870.2019-0036
正文
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鉴于拓扑异构酶(Topo)不仅是氟喹诺酮药物的抗菌作用靶点, 也是抗肿瘤药物的重要作用靶标, 同时其喹啉环又是构建药物分子的优势骨架, 因此, 基于机制或结构的理性药物设计策略, 可将氟喹诺酮的抗菌活性转为抗肿瘤活性, 扩展氟喹诺酮研究的新领域[1]。与此同时, 对氟喹诺酮的结构修饰研究发现, 其C-3羧基并非是抗肿瘤活性所必需的药效团, 用唑稠杂环[2]或唑杂环修饰的酰胺[3]骨架作为C-3羧基的等排体有利于提高其抗肿瘤活性, 表明唑杂环无论作为生物等排体或其功能修饰基对提高抗肿瘤活性发挥至关重要作用, 值得关注和进一步发展。在众多的唑杂环中, 考虑到噻唑酮骨架因存在理化性质各异的N、O、S供电子原子可与大分子靶点以多种方式相结合而表现出广泛的药理活性[4], 尤其是活泼亚甲基(COCH2)可与芳醛发生羟醛缩合形成芳苄叉基, 与噻唑酮羰基形成α, β-不饱和酮骨架不仅是许多天然有效成分如查尔酮和黄酮类[5]的活性药效团, 也是靶向小分子酪氨酸激酶抑制剂舒尼替尼[6]的特征药效团, 更重要的是它能与大分子靶点中的供电子基发生迈克尔加成反应而产生细胞毒作用[7]。因此, 芳苄叉基噻唑酮用于抗肿瘤药物分子骨架的构建备受关注, 而其作为氟喹诺酮C-3羧基等排体的研究尚未见报道。为此, 本文以噻唑酮为C-3羧基的等排体, 芳苄叉基作为其功能修饰基, 设计合成了氟喹诺酮C-3芳苄叉基噻唑酮类目标化合物(7a~7p), 并通过芳基取代基电性的变化对其活性的影响, 得出初步的构效关系(SAR), 为进一步结构修饰提供新思路。
目标化合物(7a~7p)的制备见合成路线1所示。环丙沙星(1)与甲酸和甲醛发生哌嗪NH甲基化反生成N-甲基环丙沙星(2), 在甲醇中用浓硫酸催化进行酯化反应得到N-甲基环丙沙星甲酯(3), 不经分离直接在碱的催化下与氨水发生胺解反应生成N-甲基环丙沙星酰胺(4)。中间体4与劳森试剂发生O-S交换反应可得到N-甲基环丙沙星硫代酰胺(5), 与溴乙酸乙酯发生缩环合反应得到N-甲基环丙沙星C-3噻唑酮(6), 再与芳香醛发生Claisen-Schmidt缩合反应形成芳苄叉基噻唑酮取代的N-甲基环丙沙星衍生物(7a~7p)。
结果与讨论
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1 化学部分
1与甲酸-甲醛通过Eschweiler-Clarke反应以高收率得到化合物2, 它在甲醇中用过量浓硫酸催化可顺利发生酯化反应, 经分离可得到60%甲酯化物3, 但与浓氨水难于发生胺解反应得到酰胺4, 而在浓NaOH碱液的催化下可顺利得到预期产物4。为此, 酯化反应结束后, 不经分离, 直接用NaOH中和、催化胺解两步一锅反应可简便制得酰胺4。同时, 酰胺4在四氢呋喃、乙腈、苯、甲苯、二氧六环等非质子惰性溶剂中溶解度较差, 与Lawesson试剂难于反应, 而在吡啶(Py)中有较好的溶解度且顺利反应得到硫代酰胺5。接着5的互变异构体亚氨基硫醇与溴乙酸乙酯发生亲核取代、分子内环合反应到噻唑酮6, 再与芳香醛缩合到目标化合物7。中间体4、5、6及目标化合物7的结构经1H NMR、MS及元素分析确证, 其收率、物理常数及波谱数据见表 1、2。
中间体4和5的1H NMR图谱在低场δ 8.90、7.80和7.60处出现与环丙沙星喹啉酮骨架2-H、5-H和8-H相似的化学位移外, 同时在δ 7.40、7.90和9.40、9.60处出现双质子双单峰(2s, 2H)可分别归属为酰胺(CONH2)和硫代酰胺(C(S)NH2)的H位移, 但在化合物6中这两组H峰均消失, 而在δ 4.30处出现的双质子单峰(s, 2H)可归属为噻唑酮环的5-CH2质子化学位移。类似的, 目标物7的噻唑酮环5-CH2质子化学位移消失而被低场δ 8.20处的单质子单峰(s, 1H)替代, 可归属为芳甲叉基(Ar-CH=)的H位移。另外, 元素分析值及MS测定值也与目标化合物结构组成相一致, 表明所得到的产物与预期的结构相符合。
2 抗肿瘤构效关系
体外抗肿瘤实验结果(表 3)表明, 16个目标物对Hep-3B、Capan-1及HL60三种实验癌细胞的IC50均低于25.0 μmol·L-1, 而母体环丙沙星1及其C-3羧基电子等排体环丙沙星酰胺4及硫代酰胺5中间体的IC50 > 100 μmol·L-1, 生物电子等排体C-3噻唑酮6的IC50 > 50 μmol·L-1, 表明C-3羧基及其电子等排体C-3 (硫代)酰胺并非是抗肿瘤活性所必要的, 用芳苄叉基噻唑酮替代有利于提高其抗肿瘤活性。构效关系进一步揭示芳环苯环取代基体积的增大不利于提高其活性, 如三甲氧基苯基化合物7g对3种实验癌细胞均呈现出较低的活性; 苯环取代基的种类对活性的影响次序为卤素 > 甲氧基 > 甲基, 而对肿瘤细胞选择性为Capan-1 > Hep-3B > HL60。同时, 含吸电子基的芳香杂环化合物(7n、7o、7p)均表现出最好的活性, 尤其对Capan-1的活性与抗肿瘤药多柔比星相当, 具有潜在的研究价值。因此, 由目标化合物7a~7p的活性均高于C-3噻唑酮6及母体1表明, 噻唑酮杂环替代C-3羧基是必需的, 而对等排体噻唑酮的功能化修饰是必要的, 尤其是引入芳苄叉基构建的α, β-不饱和酮结构对提高抗肿瘤活性至关重要。同时, F、Cl、Br虽然原子半径和电负性有较大的差异, 而作为苯环取代对Capan-1细胞活性的影响差异较小, 可见芳环取代基的空间效应和电效应对活性影响也是综合效应, 可能对药动学性质的影响也值得探讨。
