CN114380864B - 一种双氢青蒿素衍生物、制备方法、药物组合物和其在制备抗肿瘤药物中的应用 - Google Patents

一种双氢青蒿素衍生物、制备方法、药物组合物和其在制备抗肿瘤药物中的应用 Download PDF

Info

Publication number
CN114380864B
CN114380864B CN202111626019.3A CN202111626019A CN114380864B CN 114380864 B CN114380864 B CN 114380864B CN 202111626019 A CN202111626019 A CN 202111626019A CN 114380864 B CN114380864 B CN 114380864B
Authority
CN
China
Prior art keywords
dihydroartemisinin
preparation
chloroform
nmr
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202111626019.3A
Other languages
English (en)
Other versions
CN114380864A (zh
Inventor
杨小平
许藏藏
肖林凡
牟玲丽
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hunan Normal University
Original Assignee
Hunan Normal University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hunan Normal University filed Critical Hunan Normal University
Priority to CN202111626019.3A priority Critical patent/CN114380864B/zh
Publication of CN114380864A publication Critical patent/CN114380864A/zh
Application granted granted Critical
Publication of CN114380864B publication Critical patent/CN114380864B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02Phosphorus compounds
    • C07F9/547Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

本发明公开了一种双氢青蒿素衍生物、制备方法、药物组合物和其在制备抗肿瘤药物中的应用,所述双氢青蒿素衍生物的结构为如下式Ⅰ所示:
Figure DDA0003438819970000011
其中,所述n为3‑12,R1为三苯基膦,R2为卤素;其可以显著抑制肿瘤细胞的增殖和迁移,IC50达到nM级别,大大低于衍生化前的双氢青蒿素;在OVCAR3、SKOV3、A549、T24和J82细胞系中,本发明双氢青蒿素衍生物活性较衍生化前的双氢青蒿素显著提高。

Description

一种双氢青蒿素衍生物、制备方法、药物组合物和其在制备抗 肿瘤药物中的应用
技术领域
本发明涉及医药技术领域,具体地说,涉及一种双氢青蒿素衍生物、制备方法、药物组合物和其在制备抗肿瘤药物中的应用。
背景技术
癌症是继缺血性心脏病之后世界第二大死亡原因(897万人),2060年后有可能成为世界第一大死亡原因(约1863万人)。据统计,2018年全球新增确诊病例1800万例,2020年新增病例还在持续上升。
双氢青蒿素是一种传统的一线抗疟疾的药物,近年来发现其除了具有抗疟疾的活性外还具有抗肿瘤活性。但是其发挥抗肿瘤作用的剂量远远高于其发挥抗疟疾的剂量,并且此类化合物的神经毒性问题一直是限制此类化合物应用的主要原因。开发有较高生物活性和较低副作用的双氢青蒿素类抗癌药物非常重要和迫切。
双氢青霉素衍生物的合成及抗癌活性研究,朴明男,延边大学硕士学位论文,2011年,公开了:在青蒿素的抗肿瘤作用机制研究中,认为最主要的机制为诱导细胞凋亡和亚铁离子作用过氧键基团,反应产生氧自由基损伤癌细胞膜性结构,但是确切的作用靶点和机制并不明确。
为了寻找比青蒿素抗肿瘤作用更强的药物,在保留过氧桥键的基础上,主要在双氢青蒿素10位碳上的-OH键引入一些亲水、亲脂基团进行结构修饰,合成了烷基醚、芳香醚、酯类、杂原子取代、二聚体化合物等青蒿素衍生物,并筛选出部分烷基醚、芳香醚类和部分双活性二聚体化合物比青蒿素具有更强的抗肿瘤活性。
线粒体是细胞内重要的亚细胞器,其与细胞的死亡密切相关。目前,靶向线粒体的药物研发已经成为该领域的研究热点。由于肿瘤细胞线粒体内膜电位比正常细胞更高,线粒体靶向基团TPP+可以依据线粒体膜电势的差异积聚在肿瘤细胞线粒体内,一般认为,靶向基团只会提高药物活性成分的靶向能力,对体外抗肿瘤细胞活性的提升并不会有明显影响。
Synthesis and biological activities of novel mitochondria-targetedartemisinin ester derivatives,Cangcang,Xu,Bioorg.Med.Chem.Lett.39(2021)127912,发明人将双氢青蒿素和
Figure BDA0003438819950000011
反应得到产物,制备路线如下所示。产物2a-2d对各肿瘤细胞的IC50值可以最低达到2.7μM,但是2d相比于DHA,其抗肿瘤活性的提升并不明显。
Figure BDA0003438819950000021
发明内容
本发明的目的是针对现有技术中的不足,提供一类双氢青蒿素衍生物、制备方法、药物组合物和其在制备抗肿瘤药物中的应用,双氢青蒿素衍生物的抗肿瘤活性较高,其IC50值达到nM级别,具有开发为良好抗肿瘤药物的应用前景。
本发明提供一种双氢青蒿素衍生物,所述双氢青蒿素衍生物的结构为如下式Ⅰ所示:
Figure BDA0003438819950000022
其中,所述n为3-12,R1为三苯基膦,R2为卤素,比如溴、氯、碘,优选为溴,其他卤素元素如氯、碘取代也具有类似的性能。
具体的,所述双氢青蒿素衍生物为以下化合物之一:
Figure BDA0003438819950000031
本发明优选的化合物为D7-T和D8-T,最优选的为化合物D8-T。
优选的,所述双氢青蒿素衍生物为式Ⅰ化合物的各光学异构体、各晶型、药学上可接受的无机盐、有机盐或前药。
本发明的盐可以由化合物中带正电荷的部分与具有相反电性的带负电荷形成;或者由化合物中带负电荷的部分与正电荷形成。
所述的“结构式Ⅰ的前药”通常指一种物质,当用适当的方法施用后,可在受试者体内进行代谢或化学反应而转变成结构式Ⅰ的至少一种化合物或其盐。
本发明的化合物可按照常规方法制备为药用盐的形式;包括其有机酸盐及无机酸盐:无机酸包括(但不限于)盐酸、硫酸、磷酸、二磷酸、氢溴酸、硝酸等,有机酸包括(但不限于)乙酸、马来酸、富马酸、酒石酸、琥珀酸、乳酸、对甲苯磺酸、水杨酸、草酸等。
本发明提供一种双氢青蒿素衍生物的制备方法,步骤为,将双氢青蒿素和
Figure BDA0003438819950000041
反应,n为3-12,R2为卤素,得到中间体,中间体的结构式如下:
Figure BDA0003438819950000042
中间体和三苯基膦反应,得到双氢青蒿素衍生物。
优选反应路线如下:
Figure BDA0003438819950000043
优选的,所述双氢青蒿素和
Figure BDA0003438819950000044
反应的溶剂为二氯甲烷,催化剂为三氟化硼乙醚,优选在氮气保护下进行。
优选的,中间体和三苯基膦反应的溶剂为乙氰,反应体系中还加入有碳酸盐,如碳酸钾或碳酸钠,其作为碱催化剂。
本发明提供一种药物组合物,所述的药物组合物包括双氢青蒿素衍生物,还包括药学上可接受的赋形剂或载体。
