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Article(id=1201177210876031987, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201177206518145841, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2023-0760, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1687104000000, receivedDateStr=2023-06-19, revisedDate=1689436800000, revisedDateStr=2023-07-16, acceptedDate=null, acceptedDateStr=null, onlineDate=1764312563866, onlineDateStr=2025-11-28, pubDate=1704988800000, pubDateStr=2024-01-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764312563866, onlineIssueDateStr=2025-11-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764312563866, creator=13701087609, updateTime=1764312563866, updator=13701087609, issue=Issue{id=1201177206518145841, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='1', pageStart='1', pageEnd='268', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764312562826, creator=13701087609, updateTime=1764312760268, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1201178034725417827, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201177206518145841, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1201178034725417828, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201177206518145841, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=152, endPage=160, ext={EN=ArticleExt(id=1201177211433873419, articleId=1201177210876031987, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Synthesis and antibacterial activity evaluation of octapeptin derivatives, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Octapeptin has strong antibacterial activity against Gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii, while it also has activity against some Gram-positive bacteria. This study used natural octapeptin A3 and B3 as lead compounds for structural modification. Twenty-one peptide derivatives (including A3 and B3) containing eight amino acid residues were prepared by solid-phase synthesis, and evaluated for antibacterial activity and renal cytotoxicity. Among them, three compounds 6, 7 and 17 exhibited broad-spectrum antibacterial activity and significantly enhanced the activity for Gram-positive bacteria while maintaining the activity of Gram-negative bacteria. Several compounds improved the activity for Pseudomonas aeruginosa. Compound 7 was active against all test strains and had relatively low renal cytotoxicity. The results provide a basis for the further development of novel polypeptide antibiotics.

, correspAuthors=Zhuo-rong LI, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 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=He-xian YANG, A-long CUI, Yong-jian WANG, Shi-bo KOU, Miao LÜ, Hong YI, Zhuo-rong LI), CN=ArticleExt(id=1201177212771856474, articleId=1201177210876031987, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=八肽菌素衍生物的合成及其抗菌活性研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

八肽菌素在对大肠埃希菌、肺炎克雷伯菌、鲍曼不动杆菌等G-菌具有较强活性的同时, 对部分G+菌也有一定的活性。本研究以天然八肽菌素A3和B3为先导化合物进行结构改造, 采用固相合成法制备了21个含有8个氨基酸残基的肽类衍生物(含A3和B3), 并对其进行抗菌活性测试和肾细胞毒性评价。其中, 化合物6、7和17显示有广谱抗菌活性, 在维持抗G-菌活性的同时, 明显提升了抗G+菌活性; 部分化合物提高了抗铜绿假单胞菌活性。化合物7对所有测定菌株均有活性且肾细胞毒性相对较低。本文研究结果为进一步发展新型多肽类抗菌药物奠定了一定的基础。

, correspAuthors=李卓荣, authorNote=null, correspAuthorsNote=
*李卓荣, Tel: 86-10-63027185, E-mail:
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Advances in development of antimicrobial peptidomimetics as potential drugs [J]. Molecules, 2017, 22: 1430., articleTitle=null, refAbstract=null), Reference(id=1201177219092673095, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, 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=Cui AL, Yang HX, Xue ST, et al. Structure modification and antimicrobial activity of novel cationic melittin analogues [J]. 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The value of antimicrobial peptides in the age of resistance [J]. Lancet Infect Dis, 2020, 20: 216-230., articleTitle=null, refAbstract=null), Reference(id=1201177219428217434, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, 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=Meyers E, Brown WE, Principe PA, et al. EM49, a new peptide antibiotic. I. Fermentation, isolation, and preliminary characterization [J]. J Antibiot, 1973, 26: 444-448., articleTitle=null, refAbstract=null), Reference(id=1201177219503714910, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, 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=Han ML, Shen HH, Hansford KA, et al. Investigating the interaction of octapeptin A3 with model bacterial membranes [J]. ACS Infect Dis, 2017, 3: 606-619., articleTitle=null, refAbstract=null), Reference(id=1201177219612766819, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, 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=Velkov T, Roberts KD, Li J. Rediscovering the octapeptins [J]. Nat Prod Rep, 2017, 34: 295-309., articleTitle=null, refAbstract=null), Reference(id=1201177219709235815, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, 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=Velkov T, Gallardo-Godoy A, Swarbrick JD, et al. Structure, function, and biosynthetic origin of octapeptin antibiotics active against extensively drug-resistant Gram-negative bacteria [J]. Cell Chem Biol, 2018, 25: 380-391., articleTitle=null, refAbstract=null), Reference(id=1201177219830870636, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, 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=De Zoysa GH, Cameron AJ, Hegde VV, et al. Antimicrobial peptides with potential for biofilm eradication: synthesis and structure activity relationship studies of battacin peptides [J]. J Med Chem, 2015, 58: 625-639., articleTitle=null, refAbstract=null), Reference(id=1201177219927339634, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, 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=Yang HX, Xie ZS, Yi H, et al. Design, synthesis, and bioactivity investigation of cyclic lipopeptide antibiotics containing eight to nine amino acids [J]. J Med Chem, 2023, 66: 2524-2541., articleTitle=null, refAbstract=null), Reference(id=1201177220036391543, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, 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=Cui AL, Hu XX, Gao Y, et al. Synthesis and bioactivity investigation of the individual components of cyclic lipopeptide antibiotics [J]. J Med Chem, 2018, 61: 1845-1857., articleTitle=null, refAbstract=null)], funds=[Fund(id=1201177218409001504, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, awardId=82003600, language=CN, fundingSource=国家自然科学基金(82003600), fundOrder=null, country=null), Fund(id=1201177218488693285, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, awardId=32141003, language=CN, fundingSource=国家自然科学基金(32141003), fundOrder=null, country=null), Fund(id=1201177218593550893, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, awardId=2021-I2M-1-030, language=CN, fundingSource=中国医学科学院医学与健康科技创新工程(2021-I2M-1-030), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1201177213065457778, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, xref=null, ext=[AuthorCompanyExt(id=1201177213073846388, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, companyId=1201177213065457778, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1201177213086429300, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, companyId=1201177213065457778, 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=1201177216584479145, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, language=EN, label=null, caption=null, figureFileSmall=EuUdpezj7NoNv5xOPb5VHQ==, figureFileBig=N+DjvRUdD3me1J0QBj61Fw==, tableContent=null), ArticleFig(id=1201177216685142451, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, language=CN, label=Figure 1, caption= Chemical structures of octapeptins , figureFileSmall=EuUdpezj7NoNv5xOPb5VHQ==, figureFileBig=N+DjvRUdD3me1J0QBj61Fw==, tableContent=null), ArticleFig(id=1201177216911634882, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, language=EN, label=null, caption=null, figureFileSmall=Nacj1x8SQOGTHI8I2rxRAA==, figureFileBig=+X6eSLqfWjq9dr3Ld68nkw==, tableContent=null), ArticleFig(id=1201177217012298185, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, language=CN, label=Figure 2, caption= Chemical structures of compound Zoysa-17<sup>[<a href="javascript:;" class="mag_content_a" onclick="piaofuRef(this,'b12')" rid="b12">12</a>]</sup> and A-10<sup>[<a href="javascript:;" class="mag_content_a" onclick="piaofuRef(this,'b13')" rid="b13">13</a>]</sup> , figureFileSmall=Nacj1x8SQOGTHI8I2rxRAA==, figureFileBig=+X6eSLqfWjq9dr3Ld68nkw==, tableContent=null), ArticleFig(id=1201177217142321621, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, language=EN, label=null, caption=null, figureFileSmall=5ZH+mV1sLT0H2m5mZOSC5w==, figureFileBig=HS+Cg3eL8GoKqnkfnbVZMQ==, tableContent=null), ArticleFig(id=1201177217255567833, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, language=CN, label=Scheme 1, caption= Synthetic route of the target compounds. Reagents and conditions: (a) Fmoc-<i>L</i>-Dab-OAll, DIEA, DCM, 3 h, MeOH; (b) (ⅰ) 20% piperidine in DMF, 10 min and 10 min; (ⅱ) Fmoc-protected position 6 amino acid, HCTU, DIEA, DMF, 50 min; (c) (ⅰ) 20% piperidine in DMF, 10 min and 10 min; (ⅱ) Fmoc-protected position 5 amino acid, HCTU, DIEA, DMF, 50 min; (d) (ⅰ) 20% piperidine in DMF, 10 min and 10 min; (ⅱ) Fmoc-protected position 4 amino acid, HCTU, DIEA, DMF, 50 min; (e) (ⅰ) 20% piperidine in DMF, 10 min and 10 min; (ⅱ) Fmoc-protected position 3 amino acid, HCTU, DIEA, DMF, 50 min; (f) (ⅰ) 20% piperidine in DMF, 10 min and 10 min; (ⅱ) Fmoc-protected position 2 amino acid, HCTU, DIEA, DMF, 50 min; (g) (ⅰ) 20% piperidine in DMF, 10 min and 10 min; (ⅱ) Fmoc-protected position 1 amino acid, HCTU, DIEA, DMF, 50 min; (h) (ⅰ) 20% piperidine in DMF, 10 min and 10 min; (ⅱ) fatty acid, HCTU, DIEA, DMF, 50 min; (ⅰ) 3% hydrazine in DMF, 3×30 min; (j) Fmoc-protected position 8 amino acid, HCTU, DIEA, DMF, 50 min; (k) (ⅰ) 20% piperidine in DMF, 10 min and 10 min; (ⅱ) PhSiH<sub>3</sub>, Pd (PPh<sub>3</sub>)<sub>4</sub>, 50% DCM/50%DMF, 3 h; (l) PyAOP, HOAt, NMM, DMF, 12 h; (m) TFA: TIPS: H<sub>2</sub>O (95: 2.5:2.5), 2 h; followed by reverse phase HPLC purification , figureFileSmall=5ZH+mV1sLT0H2m5mZOSC5w==, figureFileBig=HS+Cg3eL8GoKqnkfnbVZMQ==, tableContent=null), ArticleFig(id=1201177217364619745, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Compd.Fatty acylPosition 1Position 4Position 5Position 8
A3 (R)-3-Hydroxydecanoyl D-Dab D-Leu L-Leu L-Leu
B3 (R)-3-Hydroxydecanoyl D-Dab D-Leu L-Phe L-Leu
1 (R)-3-Hydroxydecanoyl D-Dab L-Leu D-Phe L-Leu
2 (R)-3-Hydroxydecanoyl D-Dab D-Phe L-Thr L-Leu
3 (R)-3-Hydroxydecanoyl D-Dab L-Leu D-Phe L-Thr
4 (R)-3-Hydroxydecanoyl D-Dab D-Leu L-Thr L-Leu
5 (R)-3-Hydroxydecanoyl L-Dab D-Leu L-Leu L-Leu
6 Decanoyl D-Dab D-Leu L-Bip L-Thr
7 Decanoyl D-Dab D-Bip L-Leu L-Thr
8 Decanoyl D-Dab D-Chg L-Leu L-Thr
9 Decanoyl D-Dap D-Leu L-Leu L-Thr
10 Decanoyl D-Orn D-Leu L-Leu L-Thr
11 Octanoyl D-Dab D-Leu L-Phe L-Leu
12 Nonanoyl D-Dab D-Leu L-Phe L-Leu
13 Decanoyl D-Dab D-Leu L-Phe L-Leu
14 Decanoyl D-Asn D-Leu L-Phe L-Leu
15 Decanoyl D-Dab D-Phe L-Bip L-Thr
16 Decanoyl D-Dab D-Leu L-Trp L-Leu
17 Decanoyl D-Dab D-Phe L-Bip L-Leu
18 Decanoyl D-Dab D-Leu L-Phe (4-Me) L-Leu
19 Decanoyl D-Dab D-Leu L-Phe (4-OMe) L-Leu
), ArticleFig(id=1201177217482060266, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, language=CN, label=Table 1, caption=