3 结论
基于氟喹诺酮的抗菌作用机制及其结构特征, 用噻唑酮作为C-3羧基的生物等排体, 芳苄叉基为功能修饰基, 构建的C-3噻唑α, β-不饱和酮衍生物可提高其抗肿瘤活性。其中, 含有吸电子基取代苯环或吸电子的芳香杂环化合物的活性高于其他取代基, 提示增加不饱和酮双键的亲电性导致易与大分子配体发生迈克尔加成反应增加细胞毒作用, 有利于提高其抗肿瘤活性, 进一步表明α, β-不饱酮结构对抗肿瘤发挥至关重要的作用。为此, 用芳苄叉基噻唑酮骨架作为C-3的生物电子等排体可能是氟喹诺酮向抗肿瘤活性转化的有效结构修饰途径, 这为抗肿瘤氟喹诺酮分子的构建提供新方法。
实验部分
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仪器和试剂  熔点用WK-1B数字熔点仪(上海精密科学仪器厂), 毛细管法, 温度未校正; AM-400型核磁共振仪(德国Bruker公司), DMSO-d6为溶剂; Esquire LC型质谱仪(德国Bruker公司); 2400-Ⅱ元素分析仪(美国PE公司)。所用环丙沙星1为商品, N-甲基环丙沙星按文献[8]的方法制备, 其他试剂均为分析纯。
1 化学合成
1.1 N-甲基环丙沙星酰胺(4)的合成
N-甲基环丙沙星2 (20.0 g, 58.0 mmol)溶于500 mL无水甲醇中, 冰浴搅拌下慢慢滴加浓硫酸15 mL, 然后水浴搅拌回流反应10 h。冰浴0~5 ℃搅拌下慢慢滴加质量分数为30%氢氧化钠溶液至反应液pH 7.0, 常温搅拌1 h。滤除产生的固体, 滤液水浴55~60 ℃, 同时滴加浓氨水30 mL和上述碱液15 g, 然后搅拌回流反应5 h。减压蒸除溶剂, 加去离子水200 mL, 用浓盐酸中和至pH 8.0~9.0, 放置析出固体。过滤, 水洗至中性, 干燥。粗品用乙醇重结晶, 得类白色结晶4。
1.2 N-甲基环丙沙星硫代酰胺(5)的合成
N-甲基环丙沙星酰胺4 (10.0 g, 29.0 mmol)溶于无水吡啶200 mL中, 常温搅拌下慢慢加入劳森试剂(13.6 g, 34.0 mmol), 油浴搅拌回流反应24 h。减压蒸除溶剂, 残余物加无水乙腈150 mL和适量活性炭, 回流2 h。热过滤, 滤液放置析出固体, 乙腈洗涤, 干燥, 得类白色结晶5。
1.3 1-环丙基-6-氟-7-(4-甲基哌嗪-1-基)-3-[噻唑-4-(5H)酮-2-基]-喹啉-4-(1H)-酮(6)的合成
N-甲基环丙沙星硫代酰胺5 (10.0 g, 28.0 mmol)悬浮于200 mL 95%乙醇中, 滴加溴乙酸乙酯(5.6 g, 34.0 mmol), 水浴搅拌回流反应16 h。减压蒸除溶剂, 残余物加去离子水200 mL和适量活性炭, 回流1 h。热过滤, 滤液用浓氨水调pH 9.0~10.0, 放置析出固体, 过滤, 水洗至中性, 干燥, 用无水乙醇重结晶, 得淡黄色结晶6。
1.4 1-环丙基-6-氟-7-(4-甲基哌嗪-1-基)-3-[5-芳苄叉基-噻唑-4(5H)-酮-2-基]-喹啉-4(1H)-酮(7a~7p)合成通法
中间体6 (1.0 g, 2.5 mmol)与新熔融的无水乙酸钠(0.41 g, 5. 0 mmol)和芳香醛(3.0 mmol)依次加入到15 mL冰醋酸中, 混合反应物油浴磁力搅拌回流反应20 h。减压蒸除溶剂, 残余物加去离子水50 mL, 用浓氨水调pH 9.0~10.0, 二氯甲烷提取(3×25 mL), 饱和食盐水洗涤, 无水硫酸钠干燥。柱色谱(V氯仿:V甲醇 = 5:1)纯化, 得金黄色固体目标产物7a~7p。
2 体外抗癌细胞增殖活性
对合成的16个C-3噻唑不饱和酮目标化合物7a~7p及对照环丙沙星(ciprofloxacin, CFX)和结构类似抗癌药物多柔比星(doxorubicin, DOX)用DMSO配成1.0×10-2 mol·L-1浓度的储备液, 用RPMI-1640稀释到所需浓度(50、10、5、1.0、0.1×10-6 mol·L-1)。取对数生长期的人肝癌Hep-3B细胞、人胰腺癌Capan-1细胞及人白血病HL60细胞分别以每孔5 000个细胞接种于96孔板, 培养隔夜后, 加入不同浓度的上述供试化合物溶液, 继续培养48 h后弃去培养基。每孔加入1 g·L–1 MTT溶液100 μL, 继续培养4 h后弃上清液。每孔加入二甲基亚砜150 μL, 轻轻振荡30 min, 用酶标仪在570 nm波长处测其吸光度值。计算各组对癌细胞的抑制率:抑制率% = [(1-实验组吸光度值)/对照组吸光度值]×100%。然后以各药物浓度的对数值对各浓度下的抑制率作线性回归, 得浓度-效应方程, 以此计算出各供试化合物对实验癌细胞的半数抑制浓度(IC50)。所有实验在相同条件下重复进行3次, 最终结果以mean ± SD表示。