本发明提供一种双氢青蒿素衍生物在制备抗肿瘤药物中的用途。所述肿瘤为肺癌、食道癌、胃癌、肝癌、黑色素瘤、胰腺癌、肾癌、白血病、前列腺癌、膀胱癌、神经母细胞瘤、结肠癌、乳腺癌、子宫癌、卵巢癌或鼻咽癌。
本发明的有益效果是,本发明的实验结果显示双氢青蒿素衍生物能显著抑制肿瘤细胞的增殖和迁移,IC50大大低于衍生化前的双氢青蒿素,其中以化合物D7-T、D8-T的活性最好,在J82、OVCAR3和A549细胞中,本发明的双氢青蒿素衍生物活性是双氢青蒿素的2366、874和220倍,具有开发为良好抗肿瘤药物的应用前景。
附图说明
图1为D3-T~D12-T在5种癌细胞株中的半数抑制浓度(IC50)。
图2为D8-T和DHA对人膀胱癌细胞系T24和J82的克隆形成能力抑制效果染色图。
图3为D8-T和DHA对人膀胱癌细胞系T24和J82的克隆形成能力抑制效果柱状图。
图4为D8-T对人膀胱癌细胞系T24和J82迁移的抑制效果图。
图5为DHA对人膀胱癌细胞系T24和J82迁移的抑制效果图。
具体实施方式
以下具体的实例用以详细说明本发明,但本发明绝非仅限于这些例子(除另有注明外,所用原料均有市售)。
实施例1:中间体D3的制备
Figure BDA0003438819950000051
将DHA(1g,3.5mmol)溶于200mL二氯甲烷中配成溶液,在室温条件下加入3-溴-1-丙醇(0.325mL,3.6mmol),再加入4滴三氟化硼乙醚,N2保护,室温反应12h,TLC监测反应。反应结束,加入200mL饱和碳酸氢钠、二氯甲烷萃取三次,再加入无水碳酸钠干燥,过滤拌样,柱层析得中间产物D3,产率12.93%。
结构验证:
β-isomer;1H NMR(600MHz,Chloroform-d)δ5.42(s,1H),4.80(d,J=3.5Hz,1H),4.00(ddd,J=10.0,6.6,5.1Hz,1H),3.49(q,J=6.4Hz,3H),2.64(qdd,J=7.5,4.7,3.5Hz,1H),2.37(ddd,J=14.7,13.5,4.0Hz,1H),2.15–1.99(m,3H),1.88(dddd,J=13.7,6.8,4.0,3.1Hz,1H),1.80–1.69(m,2H),1.63(dq,J=13.2,3.4Hz,1H),1.55–1.44(m,2H),1.44(s,3H),1.33(qp,J=9.7,3.7,3.3Hz,1H),1.28–1.21(m,2H),0.95(d,J=6.4Hz,3H),0.90(d,J=7.4Hz,3H).13CNMR(150MHz,Chloroform-d)δ104.12,102.11,87.93,81.05,65.70,52.58,44.39,37.46,36.43,34.64,32.55,30.90,30.61,26.20,24.67,24.52,20.37,12.98.ESI-MS m/z:C18H29BrO5 427.2(M+Na)+:429.2(M+2+Na)+=1:1。
α-isomer;1H NMR(600MHz,Chloroform-d)δ5.34(s,1H),4.44(d,J=9.2Hz,1H),4.07(dt,J=10.1,5.1Hz,1H),3.64–3.47(m,3H),2.46–2.32(m,2H),2.21(ddq,J=16.7,8.5,5.6Hz,1H),2.09–1.96(m,2H),1.88(ddt,J=13.6,6.8,3.5Hz,1H),1.76(dq,J=13.6,3.7Hz,1H),1.72–1.66(m,1H),1.57–1.46(m,2H),1.43(s,3H),1.36–1.26(m,3H),1.04–0.98(m,1H),0.96(dd,J=6.8,4.7Hz,3H),0.89(d,J=7.1Hz,3H).13C NMR(150MHz,Chloroform-d)δ104.29,100.42,91.21,80.35,66.45,51.65,45.33,37.39,36.32,34.24,32.78,32.67,30.83,26.06,24.72,22.21,20.29,12.58.ESI-MS m/z:C18H29BrO5 427.2(M+Na)+:429.2(M+2+Na)+=1:1。
实施例2:中间体D4的制备
Figure BDA0003438819950000061
将DHA(1g,3.5mmol)溶于200mL二氯甲烷中配成溶液,在室温条件下加入4-溴-1-丁醇(0.328mL,3.6mmol),再加入4滴三氟化硼乙醚,N2保护,室温反应12h,TLC监测反应。反应结束,加入200mL饱和碳酸氢钠、二氯甲烷萃取三次,再加入无水碳酸钠干燥,过滤拌样,柱层析得中间产物D4,产率10.09%。
结构验证:
β-isomer;1H NMR(600MHz,Chloroform-d)δ5.37(s,1H),4.77(d,J=3.5Hz,1H),3.88(dt,J=9.8,6.2Hz,1H),3.50–3.35(m,3H),2.69–2.57(m,1H),2.36(ddd,J=14.7,13.5,4.0Hz,1H),2.03(ddd,J=14.6,5.0,3.0Hz,1H),1.97–1.84(m,3H),1.79–1.68(m,4H),1.63(dq,J=13.3,3.4Hz,1H),1.54–1.44(m,2H),1.43(s,3H),1.33(ttd,J=12.4,6.3,4.0Hz,1H),1.28–1.15(m,2H),0.95(d,J=6.4Hz,3H),0.90(d,J=7.4Hz,3H).13C NMR(150MHz,Chloroform-d)δ104.10,102.01,87.92,81.10,67.44,52.58,44.42,37.49,36.44,34.64,33.63,30.90,29.82,28.34,26.21,24.68,24.50,20.37,13.04.ESI-MS m/z:C19H31BrO5 441.2(M+Na)+:443.2(M+2+Na)+=1:1。
α-isomer;1H NMR(600MHz,Chloroform-d)δ5.44(s,1H),4.96(d,J=5.2Hz,1H),3.91(dt,J=9.8,6.3Hz,1H),3.51(dt,J=9.9,6.4Hz,1H),3.45(t,J=6.8Hz,2H),2.30(td,J=14.0,3.9Hz,1H),2.02(ddd,J=14.5,4.8,3.0Hz,1H),1.97(dq,J=9.7,7.0Hz,2H),1.90(ddq,J=13.5,6.6,3.5Hz,1H),1.76(p,J=6.9Hz,2H),1.72–1.61(m,3H),1.55–1.47(m,2H),1.47–1.42(m,2H),1.42(s,3H),1.18(d,J=7.2Hz,3H),0.99(td,J=12.3,11.7,4.1Hz,1H),0.94(d,J=5.9Hz,3H),0.93–0.86(m,1H).13C NMR(150MHz,Chloroform-d)δ103.01,102.78,89.17,81.67,67.77,51.86,46.55,39.89,37.32,36.53,34.42,33.71,31.64,29.74,28.34,25.98,24.69,20.07,19.51.ESI-MS m/z:C19H31BrO5 441.2(M+Na)+:443.2(M+2+Na)+=1:1。
实施例3:中间体D5的制备
Figure BDA0003438819950000071
将DHA(1g,3.5mmol)溶于200mL二氯甲烷中配成溶液,在室温条件下加入5-溴-1-戊醇(0.438mL,3.6mmol),再加入4滴三氟化硼乙醚,N2保护,室温反应12h,TLC监测反应。反应结束,加入200mL饱和碳酸氢钠、二氯甲烷萃取三次,再加入无水碳酸钠干燥,过滤拌样,柱层析得中间产物D5,产率19.72%。
结构验证:
β-isomer;1H NMR(600MHz,Chloroform-d)δ5.39(s,1H),4.77(d,J=3.4Hz,1H),3.85(dt,J=9.8,6.3Hz,1H),3.47–3.32(m,3H),2.68–2.52(m,1H),2.42–2.30(m,1H),2.03(ddd,J=14.6,5.0,3.0Hz,1H),1.91–1.84(m,3H),1.81(dd,J=13.9,3.6Hz,1H),1.75(tt,J=14.3,3.8Hz,1H),1.66–1.55(m,4H),1.54–1.45(m,4H),1.43(s,3H),1.42–1.28(m,3H),1.28–1.16(m,1H),0.95(d,J=6.4Hz,3H),0.90(d,J=7.8Hz 3H).13C NMR(150MHz,Chloroform-d)δ104.08,102.01,87.93,81.15,68.03,52.59,44.46,37.47,36.45,34.68,33.84,32.43,30.94,28.84,26.23,24.98,24.69,24.50,20.37,13.05.ESI-MS m/z:C20H33BrO5 455.2(M+Na)+:457.2(M+2+Na)+=1:1。
α-isomer;1H NMR(600MHz,Chloroform-d)δ5.44(s,1H),4.95(d,J=5.0Hz,1H),3.87(dt,J=9.8,6.5Hz,1H),3.48(dt,J=9.8,6.5Hz,1H),3.41(t,J=6.8Hz,2H),2.30(ddd,J=14.6,13.4,3.9Hz,1H),2.01(ddd,J=14.6,4.8,3.1Hz,1H),1.89(ddt,J=13.9,9.7,5.3Hz,3H),1.71(qd,J=13.4,3.4Hz,2H),1.63(ddt,J=12.0,8.2,4.8Hz,4H),1.57(dt,J=13.3,3.5Hz,2H),1.54–1.49(m,3H),1.41(s,3H),1.18(d,J=7.3Hz,3H),1.00–0.96(m,1H),0.94(d,J=6.1Hz,3H),0.90–0.85(m,1H).13C NMR(150MHz,Chloroform-d)δ103.04,102.80,89.10,81.66,68.40,51.89,46.52,39.82,37.30,36.53,34.44,33.78,32.54,31.61,28.83,25.98,24.92,24.69,20.07,19.54.ESI-MS m/z:C20H33BrO5 455.2(M+Na)+:457.2(M+2+Na)+=1:1。
实施例4:中间产物D6的制备
Figure BDA0003438819950000072
将DHA(1g,3.5mmol)溶于200mL二氯甲烷中配成溶液,在室温条件下加入6-溴-1-己醇(0.471mL,3.6mmol),再加入4滴三氟化硼乙醚,N2保护,室温反应12h,TLC监测反应。反应结束,加入200mL饱和碳酸氢钠、二氯甲烷萃取三次,再加入无水碳酸钠干燥,过滤拌样,柱层析得中间产物D6,产率13.10%。
结构验证:
β-isomer;1H NMR(600MHz,Chloroform-d)δ5.38(s,1H),4.77(d,J=3.5Hz,1H),3.83(dt,J=9.7,6.5Hz,1H),3.40(t,J=6.8Hz,2H),3.36(dd,J=9.7,6.4Hz,1H),2.61(qt,J=7.4,4.1Hz,1H),2.40–2.32(m,1H),2.03(ddd,J=14.6,5.0,3.0Hz,1H),1.90–1.83(m,3H),1.80(dd,J=13.7,3.6Hz,1H),1.75(tq,J=12.0,3.9Hz,1H),1.66–1.59(m,1H),1.58(d,J=4.2Hz,2H),1.56–1.45(m,4H),1.44(s,3H),1.42–1.28(m,4H),1.24–1.16(m,1H),0.95(d,J=6.3Hz,3H),0.90(d,J=7.3Hz,3H).13C NMR(150MHz,Chloroform-d)δ104.07,101.99,87.92,81.15,68.24,52.61,44.48,37.51,36.46,34.68,33.80,32.73,30.95,29.49,27.89,26.24,25.46,24.70,24.49,20.39,13.05.ESI-MS m/z:C21H35BrO5469.3(M+Na)+:471.3(M+2+Na)+=1:1。
α-isomer;1H NMR(600MHz,Chloroform-d)δ5.33(s,1H),4.41(d,J=9.2Hz,1H),3.97(dt,J=9.6,6.3Hz,1H),3.47–3.35(m,3H),2.49–2.28(m,2H),2.02(ddd,J=14.6,5.0,3.0Hz,1H),1.87(h,J=6.8Hz,3H),1.76(dq,J=13.5,3.8Hz,1H),1.66(dddd,J=33.0,15.3,7.8,4.7Hz,2H),1.57–1.45(m,4H),1.44(s,4H),1.42–1.27(m,5H),1.01(td,J=12.7,12.2,3.2Hz,1H),0.95(d,J=6.3Hz,3H),0.88(d,J=7.1Hz,3H).13C NMR(150MHz,Chloroform-d)δ104.25,100.12,91.21,80.35,68.86,51.69,45.35,37.39,36.35,34.27,33.94,32.75,32.64,29.37,27.93,26.08,25.21,24.72,22.22,20.30,12.65.ESI-MS m/z:C21H35BrO5 469.3(M+Na)+:471.3(M+2+Na)+=1:1。
实施例5:中间产物D7的制备
Figure BDA0003438819950000081
将DHA(1g,3.5mmol)溶于200mL二氯甲烷中配成溶液,在室温条件下加入7-溴-1-庚醇(0.553mL,3.6mmol),再加入4滴三氟化硼乙醚,N2保护,室温反应12h,TLC监测反应。反应结束,加入200mL饱和碳酸氢钠、二氯甲烷萃取三次,再加入无水碳酸钠干燥,过滤拌样,柱层析得中间产物D7,产率13.29%。
结构验证:
β-isomer;1H NMR(600MHz,Chloroform-d)δ5.38(s,1H),4.77(dd,J=3.5,1.0Hz,1H),3.82(dt,J=9.6,6.6Hz,1H),3.42–3.30(m,3H),2.67–2.51(m,1H),2.40–2.32(m,1H),2.07–1.99(m,1H),1.90–1.71(m,5H),1.63(dq,J=13.1,3.3Hz,1H),1.58–1.44(m,5H),1.44(s,3H),1.42–1.40(m,1H),1.39–1.29(m,6H),1.24–1.17(m,1H),0.95(d,J=6.3Hz,3H),0.90(d,J=7.4Hz,3H).13C NMR(150MHz,Chloroform-d)δ104.06,101.97,87.91,81.16,68.32,52.61,44.50,37.51,36.46,34.68,33.95,32.74,30.95,29.55,28.47,28.13,26.24,26.08,24.70,24.49,20.40,13.05.ESI-MS m/z:C22H37BrO5 483.1724(M+Na)+:485.1708(M+2+Na)+=1:1。
α-isomer;1H NMR(600MHz,Chloroform-d)δ5.33(s,1H),4.41(d,J=9.2Hz,1H),4.04–3.88(m,1H),3.45–3.29(m,3H),2.46–2.33(m,2H),2.02(ddd,J=14.6,5.0,3.0Hz,1H),1.86(tt,J=14.5,7.0Hz,3H),1.76(dq,J=13.6,3.8Hz,1H),1.68(dq,J=13.3,3.4Hz,1H),1.60–1.45(m,4H),1.44(s,3H),1.42–1.27(m,9H),1.04–0.97(m,1H),0.95(d,J=6.3Hz,3H),0.88(d,J=7.1Hz,3H).13C NMR(150MHz,Chloroform-d)δ104.25,100.12,91.21,80.36,69.02,51.69,45.35,37.39,36.35,34.27,34.01,32.76,32.64,29.45,28.54,28.12,26.08,25.83,24.73,22.23,20.30,12.65.ESI-MS m/z:C22H37BrO5 483.1724(M+Na)+:485.1708(M+2+Na)+=1:1。