The structures of synthesized octapeptin derivatives. Dab: 2, 4-Diaminobutanoic acid; Orn: 2, 5-Diaminopentanoic acid; Dap: 2, 3-Diaminopropanoic acid; Bip: 3-([1, 1'-Biphenyl]-4-yl)-2-aminopropanoic acid; Chg: 2-Amino-2-cyclohexylacetic acid; Phe(4-Me): 2-Amino-3-(p-tolyl)propanoic acid; Phe(4-OMe): 2-Amino-3-(4-methoxyphenyl)propanoic acid

, figureFileSmall=null, figureFileBig=null, tableContent=
Compd.Fatty acylPosition 1Position 4Position 5Position 8
A3 (R)-3-Hydroxydecanoyl D-Dab D-Leu L-Leu L-Leu
B3 (R)-3-Hydroxydecanoyl D-Dab D-Leu L-Phe L-Leu
1 (R)-3-Hydroxydecanoyl D-Dab L-Leu D-Phe L-Leu
2 (R)-3-Hydroxydecanoyl D-Dab D-Phe L-Thr L-Leu
3 (R)-3-Hydroxydecanoyl D-Dab L-Leu D-Phe L-Thr
4 (R)-3-Hydroxydecanoyl D-Dab D-Leu L-Thr L-Leu
5 (R)-3-Hydroxydecanoyl L-Dab D-Leu L-Leu L-Leu
6 Decanoyl D-Dab D-Leu L-Bip L-Thr
7 Decanoyl D-Dab D-Bip L-Leu L-Thr
8 Decanoyl D-Dab D-Chg L-Leu L-Thr
9 Decanoyl D-Dap D-Leu L-Leu L-Thr
10 Decanoyl D-Orn D-Leu L-Leu L-Thr
11 Octanoyl D-Dab D-Leu L-Phe L-Leu
12 Nonanoyl D-Dab D-Leu L-Phe L-Leu
13 Decanoyl D-Dab D-Leu L-Phe L-Leu
14 Decanoyl D-Asn D-Leu L-Phe L-Leu
15 Decanoyl D-Dab D-Phe L-Bip L-Thr
16 Decanoyl D-Dab D-Leu L-Trp L-Leu
17 Decanoyl D-Dab D-Phe L-Bip L-Leu
18 Decanoyl D-Dab D-Leu L-Phe (4-Me) L-Leu
19 Decanoyl D-Dab D-Leu L-Phe (4-OMe) L-Leu
), ArticleFig(id=1201177217620472305, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Compd.1H NMRHR-MS (m/z)Purity/%mp/℃
A3 (500 MHz, D2O) δ 4.47 (dd, J = 10.0, 4.6 Hz, 1H), 4.39 (dd, J = 11.0, 3.4 Hz, 1H), 4.34-4.11 (m, 6H), 3.97-3.91 (m, 1H), 3.42-3.34 (m, 1H), 3.13-2.90 (m, 9H), 2.48 (dd, J = 14.4, 3.8 Hz, 1H), 2.34 (dd, J = 14.4, 9.2 Hz, 1H), 2.29-1.94 (m, 9H), 1.80 (qd, J = 10.4, 5.1 Hz, 1H), 1.68-1.43 (m, 11H), 1.38-1.18 (m, 10H), 0.90-0.79 (m, 21H). [M+H]+:
Calcd. C48H91N13O10: 1 010.708 46; Found: 1 010.706 30.		 95.1 167.1-187.2
B3 (500 MHz, D2O) δ 7.36-7.22 (m, 5H), 4.72 (dd, J = 9.9, 6.5 Hz, 1H), 4.41 (dd, J = 10.1, 4.6 Hz, 1H), 4.31 (td, J = 9.7, 5.4 Hz, 2H), 4.20 (dd, J = 8.4, 6.6 Hz, 1H), 4.16-4.04 (m, 3H), 3.96-3.89 (m, 1H), 3.42-3.34 (m, 1H), 3.21 (dd, J = 13.9, 6.3 Hz, 1H), 3.11-2.81 (m, 9H), 2.65 (s, 1H), 2.49-2.44 (m, 1H), 2.33 (dd, J = 14.4, 9.2 Hz, 1H), 2.20-1.91 (m, 9H), 1.78 (ddt, J = 15.4, 10.2, 4.9 Hz, 1H), 1.63-1.42 (m, 5H), 1.36-1.15 (m, 12H), 1.08 (ddd, J = 13.6, 8.3, 5.5 Hz, 1H), 0.89-0.69 (m, 15H). [M+H]+:
Calcd. C51H89N13O10: 1 044.692 81; Found: 1 044.690 92.		 97.1 178.2-185.3
1 (500 MHz, D2O) δ 7.30 (ddd, J = 28.4, 17.8, 7.1 Hz, 5H), 4.60 (dd, J = 9.1, 7.3 Hz, 1H), 4.46 (dd, J = 10.8, 4.1 Hz, 1H), 4.31 (ddd, J = 14.5, 9.5, 5.2 Hz, 2H), 4.24-4.13 (m, 4H), 3.98-3.92 (m, 1H), 3.39-3.32 (m, 1H), 3.20 (dd, J = 13.8, 7.1 Hz, 1H), 3.12-2.99 (m, 7H), 2.97-2.90 (m, 1H), 2.73-2.63 (m, 1H), 2.59-2.52 (m, 1H), 2.48 (dd, J = 14.2, 4.2 Hz, 1H), 2.34 (dd, J = 14.2, 9.0 Hz, 1H), 2.22-1.78 (m, 10H), 1.62-1.18 (m, 17H), 1.02 (dp, J = 13.3, 6.6 Hz, 1H), 0.88-0.71 (m, 15H). [M+H]+:
Calcd. C51H89N13O10: 1 044.692 81; Found: 1 044.690 06.		 96.3 170.1-179.8
2 (500 MHz, D2O) δ 7.35-7.22 (m, 5H), 4.67 (t, J = 8.2 Hz, 1H), 4.39 (dd, J = 8.7, 5.8 Hz, 1H), 4.34-4.29 (m, 2H), 4.15 (dddd, J = 21.8, 15.9, 14.3, 9.8 Hz, 5H), 3.95-3.90 (m, 1H), 3.43-3.36 (m, 1H), 3.13-2.90 (m, 9H), 2.83-2.76 (m, 1H), 2.69-2.61 (m, 1H), 2.46 (dd, J = 14.4, 3.9 Hz, 1H). [M+H]+:
Calcd. C49H85N13O11: 1 032.656 43; Found: 1 032.653 20.		 96.2 204.3-211.3
3 (500 MHz, D2O) δ 7.29 (ddd, J = 27.8, 17.5, 7.1 Hz, 5H), 4.64 (dd, J = 9.7, 6.7 Hz, 1H), 4.51 (dd, J = 11.0, 4.0 Hz, 1H), 4.36-4.26 (m, 3H), 4.20 (dd, J = 9.8, 4.2 Hz, 1H), 4.12 (ddd, J = 10.0, 9.5, 5.0 Hz, 3H), 3.95 (td, J = 10.4, 6.3 Hz, 1H), 3.38-3.31 (m, 1H), 3.24 (dd, J = 13.9, 6.6 Hz, 1H), 3.14-3.00 (m, 7H), 2.90 (dd, J = 13.9, 9.8 Hz, 1H), 2.77-2.64 (m, 2H), 2.48 (dd, J = 14.2, 4.1 Hz, 1H), 2.34 (dd, J = 14.2, 9.1 Hz, 1H), 2.26-1.90 (m, 9H), 1.82 (td, J = 14.4, 7.2 Hz, 1H), 1.47 (dd, J = 13.4, 6.5 Hz, 2H), 1.37-1.19 (m, 12H), 1.14 (d, J = 6.3 Hz, 3H), 0.96 (tt, J = 13.3, 6.6 Hz, 1H), 0.81 (t, J = 6.9 Hz, 3H), 0.72 (dd, J = 19.8, 6.5 Hz, 6H). [M+H]+:
Calcd. C49H85N13O11: 1 032.656 43; Found: 1 032.654 42.		 95.2 197.2-204.0
4 (500 MHz, D2O) δ 4.47 (dd, J = 9.8, 4.8 Hz, 1H), 4.41-4.12 (m, 8H), 3.97 -3.92 (m, 1H), 3.42-3.35 (m, 1H), 3.13-2.91 (m, 9H), 2.47 (dd, J = 14.4, 3.9 Hz, 1H), 2.37-1.91 (m, 10H), 1.80 (ddt, J = 15.5, 10.6, 5.3 Hz, 1H), 1.68-1.43 (m, 8H), 1.37-1.19 (m, 10H), 1.14 (d, J = 6.4 Hz, 3H), 0.92-0.79 (m, 15H). [M+H]+:
Calcd. C46H87N13O11: 998.672 08;
Found: 998.670 59.		 99.3 157.6-161.2
5 (500 MHz, D2O) δ 4.51 (dd, J = 9.6, 4.8 Hz, 1H), 4.41-4.36 (m, 2H), 4.26-4.17 (m, 5H), 4.00-3.94 (m, 1H), 3.33 (dt, J = 14.0, 7.2 Hz, 1H), 3.11-2.92 (m, 9H), 2.47 (dd, J = 14.3, 4.6 Hz, 1H), 2.37 (dd, J = 14.3, 8.6 Hz, 1H), 2.28-1.91 (m, 9H), 1.85-1.76 (m, 1H), 1.68-1.43 (m, 11H), 1.38-1.20 (m, 10H), 0.84 (tdd, J = 18.2, 12.3, 6.2 Hz, 21H). [M+H]+:
Calcd. C48H91N13O10: 1 010.708 46; Found: 1 010.705 93.		 95.3 161.3-175.8
6 (500 MHz, D2O) δ 7.60 (dd, J = 17.9, 7.8 Hz, 4H), 7.41 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 8.2 Hz, 3H), 4.40 (dd, J = 8.6, 5.5 Hz, 1H), 4.33 (dd, J = 10.0, 4.6 Hz, 1H), 4.29-4.24 (m, 2H), 4.14 (dt, J = 12.1, 4.3 Hz, 3H), 4.04 (dd, J = 9.1, 6.1 Hz, 1H), 3.46-3.31 (m, 2H), 3.11-2.83 (m, 11H), 2.31-1.95 (m, 12H), 1.80 (td, J = 10.5, 5.3 Hz, 1H), 1.51-1.42 (m, 2H), 1.15 (d, J = 5.9 Hz, 15H), 1.00 (dt, J = 19.9, 6.5 Hz, 1H), 0.90-0.82 (m, 1H), 0.77 (t, J = 6.9 Hz, 3H), 0.56 (dd, J = 6.4, 2.6 Hz, 6H). [M+H]+:
Calcd. C55H89N13O10: 1 092.692 81; Found: 1 092.693 24.		 95.5 175.2-180.1
7 (500 MHz, D2O) δ 7.71-7.65 (m, 4H), 7.49 (t, J = 7.7 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 4.54 (dd, J = 9.4, 7.3 Hz, 1H), 4.44 (dd, J = 9.9, 4.7 Hz, 1H), 4.31 (ddd, J = 25.8, 8.9, 5.7 Hz, 2H), 4.22-4.07 (m, 5H), 3.45-3.38 (m, 1H), 3.15-2.86 (m, 11H), 2.30-1.79 (m, 13H), 1.52-1.45 (m, 2H), 1.40-1.14 (m, 17H), 0.80 (t, J = 6.9 Hz, 3H), 0.70 (s, 1H), 0.57 (dd, J = 25.9, 6.5 Hz, 5H). [M+H]+:
Calcd. C55H89N13O10: 1 092.692 81; Found: 1 092.690 43.		 95.5 172.6-186.3
8 (500 MHz, D2O) δ 4.47 (dd, J = 9.9, 4.6 Hz, 1H), 4.34 (dd, J = 9.0, 5.6 Hz, 2H), 4.29 (dd, J = 9.0, 5.6 Hz, 1H), 4.24-4.10 (m, 4H), 4.04 (d, J = 7.5 Hz, 1H), 3.44-3.37 (m, 1H), 3.11-2.93 (m, 9H), 2.26-1.94 (m, 11H), 1.83 (qd, J = 10.3, 5.0 Hz, 1H), 1.61 (dddd, J = 34.9, 28.2, 10.2, 4.9 Hz, 11H), 1.23-0.99 (m, 20H), 0.90-0.78 (m, 9H). [M+H]+:
Calcd. C48H89N13O10: 1 008.692 81; Found: 1 008.691 41.		 95.4 165.1-184.7
9 (500 MHz, D2O) δ 4.58 (dd, J = 8.4, 5.2 Hz, 1H), 4.45 (dd, J = 9.7, 4.8 Hz, 1H), 4.36 (ddd, J = 16.5, 9.8, 4.3 Hz, 2H), 4.27 (dd, J = 9.8, 5.3 Hz, 1H), 4.24-4.12 (m, 4H), 3.48-3.36 (m, 2H), 3.27 (dd, J = 13.4, 8.4 Hz, 1H), 3.13-2.93 (m, 7H), 2.31-1.95 (m, 9H), 1.84 (qd, J = 10.6, 5.3 Hz, 1H), 1.69-1.47 (m, 8H), 1.26-1.13 (m, 15H), 0.90-0.79 (m, 15H). [M+H]+:
Calcd. C45H85N13O10: 968.661 51;
Found: 968.659 67.		 96.4 185.7-199.5
10 (500 MHz, D2O) δ 4.43 (dd, J = 10.1, 4.5 Hz, 1H), 4.39-4.33 (m, 2H), 4.28-4.12 (m, 6H), 3.43-3.37 (m, 1H), 3.12-2.94 (m, 9H), 2.29-1.99 (m, 9H), 1.86-.47 (m, 14H), 1.24-1.14 (m, 14H), 0.90-0.79 (m, 15H). [M+H]+:
Calcd. C47H89N13O10: 996.692 81;
Found: 996.691 83.		 97.7 176.3-181.5
11 (500 MHz, D2O) δ 7.30 (ddd, J = 23.8, 15.5, 7.1 Hz, 5H), 4.73 (dd, J = 9.8, 6.7 Hz, 1H), 4.37 (ddd, J = 18.2, 9.6, 4.7 Hz, 2H), 4.26 (dd, J = 9.0, 5.7 Hz, 1H), 4.20 (dd, J = 8.5, 6.5 Hz, 1H), 4.15-4.09 (m, 2H), 4.04 (dd, J = 9.8, 4.6 Hz, 1H), 3.77 (d, J = 11.1 Hz, 1H), 3.44-3.36 (m, 1H), 3.20 (dd, J = 13.8, 6.5 Hz, 1H), 3.11-2.80 (m, 9H), 2.65-2.57 (m, 1H), 2.26-1.90 (m, 11H), 1.79 (qd, J = 9.9, 4.7 Hz, 1H), 1.62-1.49 (m, 4H), 1.32-1.17 (m, 10H), 1.07 (ddd, J = 13.1, 8.2, 5.2 Hz, 1H), 0.89-0.70 (m, 15H). [M+H]+:
Calcd. C49H85N13O9: 1 000.666 60; Found: 1 000.662 65.		 99.7 192.2-200.7
12 (500 MHz, D2O) δ 7.30 (ddd, J = 23.8, 15.5, 7.1 Hz, 5H), 4.73 (dd, J = 9.7, 6.7 Hz, 1H), 4.37 (ddd, J = 14.0, 9.7, 4.8 Hz, 2H), 4.26 (dd, J = 8.9, 5.7 Hz, 1H), 4.20 (dd, J = 8.5, 6.5 Hz, 1H), 4.16-4.09 (m, 2H), 4.04 (dd, J = 9.7, 4.4 Hz, 1H), 3.77 (d, J = 11.1 Hz, 1H), 3.44-3.37 (m, 1H), 3.20 (dd, J = 13.8, 6.5 Hz, 1H), 3.11-2.79 (m, 9H), 2.64-2.56 (m, 1H), 2.26-1.90 (m, 11H), 1.79 (qd, J = 10.0, 4.8 Hz, 1H), 1.63-1.49 (m, 4H), 1.32-1.16 (m, 12H), 1.07 (ddd, J = 13.7, 8.4, 5.4 Hz, 1H), 0.88-0.70 (m, 15H). [M+H]+:
Calcd. C50H87N13O9: 1 014.682 25; Found: 1 014.680 30.		 96.0 176.2-180.4
13 (500 MHz, D2O) δ 7.37-7.23 (m, 5H), 4.73 (dd, J = 9.8, 6.7 Hz, 1H), 4.42-4.01 (m, 7H), 3.43-3.36 (m, 1H), 3.20 (dd, J = 13.8, 6.5 Hz, 1H), 3.11-2.79 (m, 9H), 2.64-2.57 (m, 1H), 2.27-1.90 (m, 11H), 1.78 (qd, J = 10.1, 4.8 Hz, 1H), 1.63-1.44 (m, 5H), 1.32-1.16 (m, 14H), 1.07 (ddd, J = 13.1, 8.2, 5.2 Hz, 1H), 0.88-0.70 (m, 15H). [M+H]+:
Calcd. C51H89N13O9: 1 028.697 90; Found: 1 028.696 29.		 95.6 186.1-193.9
14 (600 MHz, D2O) δ 7.45 (t, J = 7.4 Hz, 2H), 7.42-7.33 (m, 3H), 4.68 (dd, J = 7.8, 6.1 Hz, 1H), 4.51 (dd, J = 10.3, 4.3 Hz, 1H), 4.41 (dd, J = 9.1, 5.0 Hz, 1H), 4.30 (dd, J = 8.6, 6.5 Hz, 1H), 4.25-4.17 (m, 3H), 3.44 (ddd, J = 14.0, 9.9, 4.3 Hz, 1H), 3.32 (dd, J = 13.9, 6.2 Hz, 1H), 3.19-2.95 (m, 8H), 2.84 (ddd, J = 23.7, 15.7, 6.9 Hz, 3H), 2.37-2.03 (m, 10H), 1.89 (ddd, J = 14.9, 9.7, 4.7 Hz, 1H), 1.66 (tdd, J = 17.8, 12.5, 6.6 Hz, 5H), 1.37-1.28 (m, 13H), 1.20 (ddd, J = 13.7, 8.2, 5.6 Hz, 1H), 0.99-0.89 (m, 9H), 0.82 (dd, J = 15.1, 6.5 Hz, 6H). [M+H]+:
Calcd. C51H87N13O10: 1 042.677 16; Found: 1 042.675 73.		 96.1 180.5-206.1
15 (600 MHz, D2O) δ 7.71 (dd, J = 20.7, 7.7 Hz, 4H), 7.55 (t, J = 7.7 Hz, 2H), 7.49-7.41 (m, 3H), 7.34 (dt, J = 30.5, 7.2 Hz, 3H), 7.12 (d, J = 7.2 Hz, 2H), 4.64 (dd, J = 9.8, 5.6 Hz, 1H), 4.55 (dd, J = 8.8, 5.2 Hz, 1H), 4.34 (ddd, J = 14.5, 8.6, 6.1 Hz, 2H), 4.26 (dd, J = 9.5, 4.8 Hz, 1H), 4.23-4.17 (m, 3H), 3.51-3.45 (m, 1H), 3.28 (dd, J = 13.9, 6.2 Hz, 1H), 3.21-2.91 (m, 9H), 2.85-2.61 (m, 5H), 2.39-2.03 (m, 10H), 1.92-1.84 (m, 3H), 1.62-1.53 (m, 2H), 1.32-1.24 (m, 13H), 0.90 (t, J = 7.0 Hz, 3H). [M+H]+:
Calcd. C58H87N13O10: 1 126.677 16; Found: 1 126.673 73.		 96.0 182.3-191.4
16 (600 MHz, D2O) δ 7.73 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.31 (dd, J = 9.3, 4.7 Hz, 2H), 7.23 (t, J = 7.1 Hz, 1H), 4.93 (dd, J = 9.6, 6.7 Hz, 1H), 4.48 (dd, J = 10.2, 4.4 Hz, 1H), 4.42 (dd, J = 8.8, 5.1 Hz, 1H), 4.37 (dd, J = 9.0, 5.7 Hz, 1H), 4.31 (dd, J = 8.9, 6.1 Hz, 1H), 4.25-4.18 (m, 2H), 4.13 (dd, J = 9.8, 4.7 Hz, 1H), 3.52-3.43 (m, 2H), 3.23-3.04 (m, 8H), 2.85 (ddd, J = 12.8, 9.6, 6.7 Hz, 1H), 2.72-2.67 (m, 1H), 2.34 (t, J = 7.4 Hz, 2H), 2.30-1.98 (m, 11H), 1.88 (ddt, J = 15.3, 10.2, 5.1 Hz, 1H), 1.66 (dddd, J = 25.7, 20.2, 13.5, 6.3 Hz, 6H), 1.30 (d, J = 7.2 Hz, 11H), 1.05-0.98 (m, 4H), 0.95-0.88 (m, 6H), 0.76 (dd, J = 20.2, 6.5 Hz, 6H). [M+H]+:
Calcd. C53H90N14O9: 1 067.708 80; Found: 1 067.705 98.		 98.3 173.1-200.2
17 (600 MHz, D2O) δ 7.71 (dd, J = 13.9, 7.8 Hz, 4H), 7.55 (t, J = 7.7 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 7.13 (d, J = 7.3 Hz, 2H), 4.63 (dd, J = 9.7, 5.7 Hz, 1H), 4.53 (dd, J = 8.9, 5.0 Hz, 1H), 4.32 (ddd, J = 20.0, 8.4, 5.7 Hz, 3H), 4.18 (dd, J = 10.5, 3.8 Hz, 2H), 3.53-3.48 (m, 1H), 3.26-2.78 (m, 13H), 2.69 (td, J = 14.5, 8.6 Hz, 2H), 2.34-1.83 (m, 14H), 1.71-1.56 (m, 5H), 1.30 (s, 9H), 0.97 (d, J = 6.3 Hz, 3H), 0.94-0.87 (m, 6H). [M+H]+:
Calcd. C60H91N13O9: 1 138.713 55; Found: 1 138.708 94.		 97.5 179.4-185.3
18 (600 MHz, D2O) δ 7.25 (dd, J = 29.1, 8.0 Hz, 4H), 4.49 (dd, J = 10.1, 4.5 Hz, 1H), 4.44 (dd, J = 8.7, 5.2 Hz, 1H), 4.37 (dd, J = 9.0, 5.7 Hz, 1H), 4.30 (dd, J = 8.8, 6.3 Hz, 1H), 4.25-4.17 (m, 3H), 3.53-3.46 (m, 1H), 3.29 (dd, J = 14.0, 5.7 Hz, 1H), 3.21-2.90 (m, 10H), 2.38-2.03 (m, 15H), 1.72-1.57 (m, 5H), 1.32 (dd, J = 14.8, 6.7 Hz, 15H), 1.08 (ddd, J = 13.3, 7.9, 5.5 Hz, 1H), 0.98 (d, J = 6.4 Hz, 3H), 0.94-0.89 (m, 6H), 0.81 (dd, J = 18.7, 6.5 Hz, 6H). [M+H]+:
Calcd. C52H91N13O9: 1 042.713 55; Found: 1 042.705 24.		 95.4 170.3-182.8
19 (600 MHz, D2O) δ 7.28 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 4.47 (ddd, J = 21.3, 9.5, 4.9 Hz, 2H), 4.37 (dd, J = 9.0, 5.7 Hz, 1H), 4.30 (dd, J = 8.8, 6.3 Hz, 1H), 4.25-4.21 (m, 2H), 4.17 (dd, J = 9.7, 5.6 Hz, 1H), 3.88 (d, J = 2.2 Hz, 3H), 3.52-3.47 (m, 1H), 3.31 (dd, J = 14.1, 5.5 Hz, 1H), 3.20-3.01 (m, 9H), 2.90 (dd, J = 14.1, 11.0 Hz, 1H), 2.37-2.31 (m, 3H), 2.29-2.03 (m, 9H), 1.89 (ddd, J = 19.7, 10.5, 5.2 Hz, 1H), 1.72-1.57 (m, 5H), 1.32 (dd, J = 15.1, 6.1 Hz, 13H), 1.22 (dt, J = 13.4, 6.7 Hz, 1H), 1.07-1.01 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H), 0.96-0.88 (m, 6H), 0.80 (dd, J = 17.9, 6.6 Hz, 6H). [M+H]+:
Calcd. C52H91N13O10: 1 058.708 46; Found: 1 058.709 71.		 95.1 181.3-192.8
), ArticleFig(id=1201177217746301432, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, language=CN, label=Table 2, caption=