基金
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  • 国家自然科学基金资助项目(20872028)
  • 国家自然科学基金资助项目(21072045)
  • 河南省科技发展计划项目(162102310392)
  • 河南省教育厅科学技术研究重点项目(15A350004)
文献
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参考文献 引证文献
排序方式：
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Hu W , Huang XS , Wu JF et al . Discovery of novel topoisomerase Ⅱ inhibitors by medicinal chemistry approaches[J]. J Med Chem, 2018, 61: 8947-8980.
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Gao LZ , Xie YS , Yan Q et al . Synthesis and anti-proliferative activity of fluoroquinolone (rhodanine unsaturated ketone) amide derivatives[J]. Acta Pharm Sin (药学学报), 2015, 50: 1008-1012. http://www.yxxb.com.cn:8081/aps/CN/abstract/abstract15472.shtml
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Hu GQ , Hou LL , Wang GQ et al . Design, synthesis and antitumor activity of fluoroquinolone C-3 heterocycles: bis-oxadiazole methylsulfide derivatives derived from ciprofloxacin[J]. Acta Pharm Sin (药学学报), 2012, 47: 1017-1022. http://www.yxxb.com.cn:8081/aps/CN/abstract/abstract14274.shtml
2019年第54卷第4期
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文章信息
doi: 10.16438/j.0513-4870.2019-0036
  • 接收时间：2019-01-11
  • 首发时间：2026-01-26
  • 出版时间：2019-04-12
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  • 收稿日期：2019-01-11
  • 修回日期：2019-02-10
基金
国家自然科学基金资助项目(20872028)
国家自然科学基金资助项目(21072045)
河南省科技发展计划项目(162102310392)
河南省教育厅科学技术研究重点项目(15A350004)
作者信息
    1.河南大学药物研究所, 河南 开封 475001
    2.郑州工业应用技术学院药学院, 河南 郑州 451150
    3.河南大学护理与健康研究所, 河南 开封 475004
    4.中国药科大学新药研究中心, 江苏 南京 210009

通讯作者:

*陈超然, Tel / Fax: 86-371-23885066, E-mail: ;
胡国强, Tel / Fax: 86-371-23885066, 23880680, E-mail: ;
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
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
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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