实施例6:中间产物D8的制备
Figure BDA0003438819950000091
将DHA(1g,3.5mmol)溶于200mL二氯甲烷中配成溶液,在室温条件下加入8-溴-1-辛醇(0.617mL,3.6mmol),再加入4滴三氟化硼乙醚,N2保护,室温反应12h,TLC监测反应。反应结束,加入200mL饱和碳酸氢钠、二氯甲烷萃取三次,再加入无水碳酸钠干燥,过滤拌样,柱层析得中间产物D8,产率19.07%。
结构验证:
β-isomer;1H NMR(600MHz,Chloroform-d)δ5.38(s,1H),4.76(d,J=3.5Hz,1H),3.83(ddt,J=22.6,9.7,6.6Hz,1H),3.39(td,J=6.9,1.7Hz,2H),3.35(dt,J=9.7,6.5Hz,1H),2.60(qt,J=7.4,4.0Hz,1H),2.36(td,J=14.0,4.0Hz,1H),2.02(ddd,J=14.7,5.2,3.2Hz,1H),1.84(ddd,J=14.4,8.2,5.5Hz,3H),1.81–1.67(m,2H),1.64(t,J=3.6Hz,1H),1.61–1.51(m,3H),1.51–1.44(m,2H),1.43(s,3H),1.32(dq,J=8.7,5.6,4.5Hz,9H),1.18(d,J=7.2Hz,1H),0.95(d,J=6.3Hz,3H),0.89(d,J=7.3Hz,3H).13C NMR(150MHz,Chloroform-d)δ104.04,101.95,87.91,81.16,68.39,52.61,44.50,37.50,36.46,34.70,33.98,32.80,30.95,29.62,29.13,28.72,28.09,26.24,26.15,24.70,24.48,20.40,13.05.ESI-MS m/z:C23H39BrO5 497.3(M+Na)+:499.3(M+2+Na)+=1:1。
α-isomer;1H NMR(600MHz,Chloroform-d)δ5.32(s,1H),4.41(d,J=9.2Hz,1H),4.02–3.89(m,1H),3.40(t,J=6.9Hz,3H),2.48–2.31(m,2H),2.01(ddd,J=14.6,5.0,3.0Hz,1H),1.91–1.81(m,3H),1.75(dq,J=13.6,3.9Hz,1H),1.71–1.64(m,2H),1.63–1.45(m,5H),1.43(s,3H),1.42–1.36(m,2H),1.31(dd,J=5.8,3.3Hz,5H),1.27(d,J=6.9Hz,1H),1.00(td,J=12.7,12.3,3.6Hz,1H),0.95(d,J=6.2Hz,3H),0.93–0.89(m,1H),0.87(d,J=7.1Hz,3H).13CNMR(150MHz,Chloroform-d)δ104.23,100.10,91.20,80.35,69.09,51.69,45.35,37.38,36.35,34.27,34.04,33.99,32.81,32.76,29.50,29.19,28.70,28.12,25.90,24.72,22.22,20.30,12.64.ESI-MS m/z:C23H39BrO5 497.3(M+Na)+:499.3(M+2+Na)+=1:1。
实施例7:中间产物D9的制备
Figure BDA0003438819950000101
将DHA(1g,3.5mmol)溶于200mL二氯甲烷中配成溶液,在室温条件下加入9-溴-1-壬醇(0.663mL,3.6mmol),再加入4滴三氟化硼乙醚,N2保护,室温反应12h,TLC监测反应。反应结束,加入200mL饱和碳酸氢钠、二氯甲烷萃取三次,再加入无水碳酸钠干燥,过滤拌样,柱层析得中间产物D9,产率15.14%。
结构验证:
β-isomer;1H NMR(600MHz,Chloroform-d)δ5.39(s,1H),4.77(d,J=3.5Hz,1H),3.82(dt,J=9.6,6.6Hz,1H),3.49–3.33(m,3H),2.61(qdd,J=7.4,4.6,3.5Hz,1H),2.41–2.25(m,1H),2.03(ddd,J=14.6,5.0,3.0Hz,1H),1.92–1.77(m,4H),1.74(dq,J=14.3,4.0Hz,1H),1.63(dq,J=13.1,3.4Hz,1H),1.57–1.45(m,4H),1.44(s,3H),1.42(d,J=9.8Hz,2H),1.38–1.27(m,10H),1.24–1.17(m,1H),0.95(d,J=6.3Hz,3H),0.89(d,J=7.4Hz,3H).13C NMR(150MHz,Chloroform-d)δ104.05,101.95,87.91,81.17,68.41,52.62,44.51,37.50,36.47,34.70,34.02,32.84,30.96,29.64,29.40,29.22,28.71,28.18,26.25,26.20,24.71,24.47,20.40,13.05.ESI-MS m/z:C24H41BrO5 511.4(M+Na)+:513.3(M+2+Na)+=1:1。
α-isomer;1H NMR(600MHz,Chloroform-d)δ5.33(s,1H),4.41(d,J=9.2Hz,1H),3.95(ddd,J=9.6,7.0,5.8Hz,1H),3.47–3.31(m,3H),2.49–2.30(m,2H),2.06–1.99(m,1H),1.95–1.87(m,1H),1.87–1.81(m,4H),1.77(tq,J=13.6,3.8Hz,1H),1.68(dq,J=13.4,3.4Hz,1H),1.58–1.46(m,4H),1.44(s,3H),1.41(q,J=6.2,5.4Hz,3H),1.31–1.29(m,6H),1.22–1.14(m,1H),1.08–0.98(m,2H),0.95(d,J=6.3Hz,3H),0.88(d,J=7.2Hz,3H).13C NMR(150MHz,Chloroform-d)δ104.24,100.10,91.20,80.35,69.14,51.69,45.35,37.39,36.35,34.27,34.06,32.84,32.65,29.53,29.37,29.29,28.71,28.16,26.08,25.95,24.73,22.23,20.30,12.64.ESI-MS m/z:C24H41BrO5 511.4(M+Na)+:513.3(M+2+Na)+=1:1。
实施例8:中间产物D10的制备
Figure BDA0003438819950000111
将DHA(1g,3.5mmol)溶于200mL二氯甲烷中配成溶液,在室温条件下加入10-溴-1-葵醇(0.719mL,3.6mmol),再加入4滴三氟化硼乙醚,N2保护,室温反应12h,TLC监测反应。反应结束,加入200mL饱和碳酸氢钠、二氯甲烷萃取三次,再加入无水碳酸钠干燥,过滤拌样,柱层析得中间产物D10,产率6.77%。
结构验证:
β-isomer;1H NMR(600MHz,Chloroform-d)δ5.41(s,1H),4.80(d,J=3.6Hz,1H),3.86(ddt,J=21.0,9.6,6.6Hz,1H),3.52–3.36(m,3H),2.63(qdd,J=7.4,4.6,3.5Hz,1H),2.36(dddd,J=37.8,14.6,13.5,3.9Hz,1H),2.05(dtd,J=14.1,5.4,3.1Hz,1H),1.95–1.80(m,4H),1.80–1.69(m,1H),1.65(dp,J=12.8,2.9Hz,1H),1.60–1.47(m,4H),1.46(d,J=9.2Hz,3H),1.43(d,J=8.9Hz,1H),1.32(d,J=9.8Hz,12H),1.27–1.18(m,2H),0.98(d,J=6.2Hz,3H),0.92(d,J=7.2Hz,3H).13C NMR(150MHz,Chloroform-d)δ104.04,101.94,87.91,81.17,68.42,52.62,44.51,37.50,36.47,34.71,34.04,32.84,30.96,29.65,29.49,29.37,29.28,28.77,28.19,26.25,26.22,24.71,24.47,20.40,13.05.ESI-MS m/z:C25H43BrO5 525.4(M+Na)+:527.4(M+2+Na)+=1:1。
α-isomer;1H NMR(600MHz,Chloroform-d)δ5.33(s,1H),4.41(d,J=9.2Hz,1H),3.95(ddd,J=9.5,7.1,5.8Hz,1H),3.47–3.27(m,3H),2.46–2.29(m,2H),2.02(ddd,J=14.5,4.9,3.0Hz,1H),1.91–1.81(m,3H),1.76(dq,J=13.5,3.7Hz,1H),1.68(dq,J=13.4,3.4Hz,1H),1.59–1.46(m,4H),1.44(s,3H),1.43–1.39(m,2H),1.37–1.26(m,13H),1.10(s,1H),1.05–0.98(m,1H),0.95(d,J=6.3Hz,3H),0.88(d,J=7.8Hz,3H).13C NMR(150MHz,Chloroform-d)δ104.24,100.10,91.20,80.36,69.18,51.69,45.36,37.39,36.36,34.28,34.08,32.85,32.65,29.71,29.55,29.46,29.37,28.75,28.18,26.08,25.98,24.73,22.23,20.30,12.64.ESI-MS m/z:C25H43BrO5 525.4(M+Na)+:527.4(M+2+Na)+=1:1。
实施例9:中间产物D11的制备
Figure BDA0003438819950000121
将DHA(1g,3.5mmol)溶于200mL二氯甲烷中配成溶液,在室温条件下加入11-溴-1-十一醇(0.9g,3.6mmol),再加入4滴三氟化硼乙醚,N2保护,室温反应12h,TLC监测反应。反应结束,加入200mL饱和碳酸氢钠、二氯甲烷萃取三次,再加入无水碳酸钠干燥,过滤拌样,柱层析得中间产物D11,产率12.14%。
结构验证:
β-isomer;1H NMR(600MHz,Chloroform-d)δ5.38(s,1H),4.77(d,J=3.5Hz,1H),3.81(dt,J=9.6,6.6Hz,1H),3.42–3.32(m,3H),2.68–2.56(m,1H),2.36(ddd,J=14.6,13.5,4.0Hz,1H),2.03(ddd,J=14.6,5.0,3.0Hz,1H),1.92–1.80(m,4H),1.73(dq,J=14.4,3.9Hz,1H),1.64–1.59(m,1H),1.58–1.45(m,4H),1.43(s,3H),1.42–1.39(m,2H),1.35–1.23(m,15H),0.95(d,J=6.3Hz,3H),0.89(d,J=7.4Hz,3H).13C NMR(150MHz,Chloroform-d)δ104.05,101.94,87.91,81.18,68.44,52.61,44.51,37.49,36.47,34.70,34.06,32.84,30.96,29.71,29.65,29.56,29.47,29.44,29.31,28.79,28.19,26.24,24.70,24.47,20.40,13.05.ESI-MS m/z:C26H45BrO5539.2347(M+Na)+:541.2331(M+2+Na)+=1:1。
实施例10:中间产物D12的制备
Figure BDA0003438819950000122
将DHA(1g,3.5mmol)溶于200mL二氯甲烷中配成溶液,在室温条件下加入12-溴-1-十二醇(0.855mL,3.6mmol),再加入4滴三氟化硼乙醚,N2保护,室温反应12h,TLC监测反应。反应结束,加入200mL饱和碳酸氢钠、二氯甲烷萃取三次,再加入无水碳酸钠干燥,过滤拌样,柱层析得中间产物D12,产率13.12%。
结构验证:
β-isomer;1H NMR(600MHz,Chloroform-d)δ5.39(s,1H),4.77(d,J=2.5Hz,1H),3.82(dt,J=9.6,6.6Hz,1H),3.40(t,J=6.9Hz,2H),3.36(dt,J=9.7,6.4Hz,1H),2.65–2.55(m,1H),2.37(ddd,J=14.6,13.5,4.0Hz,1H),2.03(ddd,J=14.6,5.0,3.0Hz,1H),1.92–1.78(m,4H),1.74(dq,J=14.2,3.8Hz,1H),1.62(dq,J=13.2,3.4Hz,1H),1.56–1.44(m,4H),1.44(s,3H),1.43–1.39(m,2H),1.36–1.24(m,17H),0.95(d,J=6.4Hz,3H),0.90(d,J=7.4Hz,3H).13CNMR(150MHz,Chloroform-d)δ104.04,101.94,87.92,81.18,68.45,52.62,44.52,37.49,36.47,34.71,34.07,32.85,30.97,29.66,29.60,29.55(×2),29.46,29.33,28.79,28.19,26.25(×2),24.71,24.47,20.40,13.05.ESI-MS m/z:C27H47BrO5553.4(M+Na)+:555.4(M+2+Na)+=1:1。
α-isomer;1H NMR(600MHz,Chloroform-d)δ5.33(s,1H),4.41(d,J=9.2Hz,1H),3.98–3.85(m,1H),3.44–3.30(m,3H),2.45–2.31(m,2H),2.02(ddd,J=14.5,4.9,2.9Hz,1H),1.90–1.82(m,3H),1.76(dq,J=13.6,3.7Hz,1H),1.68(dq,J=13.4,3.5Hz,1H),1.60–1.46(m,5H),1.44(s,3H),1.43–1.39(m,2H),1.38–1.27(m,13H),1.24–1.09(m,2H),1.03–0.97(m,1H),0.95(d,J=6.3Hz,3H),0.91(ddd,J=9.3,5.3,2.6Hz,1H),0.88(d,J=7.2Hz,3H).13C NMR(150MHz,Chloroform-d)δ104.24,100.10,91.20,80.36,69.22,51.69,45.36,37.39,36.36,34.28,34.09,32.86,32.65,29.57(×2),29.54,29.52,29.44,29.42,28.78,28.19,26.08,26.00,24.73,22.23,20.30,12.64.ESI-MS m/z:C27H47BrO5 553.4(M+Na)+:555.4(M+2+Na)+=1:1。
实施例11:化合物D3-T的制备
Figure BDA0003438819950000131
将中间体D3(1eq),三苯基磷(2eq),碳酸钾70mg溶于5-10mL乙腈中,N2保护,60℃回流24h。TLC监测,待反应结束后过滤,旋干样品,柱层析得化合物D3-T,产率26.19%。
结构验证:
β-isomer;1H NMR(600MHz,Chloroform-d)δ7.85–7.77(m,9H),7.69(td,J=7.8,3.4Hz,6H),5.26(s,1H),4.72(d,J=3.5Hz,1H),4.04–3.87(m,2H),3.82–3.67(m,2H),2.57(qt,J=7.4,4.1Hz,1H),2.32(td,J=14.0,3.9Hz,1H),1.99(ddd,J=14.6,4.9,3.0Hz,2H),1.96–1.90(m,2H),1.84(ddt,J=13.5,6.7,3.5Hz,1H),1.73–1.48(m,4H),1.44–1.38(m,2H),1.36(s,3H),1.19(td,J=11.0,6.2Hz,1H),0.92(d,J=6.0Hz,3H),0.83(d,J=7.3Hz,3H).13C NMR(150MHz,Chloroform-d)δ135.13(d,J=3.0Hz,Ph-C),133.67(d,J=9.0Hz,Ph-C),130.55(d,J=12.0Hz,Ph-C),118.18(d,J=85.5Hz,Ph-C),104.11,101.78,87.78,80.88,67.06,66.92,52.42,44.20,37.35,36.33,34.56,30.79,29.68,26.09,24.61(d,J=7.5Hz,Ph-C),23.11(d,J=3.0Hz,Ph-C),20.34,13.19.ESI-MS m/z C36H44O5P+587.4(M-Br)+
实施例12:化合物D4-T的制备
Figure BDA0003438819950000141
将中间体D4(1eq),三苯基磷(2eq),碳酸钾70mg溶于5-10mL乙腈中,N2保护,60℃回流24h。TLC监测,待反应结束后过滤,旋干样品,柱层析得化合物D4-T,产率21.09%。
结构验证:
α:β=5:4;1H NMR(600MHz,Chloroform-d)δ7.88–7.75(m,9H),7.72–7.66(m,6H),5.31/5.24(s,1H),4.66/4.44(d,J=3.5Hz and J=9.2Hz,1H),4.06–3.95/3.94–3.88(m,1H),3.82–3.74(m,3H),3.61–3.53/3.37–3.33(m,1H),2.79–2.59(m,1H),2.53(tdd,J=10.0,6.7,3.3Hz,1H),2.43–2.16(m,5H),2.04–1.93(m,3H),1.79–1.65(m,2H),1.58–1.44(m,3H),1.40/1.39(s,3H),0.93/0.91(d,J=6.0Hz,3H),0.75/0.69(d,J=3Hz,3H).13C NMR(150MHz,Chloroform-d)δ134.97/134.92(d,J=3.0Hz,Ph-C),133.81/133.72/133.69(d,J=9.0Hz,Ph-C),130.48/130.46(d,J=12.0Hz,Ph-C),118.39/118.33(d,J=85.5Hz,Ph-C),104.07/103.99,101.88/99.84,91.20/87.80,80.96/80.59,67.53/66.66,59.90/59.52,52.46/51.76,45.41/45.31,38.15,37.36/37.28,36.38/36.27,34.51/34.19,32.96,31.24/30.77,26.16/25.70,24.65/24.42,22.69,20.37/20.28,13.01/12.63.ESI-MS m/z C37H46O5P+601.4(M-Br)+
实施例13:化合物D5-T的制备
Figure BDA0003438819950000142
将中间体D5(1eq),三苯基磷(2eq),碳酸钾70mg溶于5-10mL乙腈中,N2保护,60℃回流24h。TLC监测,待反应结束后过滤,旋干样品,柱层析得化合物D5-T,产率43.12%。
结构验证:
α:β=1:5;1H NMR(600MHz,Chloroform-d)δ7.85–7.82/7.68 7.63(m,6H),7.78–7.76/7.56–7.52(m,3H),7.71–7.70/7.48–7.43(m,6H),5.32/5.37(s,1H),4.67/4.88(d,J=3.6Hz and 5.4Hz,1H),3.84–3.77(m,2H),3.72(dt,J=9.7,6.4Hz,2H),3.28(dt,J=9.7,6.5Hz,1H),2.61–2.50(m,1H),2.34(td,J=14.0,4.0Hz,2H),2.00(ddd,J=14.5,4.9,3.1Hz,2H),1.85(ddd,J=10.1,6.4,3.2Hz,2H),1.54–1.41(m,4H),1.39/1.40(s,3H),1.34–1.27(m,3H),1.22–1.12(m,3H),0.93(d,J=6.3Hz,3H),0.80(d,J=7.3Hz,3H).13CNMR(150MHz,Chloroform-d)δ135.00(d,J=3.0Hz,Ph-C),133.77(d,J=9.0Hz,Ph-C),133.70(d,J=7.5Hz,Ph-C),132.09(d,J=9.0Hz,Ph-C),131.97,131.96,130.51/128.51(d,J=12.0Hz,Ph-C),118.43(d,J=85.5Hz,Ph-C),104.04,101.98/102.15,87.90/88.30,81.12/80.53,67.89,59.52,55.62/52.55,44.41,38.15,37.40,36.43,34.60,31.93/31.24,30.87,29.16,26.19,24.67,24.46,20.37,14.12/13.09.ESI-MS m/zC38H48O5P+615.5(M-Br)+
实施例14:化合物D6-T的制备
Figure BDA0003438819950000151
将中间体D6(1eq),三苯基磷(2eq),碳酸钾70mg溶于5-10mL乙腈中,N2保护,60℃回流24h。TLC监测,待反应结束后过滤,旋干样品,柱层析得化合物D6-T,产率25.52%
结构验证:
α:β=1:1;1H NMR(600MHz,Chloroform-d)δ7.85(dddd,J=14.0,12.5,8.4,1.3Hz,6H),7.78(tt,J=7.4,1.6Hz,3H),7.70(ddt,J=11.0,7.4,3.3Hz,6H),5.33/5.31(s,1H),4.70/4.38(d,J=3.5Hz and 9.2Hz,1H),3.93–3.69(m,3H),3.38–3.24(m,1H),2.38–2.29(m,1H),2.04–1.95(m,1H),1.85(ddt,J=13.9,7.0,3.6Hz,1H),1.78–1.73(m,2H),1.71–1.66(m,3H),1.64–1.58(m,3H),1.56–1.42(m,5H),1.40/1.39(s,3H),1.37–1.25(m,4H),0.94/0.93(d,J=6.6Hz,3H),0.84/0.82(d,J=7.2Hz,3H).13C NMR(150MHz,Chloroform-d)δ134.98/134.95(d,J=3.0Hz,Ph-C),133.75/133.69(d,J=9.0Hz,Ph-C),130.50/130.46(d,J=12.0Hz,Ph-C),118.50/118.43(d,J=85.5Hz,Ph-C),104.18/104.03,101.91/100.07,91.19/87.89,81.16/80.45,68.94/68.29,52.58/51.70,45.36/44.45,38.15,37.41/37.33,36.45/36.35,34.59/34.23,32.74,31.24/30.92,29.25/28.90,26.22/26.08,25.97/25.48,24.68/24.46,22.21,20.37/20.29,14.13/13.87,13.06/12.67.ESI-MS m/z C39H50O5P+629.5(M-Br)+
实施例15:化合物D7-T的制备
Figure BDA0003438819950000152
将中间体D7(1eq),三苯基磷(2eq),碳酸钾70mg溶于5-10mL乙腈中,N2保护,60℃回流24h。TLC监测,待反应结束后过滤,旋干样品,柱层析得化合物D7-T,产率25.52%。
结构验证:
α:β=1:3;1H NMR(600MHz,Chloroform-d)δ7.87–7.75(m,9H),7.70(td,J=7.7,3.3Hz,6H),5.34/5.31(s,1H),4.71/4.38(d,J=3.6Hz and 9.2Hz,1H),3.90–3.65(m,3H),3.36–3.24(m,1H),2.38–2.27(m,2H),2.24–1.93(m,2H),1.84–1.82(m,2H),1.77–1.65(m,2H),1.54–1.43(m,4H),1.40/1.39(s,3H),1.33–1.13(m,10H),0.94/0.93(d,J=6.0Hz,3H),0.84/0.81(d,J=7.2Hz,3H).13C NMR(150MHz,Chloroform-d)δ135.02/134.98(d,J=3.0Hz,Ph-C),133.71/133.68(d,J=9.0Hz,Ph-C),130.51/130.48(d,J=12.0Hz,Ph-C),118.40/118.44(d,J=85.5Hz,Ph-C),104.21/104.04,101.94/100.13,91.18/87.90,81.19/80.44,69.14/68.38,52.59/51.69,45.35/44.48,37.42/37.34,36.45/36.34,34.62/34.23,32.71,30.92,30.26,30.16,29.54/29.35,29.04/28.80,26.23/26.07,25.82/25.50,24.68/24.44,22.46/22.21,20.39/20.29,13.06/12.66.ESI-MS m/zC40H52O5P+643.5(M-Br)+
实施例16:化合物D8-T的制备
Figure BDA0003438819950000161
将中间体D8(1eq),三苯基磷(2eq),碳酸钾70mg溶于5-10mL乙腈中,N2保护,60℃回流24h。TLC监测,待反应结束后过滤,旋干样品,柱层析得化合物D8-T,产率22.36%。
结构验证:
α:β=1:1;β-isomer;1H NMR(600MHz,Chloroform-d)δ7.87–7.76(m,10H),7.72–7.67(m,5H),5.35/5.31(s,1H),4.72/4.38(d,J=3.5and 9.3Hz,1H),3.92–3.69(m,3H),3.63/3.58(t,J=6.6Hz,1H),3.38–3.26(m,2H),2.64–2.29(m,2H),2.03–1.96(m,2H),1.94–1.80(m,4H),1.80–1.65(m,3H),1.56–1.44(m,5H),1.41/1.40(s,1H),1.34–1.27(m,3H),1.21–1.13(m,3H),1.07–0.95(m,1H),0.94/0.93(d,J=6.6Hz,3H),0.91–0.87(m,1H),0.86/0.84(d,J=7.2Hz,3H).13C NMR(150MHz,Chloroform-d)δ135.02/134.99(d,J=3.0Hz,Ph-C),133.70/133.68(d,J=9.0Hz,Ph-C),132.08(d,J=9.0Hz,Ph-C),131.97(d,J=3.0Hz,Ph-C),130.51/130.48(d,J=12.0Hz,Ph-C),128.51(d,J=12.0Hz,Ph-C),118.44/118.40(d,J=85.5Hz,Ph-C),104.21/104.03,101.90/100.13,91.19/87.90,81.18/80.43,69.21/68.41,52.60/51.69,45.35/44.48,38.14,37.44/37.35,36.45/36.35,34.87/34.84,34.23,31.92,31.24/30.94,29.56/29.39,29.21/29.01,28.95/28.84,26.23/26.13,26.08/25.79,24.68/24.45,22.59/22.22,20.39/20.29,13.06/12.66.ESI-MS m/z C41H54O5P+657.5(M-Br)+
实施例17:化合物D9-T的制备
Figure BDA0003438819950000171
将中间体D9(1eq),三苯基磷(2eq),碳酸钾70mg溶于5-10mL乙腈中,N2保护,60℃回流24h。TLC监测,待反应结束后过滤,旋干样品,柱层析得化合物D9-T,产率17.71%。
结构验证:
α:β=1:4;β-isomer;1H NMR(600MHz,Chloroform-d)δ7.87(dddd,J=12.5,6.7,3.2,1.3Hz,6H),7.83–7.79(m,3H),7.76–7.69(m,6H),5.39/5.35(s,1H),4.77/4.42(d,J=3.0Hz and9.2Hz,1H),3.99–3.61(m,4H),3.42–3.31(m,1H),2.44–2.30(m,1H),2.07–1.98(m,1H),1.95–1.68(m,7H),1.59–1.47(m,4H),1.46–1.38(m,4H),1.37–1.28(m,6H),1.24–1.16(m,5H),0.97/0.96(d,J=6.6Hz,3H),0.89/0.88(d,J=7.2Hz,3H).13C NMR(150MHz,Chloroform-d)δ134.97(d,J=3.0Hz,Ph-C),133.73/133.71(d,J=10.5Hz,Ph-C),132.09(d,J=9.0Hz,Ph-C),131.95(d,J=3.0Hz,Ph-C),130.48/130.43(d,J=13.5Hz,Ph-C),128.54/128.51(d,J=12.0Hz,Ph-C),118.48(d,J=85.5Hz,Ph-C),104.21/104.03,101.93/100.10,91.20/87.91,81.20/80.41,69.23/68.45,52.61/51.70,45.37/44.51,38.15,37.44/37.36,36.47/36.36,34.24,32.71,31.24/30.96,29.66,29.45/29.36,29.17,26.08,25.84,24.70,22.56,22.27/22.23,20.40/20.29,14.13/13.84,13.06/12.66.ESI-MS m/z C42H56O5P+671.5(M-Br)+
实施例18:化合物D10-T的制备
Figure BDA0003438819950000172
将中间体D10(1eq),三苯基磷(2eq),碳酸钾70mg溶于5-10mL乙腈中,N2保护,60℃回流24h。TLC监测,待反应结束后过滤,旋干样品,柱层析得化合物D10-T,产率20.86%。
结构验证:
α:β=1:10;1H NMR(600MHz,Chloroform-d)δ7.87–7.75(m,9H),7.70(td,J=7.8,3.4Hz,6H),5.36/5.31(s,1H),4.74/4.39(d,J=3.0Hz and 9.2Hz,1H),3.94–3.56(m,4H),3.41–3.28(m,1H),2.41–2.28(m,2H),1.92–1.81(m,4H),1.79–1.66(m,3H),1.56–1.43(m,5H),1.41(s,3H),1.34–1.25(m,4H),1.22–1.12(m,8H),1.02–0.95(m,1H),0.94/0.93(d,J=6.6Hz,3H),0.86/0.85(d,J=7.2Hz,3H).13C NMR(150MHz,Chloroform-d)δ135.03/130.54(d,J=3.0Hz,Ph-C),134.67/132.08(d,J=9.0Hz,Ph-C),130.52/130.49(d,J=10.5Hz,Ph-C),128.52(d,J=12.0Hz,Ph-C),118.43/118.40(d,J=85.5Hz,Ph-C),104.22/104.03,100.14,91.19,80.42,69.29,52.60/51.69,45.35,37.36,36.35,34.24,32.70/32.62,29.51,29.36,29.26,29.11,29.02,26.07,25.90,24.70,24.45,22.61,22.22,20.40,20.29,13.05/12.65.ESI-MS m/z C43H58O5P+685.5(M-Br)+