The spectral data and purity of target compounds

, figureFileSmall=null, figureFileBig=null, tableContent=
Compd.1H NMRHR-MS (m/z)Purity/%mp/℃
A3 (500 MHz, D2O) δ 4.47 (dd, J = 10.0, 4.6 Hz, 1H), 4.39 (dd, J = 11.0, 3.4 Hz, 1H), 4.34-4.11 (m, 6H), 3.97-3.91 (m, 1H), 3.42-3.34 (m, 1H), 3.13-2.90 (m, 9H), 2.48 (dd, J = 14.4, 3.8 Hz, 1H), 2.34 (dd, J = 14.4, 9.2 Hz, 1H), 2.29-1.94 (m, 9H), 1.80 (qd, J = 10.4, 5.1 Hz, 1H), 1.68-1.43 (m, 11H), 1.38-1.18 (m, 10H), 0.90-0.79 (m, 21H). [M+H]+:
Calcd. C48H91N13O10: 1 010.708 46; Found: 1 010.706 30.		 95.1 167.1-187.2
B3 (500 MHz, D2O) δ 7.36-7.22 (m, 5H), 4.72 (dd, J = 9.9, 6.5 Hz, 1H), 4.41 (dd, J = 10.1, 4.6 Hz, 1H), 4.31 (td, J = 9.7, 5.4 Hz, 2H), 4.20 (dd, J = 8.4, 6.6 Hz, 1H), 4.16-4.04 (m, 3H), 3.96-3.89 (m, 1H), 3.42-3.34 (m, 1H), 3.21 (dd, J = 13.9, 6.3 Hz, 1H), 3.11-2.81 (m, 9H), 2.65 (s, 1H), 2.49-2.44 (m, 1H), 2.33 (dd, J = 14.4, 9.2 Hz, 1H), 2.20-1.91 (m, 9H), 1.78 (ddt, J = 15.4, 10.2, 4.9 Hz, 1H), 1.63-1.42 (m, 5H), 1.36-1.15 (m, 12H), 1.08 (ddd, J = 13.6, 8.3, 5.5 Hz, 1H), 0.89-0.69 (m, 15H). [M+H]+:
Calcd. C51H89N13O10: 1 044.692 81; Found: 1 044.690 92.		 97.1 178.2-185.3
1 (500 MHz, D2O) δ 7.30 (ddd, J = 28.4, 17.8, 7.1 Hz, 5H), 4.60 (dd, J = 9.1, 7.3 Hz, 1H), 4.46 (dd, J = 10.8, 4.1 Hz, 1H), 4.31 (ddd, J = 14.5, 9.5, 5.2 Hz, 2H), 4.24-4.13 (m, 4H), 3.98-3.92 (m, 1H), 3.39-3.32 (m, 1H), 3.20 (dd, J = 13.8, 7.1 Hz, 1H), 3.12-2.99 (m, 7H), 2.97-2.90 (m, 1H), 2.73-2.63 (m, 1H), 2.59-2.52 (m, 1H), 2.48 (dd, J = 14.2, 4.2 Hz, 1H), 2.34 (dd, J = 14.2, 9.0 Hz, 1H), 2.22-1.78 (m, 10H), 1.62-1.18 (m, 17H), 1.02 (dp, J = 13.3, 6.6 Hz, 1H), 0.88-0.71 (m, 15H). [M+H]+:
Calcd. C51H89N13O10: 1 044.692 81; Found: 1 044.690 06.		 96.3 170.1-179.8
2 (500 MHz, D2O) δ 7.35-7.22 (m, 5H), 4.67 (t, J = 8.2 Hz, 1H), 4.39 (dd, J = 8.7, 5.8 Hz, 1H), 4.34-4.29 (m, 2H), 4.15 (dddd, J = 21.8, 15.9, 14.3, 9.8 Hz, 5H), 3.95-3.90 (m, 1H), 3.43-3.36 (m, 1H), 3.13-2.90 (m, 9H), 2.83-2.76 (m, 1H), 2.69-2.61 (m, 1H), 2.46 (dd, J = 14.4, 3.9 Hz, 1H). [M+H]+:
Calcd. C49H85N13O11: 1 032.656 43; Found: 1 032.653 20.		 96.2 204.3-211.3
3 (500 MHz, D2O) δ 7.29 (ddd, J = 27.8, 17.5, 7.1 Hz, 5H), 4.64 (dd, J = 9.7, 6.7 Hz, 1H), 4.51 (dd, J = 11.0, 4.0 Hz, 1H), 4.36-4.26 (m, 3H), 4.20 (dd, J = 9.8, 4.2 Hz, 1H), 4.12 (ddd, J = 10.0, 9.5, 5.0 Hz, 3H), 3.95 (td, J = 10.4, 6.3 Hz, 1H), 3.38-3.31 (m, 1H), 3.24 (dd, J = 13.9, 6.6 Hz, 1H), 3.14-3.00 (m, 7H), 2.90 (dd, J = 13.9, 9.8 Hz, 1H), 2.77-2.64 (m, 2H), 2.48 (dd, J = 14.2, 4.1 Hz, 1H), 2.34 (dd, J = 14.2, 9.1 Hz, 1H), 2.26-1.90 (m, 9H), 1.82 (td, J = 14.4, 7.2 Hz, 1H), 1.47 (dd, J = 13.4, 6.5 Hz, 2H), 1.37-1.19 (m, 12H), 1.14 (d, J = 6.3 Hz, 3H), 0.96 (tt, J = 13.3, 6.6 Hz, 1H), 0.81 (t, J = 6.9 Hz, 3H), 0.72 (dd, J = 19.8, 6.5 Hz, 6H). [M+H]+:
Calcd. C49H85N13O11: 1 032.656 43; Found: 1 032.654 42.		 95.2 197.2-204.0
4 (500 MHz, D2O) δ 4.47 (dd, J = 9.8, 4.8 Hz, 1H), 4.41-4.12 (m, 8H), 3.97 -3.92 (m, 1H), 3.42-3.35 (m, 1H), 3.13-2.91 (m, 9H), 2.47 (dd, J = 14.4, 3.9 Hz, 1H), 2.37-1.91 (m, 10H), 1.80 (ddt, J = 15.5, 10.6, 5.3 Hz, 1H), 1.68-1.43 (m, 8H), 1.37-1.19 (m, 10H), 1.14 (d, J = 6.4 Hz, 3H), 0.92-0.79 (m, 15H). [M+H]+:
Calcd. C46H87N13O11: 998.672 08;
Found: 998.670 59.		 99.3 157.6-161.2
5 (500 MHz, D2O) δ 4.51 (dd, J = 9.6, 4.8 Hz, 1H), 4.41-4.36 (m, 2H), 4.26-4.17 (m, 5H), 4.00-3.94 (m, 1H), 3.33 (dt, J = 14.0, 7.2 Hz, 1H), 3.11-2.92 (m, 9H), 2.47 (dd, J = 14.3, 4.6 Hz, 1H), 2.37 (dd, J = 14.3, 8.6 Hz, 1H), 2.28-1.91 (m, 9H), 1.85-1.76 (m, 1H), 1.68-1.43 (m, 11H), 1.38-1.20 (m, 10H), 0.84 (tdd, J = 18.2, 12.3, 6.2 Hz, 21H). [M+H]+:
Calcd. C48H91N13O10: 1 010.708 46; Found: 1 010.705 93.		 95.3 161.3-175.8
6 (500 MHz, D2O) δ 7.60 (dd, J = 17.9, 7.8 Hz, 4H), 7.41 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 8.2 Hz, 3H), 4.40 (dd, J = 8.6, 5.5 Hz, 1H), 4.33 (dd, J = 10.0, 4.6 Hz, 1H), 4.29-4.24 (m, 2H), 4.14 (dt, J = 12.1, 4.3 Hz, 3H), 4.04 (dd, J = 9.1, 6.1 Hz, 1H), 3.46-3.31 (m, 2H), 3.11-2.83 (m, 11H), 2.31-1.95 (m, 12H), 1.80 (td, J = 10.5, 5.3 Hz, 1H), 1.51-1.42 (m, 2H), 1.15 (d, J = 5.9 Hz, 15H), 1.00 (dt, J = 19.9, 6.5 Hz, 1H), 0.90-0.82 (m, 1H), 0.77 (t, J = 6.9 Hz, 3H), 0.56 (dd, J = 6.4, 2.6 Hz, 6H). [M+H]+:
Calcd. C55H89N13O10: 1 092.692 81; Found: 1 092.693 24.		 95.5 175.2-180.1
7 (500 MHz, D2O) δ 7.71-7.65 (m, 4H), 7.49 (t, J = 7.7 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 4.54 (dd, J = 9.4, 7.3 Hz, 1H), 4.44 (dd, J = 9.9, 4.7 Hz, 1H), 4.31 (ddd, J = 25.8, 8.9, 5.7 Hz, 2H), 4.22-4.07 (m, 5H), 3.45-3.38 (m, 1H), 3.15-2.86 (m, 11H), 2.30-1.79 (m, 13H), 1.52-1.45 (m, 2H), 1.40-1.14 (m, 17H), 0.80 (t, J = 6.9 Hz, 3H), 0.70 (s, 1H), 0.57 (dd, J = 25.9, 6.5 Hz, 5H). [M+H]+:
Calcd. C55H89N13O10: 1 092.692 81; Found: 1 092.690 43.		 95.5 172.6-186.3
8 (500 MHz, D2O) δ 4.47 (dd, J = 9.9, 4.6 Hz, 1H), 4.34 (dd, J = 9.0, 5.6 Hz, 2H), 4.29 (dd, J = 9.0, 5.6 Hz, 1H), 4.24-4.10 (m, 4H), 4.04 (d, J = 7.5 Hz, 1H), 3.44-3.37 (m, 1H), 3.11-2.93 (m, 9H), 2.26-1.94 (m, 11H), 1.83 (qd, J = 10.3, 5.0 Hz, 1H), 1.61 (dddd, J = 34.9, 28.2, 10.2, 4.9 Hz, 11H), 1.23-0.99 (m, 20H), 0.90-0.78 (m, 9H). [M+H]+:
Calcd. C48H89N13O10: 1 008.692 81; Found: 1 008.691 41.		 95.4 165.1-184.7
9 (500 MHz, D2O) δ 4.58 (dd, J = 8.4, 5.2 Hz, 1H), 4.45 (dd, J = 9.7, 4.8 Hz, 1H), 4.36 (ddd, J = 16.5, 9.8, 4.3 Hz, 2H), 4.27 (dd, J = 9.8, 5.3 Hz, 1H), 4.24-4.12 (m, 4H), 3.48-3.36 (m, 2H), 3.27 (dd, J = 13.4, 8.4 Hz, 1H), 3.13-2.93 (m, 7H), 2.31-1.95 (m, 9H), 1.84 (qd, J = 10.6, 5.3 Hz, 1H), 1.69-1.47 (m, 8H), 1.26-1.13 (m, 15H), 0.90-0.79 (m, 15H). [M+H]+:
Calcd. C45H85N13O10: 968.661 51;
Found: 968.659 67.		 96.4 185.7-199.5
10 (500 MHz, D2O) δ 4.43 (dd, J = 10.1, 4.5 Hz, 1H), 4.39-4.33 (m, 2H), 4.28-4.12 (m, 6H), 3.43-3.37 (m, 1H), 3.12-2.94 (m, 9H), 2.29-1.99 (m, 9H), 1.86-.47 (m, 14H), 1.24-1.14 (m, 14H), 0.90-0.79 (m, 15H). [M+H]+:
Calcd. C47H89N13O10: 996.692 81;
Found: 996.691 83.		 97.7 176.3-181.5
11 (500 MHz, D2O) δ 7.30 (ddd, J = 23.8, 15.5, 7.1 Hz, 5H), 4.73 (dd, J = 9.8, 6.7 Hz, 1H), 4.37 (ddd, J = 18.2, 9.6, 4.7 Hz, 2H), 4.26 (dd, J = 9.0, 5.7 Hz, 1H), 4.20 (dd, J = 8.5, 6.5 Hz, 1H), 4.15-4.09 (m, 2H), 4.04 (dd, J = 9.8, 4.6 Hz, 1H), 3.77 (d, J = 11.1 Hz, 1H), 3.44-3.36 (m, 1H), 3.20 (dd, J = 13.8, 6.5 Hz, 1H), 3.11-2.80 (m, 9H), 2.65-2.57 (m, 1H), 2.26-1.90 (m, 11H), 1.79 (qd, J = 9.9, 4.7 Hz, 1H), 1.62-1.49 (m, 4H), 1.32-1.17 (m, 10H), 1.07 (ddd, J = 13.1, 8.2, 5.2 Hz, 1H), 0.89-0.70 (m, 15H). [M+H]+:
Calcd. C49H85N13O9: 1 000.666 60; Found: 1 000.662 65.		 99.7 192.2-200.7
12 (500 MHz, D2O) δ 7.30 (ddd, J = 23.8, 15.5, 7.1 Hz, 5H), 4.73 (dd, J = 9.7, 6.7 Hz, 1H), 4.37 (ddd, J = 14.0, 9.7, 4.8 Hz, 2H), 4.26 (dd, J = 8.9, 5.7 Hz, 1H), 4.20 (dd, J = 8.5, 6.5 Hz, 1H), 4.16-4.09 (m, 2H), 4.04 (dd, J = 9.7, 4.4 Hz, 1H), 3.77 (d, J = 11.1 Hz, 1H), 3.44-3.37 (m, 1H), 3.20 (dd, J = 13.8, 6.5 Hz, 1H), 3.11-2.79 (m, 9H), 2.64-2.56 (m, 1H), 2.26-1.90 (m, 11H), 1.79 (qd, J = 10.0, 4.8 Hz, 1H), 1.63-1.49 (m, 4H), 1.32-1.16 (m, 12H), 1.07 (ddd, J = 13.7, 8.4, 5.4 Hz, 1H), 0.88-0.70 (m, 15H). [M+H]+:
Calcd. C50H87N13O9: 1 014.682 25; Found: 1 014.680 30.		 96.0 176.2-180.4
13 (500 MHz, D2O) δ 7.37-7.23 (m, 5H), 4.73 (dd, J = 9.8, 6.7 Hz, 1H), 4.42-4.01 (m, 7H), 3.43-3.36 (m, 1H), 3.20 (dd, J = 13.8, 6.5 Hz, 1H), 3.11-2.79 (m, 9H), 2.64-2.57 (m, 1H), 2.27-1.90 (m, 11H), 1.78 (qd, J = 10.1, 4.8 Hz, 1H), 1.63-1.44 (m, 5H), 1.32-1.16 (m, 14H), 1.07 (ddd, J = 13.1, 8.2, 5.2 Hz, 1H), 0.88-0.70 (m, 15H). [M+H]+:
Calcd. C51H89N13O9: 1 028.697 90; Found: 1 028.696 29.		 95.6 186.1-193.9
14 (600 MHz, D2O) δ 7.45 (t, J = 7.4 Hz, 2H), 7.42-7.33 (m, 3H), 4.68 (dd, J = 7.8, 6.1 Hz, 1H), 4.51 (dd, J = 10.3, 4.3 Hz, 1H), 4.41 (dd, J = 9.1, 5.0 Hz, 1H), 4.30 (dd, J = 8.6, 6.5 Hz, 1H), 4.25-4.17 (m, 3H), 3.44 (ddd, J = 14.0, 9.9, 4.3 Hz, 1H), 3.32 (dd, J = 13.9, 6.2 Hz, 1H), 3.19-2.95 (m, 8H), 2.84 (ddd, J = 23.7, 15.7, 6.9 Hz, 3H), 2.37-2.03 (m, 10H), 1.89 (ddd, J = 14.9, 9.7, 4.7 Hz, 1H), 1.66 (tdd, J = 17.8, 12.5, 6.6 Hz, 5H), 1.37-1.28 (m, 13H), 1.20 (ddd, J = 13.7, 8.2, 5.6 Hz, 1H), 0.99-0.89 (m, 9H), 0.82 (dd, J = 15.1, 6.5 Hz, 6H). [M+H]+:
Calcd. C51H87N13O10: 1 042.677 16; Found: 1 042.675 73.		 96.1 180.5-206.1
15 (600 MHz, D2O) δ 7.71 (dd, J = 20.7, 7.7 Hz, 4H), 7.55 (t, J = 7.7 Hz, 2H), 7.49-7.41 (m, 3H), 7.34 (dt, J = 30.5, 7.2 Hz, 3H), 7.12 (d, J = 7.2 Hz, 2H), 4.64 (dd, J = 9.8, 5.6 Hz, 1H), 4.55 (dd, J = 8.8, 5.2 Hz, 1H), 4.34 (ddd, J = 14.5, 8.6, 6.1 Hz, 2H), 4.26 (dd, J = 9.5, 4.8 Hz, 1H), 4.23-4.17 (m, 3H), 3.51-3.45 (m, 1H), 3.28 (dd, J = 13.9, 6.2 Hz, 1H), 3.21-2.91 (m, 9H), 2.85-2.61 (m, 5H), 2.39-2.03 (m, 10H), 1.92-1.84 (m, 3H), 1.62-1.53 (m, 2H), 1.32-1.24 (m, 13H), 0.90 (t, J = 7.0 Hz, 3H). [M+H]+:
Calcd. C58H87N13O10: 1 126.677 16; Found: 1 126.673 73.		 96.0 182.3-191.4
16 (600 MHz, D2O) δ 7.73 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.31 (dd, J = 9.3, 4.7 Hz, 2H), 7.23 (t, J = 7.1 Hz, 1H), 4.93 (dd, J = 9.6, 6.7 Hz, 1H), 4.48 (dd, J = 10.2, 4.4 Hz, 1H), 4.42 (dd, J = 8.8, 5.1 Hz, 1H), 4.37 (dd, J = 9.0, 5.7 Hz, 1H), 4.31 (dd, J = 8.9, 6.1 Hz, 1H), 4.25-4.18 (m, 2H), 4.13 (dd, J = 9.8, 4.7 Hz, 1H), 3.52-3.43 (m, 2H), 3.23-3.04 (m, 8H), 2.85 (ddd, J = 12.8, 9.6, 6.7 Hz, 1H), 2.72-2.67 (m, 1H), 2.34 (t, J = 7.4 Hz, 2H), 2.30-1.98 (m, 11H), 1.88 (ddt, J = 15.3, 10.2, 5.1 Hz, 1H), 1.66 (dddd, J = 25.7, 20.2, 13.5, 6.3 Hz, 6H), 1.30 (d, J = 7.2 Hz, 11H), 1.05-0.98 (m, 4H), 0.95-0.88 (m, 6H), 0.76 (dd, J = 20.2, 6.5 Hz, 6H). [M+H]+:
Calcd. C53H90N14O9: 1 067.708 80; Found: 1 067.705 98.		 98.3 173.1-200.2
17 (600 MHz, D2O) δ 7.71 (dd, J = 13.9, 7.8 Hz, 4H), 7.55 (t, J = 7.7 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 7.13 (d, J = 7.3 Hz, 2H), 4.63 (dd, J = 9.7, 5.7 Hz, 1H), 4.53 (dd, J = 8.9, 5.0 Hz, 1H), 4.32 (ddd, J = 20.0, 8.4, 5.7 Hz, 3H), 4.18 (dd, J = 10.5, 3.8 Hz, 2H), 3.53-3.48 (m, 1H), 3.26-2.78 (m, 13H), 2.69 (td, J = 14.5, 8.6 Hz, 2H), 2.34-1.83 (m, 14H), 1.71-1.56 (m, 5H), 1.30 (s, 9H), 0.97 (d, J = 6.3 Hz, 3H), 0.94-0.87 (m, 6H). [M+H]+:
Calcd. C60H91N13O9: 1 138.713 55; Found: 1 138.708 94.		 97.5 179.4-185.3
18 (600 MHz, D2O) δ 7.25 (dd, J = 29.1, 8.0 Hz, 4H), 4.49 (dd, J = 10.1, 4.5 Hz, 1H), 4.44 (dd, J = 8.7, 5.2 Hz, 1H), 4.37 (dd, J = 9.0, 5.7 Hz, 1H), 4.30 (dd, J = 8.8, 6.3 Hz, 1H), 4.25-4.17 (m, 3H), 3.53-3.46 (m, 1H), 3.29 (dd, J = 14.0, 5.7 Hz, 1H), 3.21-2.90 (m, 10H), 2.38-2.03 (m, 15H), 1.72-1.57 (m, 5H), 1.32 (dd, J = 14.8, 6.7 Hz, 15H), 1.08 (ddd, J = 13.3, 7.9, 5.5 Hz, 1H), 0.98 (d, J = 6.4 Hz, 3H), 0.94-0.89 (m, 6H), 0.81 (dd, J = 18.7, 6.5 Hz, 6H). [M+H]+:
Calcd. C52H91N13O9: 1 042.713 55; Found: 1 042.705 24.		 95.4 170.3-182.8
19 (600 MHz, D2O) δ 7.28 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 4.47 (ddd, J = 21.3, 9.5, 4.9 Hz, 2H), 4.37 (dd, J = 9.0, 5.7 Hz, 1H), 4.30 (dd, J = 8.8, 6.3 Hz, 1H), 4.25-4.21 (m, 2H), 4.17 (dd, J = 9.7, 5.6 Hz, 1H), 3.88 (d, J = 2.2 Hz, 3H), 3.52-3.47 (m, 1H), 3.31 (dd, J = 14.1, 5.5 Hz, 1H), 3.20-3.01 (m, 9H), 2.90 (dd, J = 14.1, 11.0 Hz, 1H), 2.37-2.31 (m, 3H), 2.29-2.03 (m, 9H), 1.89 (ddd, J = 19.7, 10.5, 5.2 Hz, 1H), 1.72-1.57 (m, 5H), 1.32 (dd, J = 15.1, 6.1 Hz, 13H), 1.22 (dt, J = 13.4, 6.7 Hz, 1H), 1.07-1.01 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H), 0.96-0.88 (m, 6H), 0.80 (dd, J = 17.9, 6.6 Hz, 6H). [M+H]+:
Calcd. C52H91N13O10: 1 058.708 46; Found: 1 058.709 71.		 95.1 181.3-192.8
), ArticleFig(id=1201177217884713472, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Compd.MIC/μg·mL-1
S. aureusS. epidermidisE. coliK. pneumoniaeP. aeruginosaA. baumannii
ATCC 33591aATCC 29213MRSE 19-5bMRSE 19-6bATCC BAA-2523NCTC 13353ECO-19-2cATCC BAA-2340 (KPC)KPN+19-15dKPN+19-17dATCC BAA-1705 (KPC)PAE 19-1cPAE 19-3dPAE 17-1dATCC 27853ABA 19-8dNCTC 13304 (OXA-27)
A3> 64> 642161616168161616242148
B332322881616816168442248
16432283264326464> 6432> 64> 64> 64> 64> 64> 64
2> 646441616161616816222111616
3> 64> 64166464> 646464> 64> 64> 64> 64> 64> 64> 64> 64> 64
4> 64> 641664161616161632424113232
5> 6464216161632481622211416
6440.514164884242421616
7881214122412221168
8> 64> 642816323232163288284> 64> 64
9> 64> 64232161684161641220.5> 6464
10> 64> 644323264323264> 64322441> 64> 64
11> 64> 64181688181612481> 648
1232640.54888181614441164
1316160.52488141622241164
1464164481616216328881616> 6432
15816228164448444441616
161681188844444488> 6432
1784228168416168888488
18168114882482448444
1964162281684816444161688
Polymyxin B> 64> 64416≤0.060.5≤0.06≤0.060.1250.25≤0.060.250.1250.250.5≤0.06≤0.06
Meropenem160.125220.25≤0.06≤0.06464> 64160.5163211664
), ArticleFig(id=1201177218010542601, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, language=CN, label=Table 3, caption=

The MIC values of octapeptin derivatives and control drugs against bacterial strains. KPC: Klebsiella Pneumoniae carbapenemase; OXA: Oxacillinase; a Methicillin-resistant standard isolates; b Methicillin-resistant clinical isolates; c Clinical isolates; d Carbapenem-resistant clinical isolates

, figureFileSmall=null, figureFileBig=null, tableContent=
Compd.MIC/μg·mL-1
S. aureusS. epidermidisE. coliK. pneumoniaeP. aeruginosaA. baumannii
ATCC 33591aATCC 29213MRSE 19-5bMRSE 19-6bATCC BAA-2523NCTC 13353ECO-19-2cATCC BAA-2340 (KPC)KPN+19-15dKPN+19-17dATCC BAA-1705 (KPC)PAE 19-1cPAE 19-3dPAE 17-1dATCC 27853ABA 19-8dNCTC 13304 (OXA-27)
A3> 64> 642161616168161616242148
B332322881616816168442248
16432283264326464> 6432> 64> 64> 64> 64> 64> 64
2> 646441616161616816222111616
3> 64> 64166464> 646464> 64> 64> 64> 64> 64> 64> 64> 64> 64
4> 64> 641664161616161632424113232
5> 6464216161632481622211416
6440.514164884242421616
7881214122412221168
8> 64> 642816323232163288284> 64> 64
9> 64> 64232161684161641220.5> 6464
10> 64> 644323264323264> 64322441> 64> 64
11> 64> 64181688181612481> 648
1232640.54888181614441164
1316160.52488141622241164
1464164481616216328881616> 6432
15816228164448444441616
161681188844444488> 6432
1784228168416168888488
18168114882482448444
1964162281684816444161688
Polymyxin B> 64> 64416≤0.060.5≤0.06≤0.060.1250.25≤0.060.250.1250.250.5≤0.06≤0.06
Meropenem160.125220.25≤0.06≤0.06464> 64160.5163211664
), ArticleFig(id=1201177218123788817, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Compd.CC50/μg·mL-1
HK-2 cellP value vs polymyxin B
A360.7 ± 5.80.585 4
B316.1 ± 6.80.008 8
136.1 ± 3.10.058 7
254.8 ± 17.10.929 4
3214.2 ± 80.70.028 4
4169.1 ± 27.70.003 0
538.2 ± 4.20.083 3
613.5 ± 2.00.004 7
724.6 ± 2.20.013 8
8101.9 ± 16.90.019 9
9266.7 ± 30.10.000 4
10135.2 ± 20.10.004 5
1158.7 ± 17.10.837 3
1248.0 ± 14.20.507 1
139.4 ± 4.50.004 0
1437.3 ± 21.60.267 6
1515.6 ± 4.50.006 7
1632.2 ± 25.60.223 1
17< 10.001 7
1810.4 ± 4.40.004 3
1925.6 ± 9.20.028 9
Polymyxin B55.9 ± 12.8-
), ArticleFig(id=1201177218207674902, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210876031987, language=CN, label=Table 4, caption=

The renal cytotoxicity of octapeptin derivatives on the HK-2 cell. n = 3, $ \overline{x} $ ± s

, figureFileSmall=null, figureFileBig=null, tableContent=
Compd.CC50/μg·mL-1
HK-2 cellP value vs polymyxin B
A360.7 ± 5.80.585 4
B316.1 ± 6.80.008 8
136.1 ± 3.10.058 7
254.8 ± 17.10.929 4
3214.2 ± 80.70.028 4
4169.1 ± 27.70.003 0
538.2 ± 4.20.083 3
613.5 ± 2.00.004 7
724.6 ± 2.20.013 8
8101.9 ± 16.90.019 9
9266.7 ± 30.10.000 4
10135.2 ± 20.10.004 5
1158.7 ± 17.10.837 3
1248.0 ± 14.20.507 1
139.4 ± 4.50.004 0
1437.3 ± 21.60.267 6
1515.6 ± 4.50.006 7
1632.2 ± 25.60.223 1
17< 10.001 7
1810.4 ± 4.40.004 3
1925.6 ± 9.20.028 9
Polymyxin B55.9 ± 12.8-
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八肽菌素衍生物的合成及其抗菌活性研究
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杨鹤显 , 崔阿龙 , 王永健 , 寇世博 , 吕苗 , 易红 , 李卓荣 *
药学学报 | 研究论文 2024,59(1): 152-160
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药学学报 | 研究论文 2024, 59(1): 152-160
八肽菌素衍生物的合成及其抗菌活性研究
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杨鹤显, 崔阿龙, 王永健, 寇世博, 吕苗, 易红, 李卓荣*
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:

*李卓荣, Tel: 86-10-63027185, E-mail:
Synthesis and antibacterial activity evaluation of octapeptin derivatives
He-xian YANG, A-long CUI, Yong-jian WANG, Shi-bo KOU, Miao LÜ, Hong YI, Zhuo-rong LI*
Affiliations
  • Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
出版时间: 2024-01-12 doi: 10.16438/j.0513-4870.2023-0760
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摘要
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八肽菌素在对大肠埃希菌、肺炎克雷伯菌、鲍曼不动杆菌等G-菌具有较强活性的同时, 对部分G+菌也有一定的活性。本研究以天然八肽菌素A3和B3为先导化合物进行结构改造, 采用固相合成法制备了21个含有8个氨基酸残基的肽类衍生物(含A3和B3), 并对其进行抗菌活性测试和肾细胞毒性评价。其中, 化合物6、7和17显示有广谱抗菌活性, 在维持抗G-菌活性的同时, 明显提升了抗G+菌活性; 部分化合物提高了抗铜绿假单胞菌活性。化合物7对所有测定菌株均有活性且肾细胞毒性相对较低。本文研究结果为进一步发展新型多肽类抗菌药物奠定了一定的基础。

细菌耐药  /  八肽菌素  /  结构修饰  /  广谱抗菌活性

Octapeptin has strong antibacterial activity against Gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii, while it also has activity against some Gram-positive bacteria. This study used natural octapeptin A3 and B3 as lead compounds for structural modification. Twenty-one peptide derivatives (including A3 and B3) containing eight amino acid residues were prepared by solid-phase synthesis, and evaluated for antibacterial activity and renal cytotoxicity. Among them, three compounds 6, 7 and 17 exhibited broad-spectrum antibacterial activity and significantly enhanced the activity for Gram-positive bacteria while maintaining the activity of Gram-negative bacteria. Several compounds improved the activity for Pseudomonas aeruginosa. Compound 7 was active against all test strains and had relatively low renal cytotoxicity. The results provide a basis for the further development of novel polypeptide antibiotics.

bacterial resistance  /  octapeptin  /  structural modification  /  broad-spectrum antibacterial activity
杨鹤显, 崔阿龙, 王永健, 寇世博, 吕苗, 易红, 李卓荣. 八肽菌素衍生物的合成及其抗菌活性研究. 药学学报, 2024 , 59 (1) : 152 -160 . DOI: 10.16438/j.0513-4870.2023-0760
He-xian YANG, A-long CUI, Yong-jian WANG, Shi-bo KOU, Miao LÜ, Hong YI, Zhuo-rong LI. Synthesis and antibacterial activity evaluation of octapeptin derivatives[J]. Acta Pharmaceutica Sinica, 2024 , 59 (1) : 152 -160 . DOI: 10.16438/j.0513-4870.2023-0760
正文
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抗生素耐药问题已严重威胁人类健康, 日趋增多的耐药病原体制约了现有抗生素(如碳青霉烯类、氟喹诺酮类等) 的使用, 耐药菌感染的临床治疗方案疗效甚微[1]。细菌耐药已成为全球公共卫生危机之一, 美国疾病控制与预防中心预测, 到2050年, 耐药细菌感染每年将导致大约1 000万人死亡[2]。含有多个正电荷中心的肽类抗生素多黏菌素成为临床治疗革兰阴性(G-) 菌重症感染的最后一道防线[3], 但是, 肾毒性问题严重限制了该类抗生素的使用。因此, 临床对新型抗菌剂的迫切需求, 使得发现新型抗生素成为全球的研究热点之一。以多黏菌素为代表的碱性肽类抗生素具有抗G-菌活性强、难产生耐药性等特点[4-6], 但是对G+菌无效。拓宽该类抗生素的抗菌谱或许是细菌耐药问题的一个解决方案[7]。
1973年从环状芽孢杆菌中分离得到一种抗菌肽——八肽菌素EM49, 自此之后一系列天然产物八肽菌素A、B、C、D等逐渐被发现[8]。八肽菌素(octapeptin) 单一组分的化学结构由含有羟基的脂肪酰基链和环状七肽通过一个D构型氨基酸连接而成(图 1)。其与细菌细胞膜上的脂质A和磷脂发生相互作用, 破坏细菌细胞膜结构, 从而发挥抗菌活性[9]。八肽菌素在对大肠埃希菌、肺炎克雷伯菌、鲍曼不动杆菌具有较强活性的同时, 对部分G+菌也有活性但相对不强, 小鼠体内毒性比多黏菌素B小[10, 11], 表现出较多黏菌素等药物更广的抗菌谱和较低的毒性, 具有成为新一类广谱抗生素候选物的潜力。
在八肽菌素结构改造的现有文献中, 主要集中于提高G-菌活性, 对G+菌活性的研究较少。已发现具有G+菌和G-菌广谱活性的八肽菌素衍生物仅有两个——Zoysa-17[12]和A-10[13] (图 2)。衍生物Zoysa-17为线性肽, 而非环肽, 相对稳定性较差; 衍生物A-10具有较大的肾细胞毒性, 安全性低。八肽菌素类抗生素的结构修饰与构效关系研究尚不够系统和深入。
本研究以天然八肽菌素A3和B3为先导化合物, 通过对部分氨基酸及脂肪酰基片段的结构改造, 共设计合成了19个新衍生物, 同时, 采用化学合成法制得了A3和B3, 对所有目标化合物进行了抗菌活性评价及肾细胞毒性评价, 探究了初步的构效关系及构毒关系。研究结果发现化合物7对G+菌和G-菌均有抗菌作用且肾毒性较低, 具有作为广谱抗生素先导化合物的潜力。
结果与讨论
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1 化合物的设计与合成
根据前期文献[13]报道, 八肽菌素的脂肪酰基及部分氨基酸的疏水性与抗G+菌活性密切相关。为了进一步挖掘广谱抗生素的优势候选物, 本研究设计了八肽菌素衍生物(表 1)。以天然八肽菌素A3和B3为先导化合物, 对1, 4, 5, 8位氨基酸进行结构改造, 替换不同氨基酸, 适当增强疏水性。改变脂肪酰基部分的碳链长度以及羟基是否存在, 改善极性, 以求维持或提高抗菌活性的同时降低肾毒性, 拓宽抗菌谱。
本文共合成包括先导化合物A3和B3在内的八肽菌素衍生物21个, 化合物的纯度经高效液相色谱检测, 结构经高分辨质谱和核磁氢谱确证(表 2)。在参考文献[9]中报道了先导化合物A3的高分辨质谱数据, 本研究中也对其进行了高分辨质谱检测, 结果一致。
2 化合物的抗菌活性
对合成的21个化合物进行抗菌活性检测, 所测得的最小抑菌浓度(MIC) 结果如表 3所示。可以看出化合物6、7和17对检测的G+菌和G-菌均有抗菌活性(MIC ≤ 8 μg·mL-1), 具有广谱抗菌活性, 尤其是对测定的敏感或耐药的G+菌活性明显强于多黏菌素B (MIC: 4~ > 64 μg·mL-1) 和先导化合物A3、B3 (MIC: 2~ > 64 μg·mL-1), 对测定的敏感或耐药的表皮葡萄球菌活性(MIC: 0.5~2 μg·mL-1) 与美罗培南(MIC: 2 μg·mL-1) 相当。化合物2、4、5、9、10对铜绿假单胞菌具有较强抗菌活性(MIC: 0.5~4 μg·mL-1), 强于对照药美罗培南, 与多黏菌素B (MIC: 0.125~0.5 μg·mL-1) 接近, 较先导物略有提高。根据这些结果, 发现1位氨基酸构型对抗菌活性无明显影响(化合物5), 替换为D-Dap时抗铜绿假单胞菌活性略有提升, 但失去抗鲍曼不动杆菌活性(化合物9、10)。4位、5位氨基酸构型是活性关键, 改变时活性完全丧失(化合物1)。当提高4、5位两个氨基酸的疏水性时, G+菌活性明显提高(化合物6、7)。8位亮氨酸替换为苏氨酸后, 抗铜绿假单胞菌活性提高(化合物15、17)。脂肪酰基部分的羟基去除后, 抗G+菌及大肠杆菌活性均提高(化合物13), 碳链长度从10减少到8, 活性逐渐降低(化合物11、12、13)。
3 化合物的肾细胞毒性
肾毒性是阳离子肽类抗生素普遍存在的缺点, 因此本研究测定了合成的八肽菌素衍生物对人肾小管上皮细胞(HK-2) 的毒性(表 4)。化合物3、4、8、9、10的CC50值均大于100 μg·mL-1, 肾细胞毒性明显低于先导化合物及对照药多黏菌素B。具有广谱活性的化合物7 (CC50 = 24.6 μg·mL-1) 较已发现的广谱八肽菌素衍生物A-10的肾细胞毒性(CC50 = 9.1 μg·mL-1) 有明显改善[13]。5位氨基酸亮氨酸替换为苏氨酸时, 肾毒性明显降低(化合物2、4)。缩短脂肪酰基的碳链长度可减弱肾毒性(化合物11、12、13)。1位D-Dab替换为碱性氨基酸D-Dap与D-Orn时肾毒性降低(化合物9、10)。由此可见, 肾细胞毒性与多肽的脂溶性氨基酸和脂肪酰基片段密切相关。
小结
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本研究设计合成天然八肽菌素A3和B3及新衍生物19个, 并对其进行了体外抗菌活性评价和肾细胞毒性评价。其中, 化合物6、7、17具有广谱抗菌活性; 与天然八肽菌素A3和B3相比, 它们在保持G-菌活性的同时, 明显提高了G+菌活性; 抗表皮葡萄球菌活性与美罗培南相当。化合物2、4、5、9、10的抗铜绿假单胞菌活性与多黏菌素B接近。化合物3、4、8、9、10的CC50值均大于100 μg·mL-1, 提示肾毒性低。化合物7对所有测定菌株均有活性(MIC ≤ 16 μg·mL-1), 且肾细胞毒性相对较低(CC50 = 24.6 μg·mL-1), 具有进一步发展为广谱抗生素先导化合物的潜力。通过总结构效关系和构毒关系, 发现降低部分氨基酸和脂肪酰基片段的极性, 对提高抗G+菌活性有利, 但肾毒性相应有所提升; 增强部分氨基酸极性时, 抗G-菌活性维持且肾毒性下降。本研究可以为进一步发展具有广谱抗菌活性且肾细胞毒性低的新型抗生素研究提供新的提示。
实验部分
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恒温振荡器(CHA-S, 中国常州国华仪器公司), 旋转蒸发仪(R-300, 瑞士Buchi公司), 半制备型高效液相色谱仪(LC-20AT, 日本岛津公司), 分析型高效液相色谱仪(Agilent 1200 series, 美国Agilent公司), C18反相分析柱(Eclipse XDB-C18 4.6 mm × 150 mm, 5 μm), 核磁共振波谱仪(500 MHz和600 MHz, Bruker公司), 高分辨质谱仪(LTQ Orbitrap XL, 美国Thermo Fisher Scientific公司), 熔点仪(MP90, 梅特勒-托利多国际有限公司)。
芴甲氧羰基(Fmoc) 保护的相应氨基酸、6-氯苯并三氮唑-1, 1, 3, 3-四甲基脲六氟磷酸酯(HCTU) 购自吉尔生化, 2-CTC树脂购自天津南开合成科技有限公司, 色谱级乙腈、三氟乙酸(TFA)、苯硅烷、N-甲基吗啉(NMM)、三异丙基硅烷(TIPS)、N, N-二异丙基乙胺(DIEA) 购自百灵威科技公司, (7-氮杂苯并三唑-1-氧) 三吡咯磷六氟磷酸盐(PyAOP)、四(三苯基膦) 钯和N-羟基-7-氮杂苯并三氮唑(HOAt) 购自迈瑞尔化学技术有限公司, 甲醇、哌啶、二氯甲烷(DCM)、无水乙醚、水合肼(40%) 购自北京化工厂, N, N-二甲基甲酰胺(DMF) 购自博迈杰有限公司。
实验所用标准菌株购自美国典型菌株保藏中心和英国国家典型菌株保藏中心, 临床菌株为2019年在四川、北京、广东、上海等地区收集的临床分离致病菌。人肾皮质近曲小管上皮HK-2细胞株购自美国ATCC (American Type Culture Collection)。
1 八肽菌素及其衍生物的合成
1.1 八肽菌素A3的合成
参照文献[13, 14]报道的方法, 目标化合物采用固相合成法合成得到, 化合物的合成如合成路线 1所示。
以化合物A3的合成为例, 具体实验操作如下: 以2-CTC树脂(0.5 mmol) 为固相载体, DCM (10 mL) 为溶剂, DIEA (4 mmol) 为催化剂, 30 ℃下摇床反应3 h, 将7位氨基酸Fmoc-L-Dab-OAll (2 mmol) 连接在树脂上。用20%哌啶/DMF 10 mL搅拌(10 min, 两次) 脱除Fmoc保护基。而后, 分别将对应的Fmoc保护的氨基酸和脂肪酸(2 mmol)、缩合剂HCTU (1.8 mmol)、催化剂DIEA (4 mmol) 溶于DMF (10 mL) 与树脂在30 ℃反应50 min, 重复以上Fmoc脱保护和Fmoc保护氨基酸缩合操作, 得到连接脂肪酰基和1~7位氨基酸残基的树脂样品。用3%水合肼/DMF 15 mL搅拌(30 min, 3次) 脱除2位氨基酸的Dde (1-(4, 4-二甲基-2, 6-二氧代环己亚基) 乙基) 保护基, 将8位氨基酸(2 mmol)、缩合剂HCTU (1.8 mmol)、催化剂DIEA (4 mmol)、溶剂DMF (10 mL) 与树脂在30 ℃反应50 min。用20%哌啶/DMF 10 mL (10 min, 两次) 脱除Fmoc保护基, 将四(三苯基膦) 钯(0.2 mmol) 和苯硅烷(3.5 mmol) 溶于DCM∶DMF = 1∶1的溶剂(10 mL), 加入树脂中, 脱除烯丙基(30 ℃反应3 h)。将PyAOP (2 mmol)、HOAt (2 mmol)、NMM (4 mmol) 溶于DMF (10 mL), 加入到树脂中于30 ℃下反应过夜。以10 mL的TFA∶TIPS∶H2O = 95∶2.5∶2.5混合溶液浸泡并搅拌树脂, 将多肽从树脂上切下并脱除Boc (叔丁氧羰基) 保护基, 经半制备型高效液相色谱仪纯化(流动相为含0.08%三氟乙酸的水和含0.08%三氟乙酸的乙腈, 柱子为Shim-pack PREP-ODS (20 mm × 250 mm, 10 μm), 梯度洗脱, 流速为8 mL·min-1, 检测波长为214 nm), 含有产物的流分冷冻干燥, 得白色固体产物。用分析型高效液相色谱仪检测产物纯度(流动相为各含0.08%三氟乙酸的水和乙腈, 柱子为Eclipse XDB-C18 (4.6 mm × 150 mm, 5 μm), 流速为0.8 mL·min-1, 检测波长为214 nm), 归一化法计算。用核磁共振波谱仪和高分辨质谱仪确证产物结构。
1.2 化合物B3、1~19的合成
采用与上述A3类似的方法, 合成得到不同氨基酸和脂肪酸组成的多肽产物B3、1~19 (表 1)。目标化合物的HPLC含量(均大于95%)、结构确证数据如表 2所示。
2 生物活性测试
参考美国临床实验室标准协会(CLSI) 抗菌药物敏感性试验操作规程, 采用微量肉汤稀释法测定化合物的最小抑菌浓度(MIC)。称取样品, 用无菌MH肉汤配置药液, 使加样槽内的化合物浓度依次为256、128、64、32、16、8、4、2、1、0.5、0.25、0.125 μg·mL-1。用MH肉汤配置相应菌悬液, 终浓度为(4~8)×105 CFU·mL-1。分别吸取100 μL的不同浓度药液到无菌的96孔聚苯乙烯板各孔中, 另加100 μL的菌液加入各孔。孔内样品终浓度为128、64、32、16、8、4、2、1、0.5、0.25、0.125、0.06 μg·mL-1, 菌液终浓度为(2~4)×105 CFU·mL-1。设置生长对照组和阳性对照组(多黏菌素B和美罗培南)。加样的96孔板在35~37 ℃培养箱内培养16~20 h。观察孔内完全抑制细菌生长的最低药物浓度, 即为其MIC值。
3 肾细胞毒性测试
采用CCK-8法检测化合物的人肾HK-2细胞毒性。称取化合物, 用无菌水配置浓度为250、100、50、25、12.5 μg·mL-1。HK-2细胞在37 ℃含5% CO2的湿润环境无菌培养箱中培养, 待细胞密度生长至70%~80%, 进行消化传代。每毫升5×104个细胞, 铺于96孔板中, 每孔100 μL细胞悬液, 稳定培养24 h后更换含药培养基, 置于培养箱中培养72 h。吸掉培养基, 加100 μL含10%的CCK-8空白培养基, 置于培养箱中孵育3 h, 用BioTek读板酶标仪测定OD450 nm值, 实验进行3次重复, 每次设定多黏菌素B做阳性药和未含药空白处理组做对照。计算细胞存活率, 利用Log回归计算CC50值, 与阳性药进行t检验, P < 0.05认为有统计学差异。
致谢: 感谢四川普莱美行之生物科技有限公司对抗菌活性的测试。
作者贡献: 杨鹤显负责化合物合成以及文章的撰写; 崔阿龙负责实验技术指导; 王永健、寇世博、吕苗参与了部分合成、体外活性和毒性实验; 易红参与了数据分析及文献整理; 李卓荣负责研究方案设计与指导论文撰写。
利益冲突: 所有作者声明不存在利益冲突。
基金
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  • 国家自然科学基金(82003600)
  • 国家自然科学基金(32141003)
  • 中国医学科学院医学与健康科技创新工程(2021-I2M-1-030)
文献
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参考文献 引证文献
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2024年第59卷第1期
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文章信息
doi: 10.16438/j.0513-4870.2023-0760
  • 接收时间：2023-06-19
  • 首发时间：2025-11-28
  • 出版时间：2024-01-12
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  • 收稿日期：2023-06-19
  • 修回日期：2023-07-16
基金
国家自然科学基金(82003600)
国家自然科学基金(32141003)
中国医学科学院医学与健康科技创新工程(2021-I2M-1-030)
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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*李卓荣, Tel: 86-10-63027185, 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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