实施例18:化合物D11-T的制备
Figure BDA0003438819950000181
将中间体D11(1eq),三苯基磷(2eq),碳酸钾70mg溶于5-10mL乙腈中,N2保护,60℃回流24h。TLC监测,待反应结束后过滤,旋干样品,柱层析得化合物D11-T,产率18.18%。
结构验证:
α:β=1:4;1H NMR(600MHz,Chloroform-d)δ7.87–7.80/7.67–7.62(m,6H),7.90–7.79/7.56–7.52(m,3H),7.70/7.45(ddd,J=11.2,6.4,3.4Hz,6H),5.37/5.32(s,1H),4.75/4.40(d,J=3.0Hz and 9.2Hz,1H),3.96–3.68(m,3H),3.64–3.30(m,1H),2.43–2.32(m,2H),2.05–1.97(m,1H),1.94–1.78(m,5H),1.77–1.65(m,3H),1.58–1.44(m,4H),1.42/1.41(s,3H),1.40–1.37(m,1H),1.36–1.27(m,5H),1.22–1.14(m,8H),1.03–0.97(m,1H),0.95/0.92(d,J=6.6Hz,3H),0.86(d,J=7.2Hz,3H).13C NMR(150MHz,Chloroform-d)δ135.00(d,J=3.0Hz,Ph-C),133.71/133.69(d,J=9.0Hz,Ph-C),132.09(d,J=10.5Hz,Ph-C),131.97(d,J=3.0Hz,Ph-C),130.49/130.47(d,J=12.0Hz,Ph-C),128.51(d,J=12.0Hz,Ph-C),118.47/118.44(d,J=85.5Hz,Ph-C),104.22/104.03,101.92/100.13,91.20/87.91,81.19/80.41,69.30/68.46,52.61/51.69,45.36/44.51,37.46/37.37,36.46/36.35,34.68/34.25,31.24,29.52/29.49,29.41,29.37,29.31,29.21,29.15,29.09,26.07,25.93,24.71/24.46,22.92,22.64/22.60,22.22,20.40/20.29,13.06/12.65.ESI-MS m/z C44H60O5P+699.5(M-Br)+
实施例19:化合物D12-T的制备
Figure BDA0003438819950000191
将中间体D12(1eq),三苯基磷(2eq),碳酸钾70mg溶于5-10mL乙腈中,N2保护,60℃回流24h。TLC监测,待反应结束后过滤,旋干样品,柱层析得化合物D12-T,产率28.93%
结构验证:
α:β=1:10;1H NMR(600MHz,Chloroform-d)δ7.83/7.65(ddt,J=12.5,7.0,1.3Hz,6H),7.80–7.76/7.55–7.52(m,3H),7.73–7.67/7.47–7.44(m,6H),5.32/5.37(s,1H),4.40/4.75(d,J=9.2Hz and 3.6Hz,1H),3.93(ddd,J=9.6,7.1,5.8Hz,1H),3.83–3.65(m,2H),3.41–3.32(m,1H),2.37(dddd,J=17.4,14.5,10.2,4.3Hz,2H),2.05–1.93(m,1H),1.86(ddt,J=13.7,6.8,3.5Hz,1H),1.74(dt,J=13.6,3.8Hz,2H),1.68(dq,J=13.3,3.4Hz,1H),1.56–1.43(m,4H),1.42–1.39(m,4H),1.35–1.25(m,7H),1.23–1.15(m,11H),1.10(s,2H),1.03–0.96(m,1H),0.94(d,J=6.2Hz,3H),0.89–0.82(m,3H).13C NMR(150MHz,Chloroform-d)δ134.98/131.96(d,J=3.0Hz,Ph-C),133.70/132.09(d,J=9.0Hz,Ph-C),130.48/130.47(d,J=12.0Hz,Ph-C),128.51(d,J=12.0Hz,Ph-C),118.42/118.41(d,J=85.5Hz,Ph-C),104.22/104.03,101.93/100.13,91.20,80.40,69.30,51.69,45.36,38.15,37.37,36.35,34.25,32.69,31.24,30.38(d,J=15.0Hz),29.55,29.48,29.45,29.37,29.18,29.11,26.07,25.97,24.71,22.92,22.62(d,J=4.5Hz),22.22,20.30,12.65.ESI-MS m/z C45H62O5P+713.6(M-Br)+
实验例1:药物IC50值测定
一、实验材料
人膀胱癌细胞系J82购自上海兴泊生物科技有限公司;
人膀胱癌细胞系T24购自上海兴泊生物科技有限公司;
人肺癌细胞系A549购自上海兴泊生物科技有限公司;
人卵巢癌细胞系OVCAR3购自武汉细胞所;
人卵巢癌细胞系SKOV3来自湘雅医院。
MTT购自Solarbio公司。
二、实验方法及结果
取处于对数期的人膀胱癌细胞(J82、T24)、人卵巢癌细胞(OVCAR3、SKOV3)和人肺癌细胞A549分别按照每孔5000个细胞进行种板,将接种完的96孔培养板放置于培养箱中过夜,用不同浓度的化合物D3-T、化合物D4-T、化合物D5-T、化合物D6-T、化合物D7-T、化合物D8-T、化合物D9-T、化合物D10-T、化合物D11-T、化合物D12-T处理96孔板,处理完成后将96孔培养板均放回培养箱中培养72小时,然后用MTT比色法检测细胞生存率,并分别计算IC50值,实验结果如表1所示。
表1 D3-T~D12-T对5株肿瘤细胞的半数抑制浓度(IC50)
Figure BDA0003438819950000201
实验例2:细胞克隆试验
一、实验材料
10%的福尔马林购自国药集团化学试剂有限公司;
结晶紫染液购自Sigma-Aldrich公司。
二、实验方法及结果
取处于对数生长期的人膀胱癌细胞系J82、T24,分别按照每孔1000个细胞接种于24孔培养板,将接种完的培养板均放置在培养箱中过夜,使细胞贴壁;人膀胱癌细胞系J82、T24分别给予0nM、6.25nM、12.5nM、25nM、50nM的药物(药物为D8-T和DHA)处理;处理完后将培养板均放回培养箱中继续培养一周;待细胞融合至80%后,倒掉培养液,用PBS洗一遍,10%的福尔马林固定1个小时,用并500μL结晶紫染液染色一个小时,最后回收结晶紫染液;之后,分别将24孔板流水冲洗干净,并将24孔板倒置放在滤纸上,干燥后用相机拍摄图像并用酶标仪(Biotek,SYNERGY HTX,Vermont,USA)进行定量分析,实验结果如图2-3所示。
实验例3:细胞划痕试验
取处于对数生长期的人膀胱癌细胞系J82分别按照每孔3×105个细胞接种于12孔培养板,将接种完的培养板均放置在培养箱中使细胞融合至70%-80%。用marker笔在12孔板背后用直尺在中间划一个十字作为固定监测点,使前后观察时位置固定。用10μL枪头比着直尺背后的横线划痕。PBS洗细胞一次,去除划下的细胞,加入无血清培养基。然后膀胱癌细胞系J82分别给予12.5nM、25nM、50nM的药物(药物为D8-T和DHA)处理,放入37度5%CO2培养箱培养。分别于0,24,48小时用显微镜(Leica,DFC450C,Wetzlar,Germany)拍摄图像。实验结果如图4-5所示。由图可以看出,化合物对人膀胱癌细胞系T24、人膀胱癌细胞系UMUC3、人肺癌细胞系A549的迁移抑制效果明显优于双氢青蒿素。

Claims (10)

1.一种双氢青蒿素衍生物,其特征是,所述双氢青蒿素衍生物的结构为如下式Ⅰ所示:
Figure QLYQS_1
其中,所述n为3-12,R1为三苯基膦,R2为卤素;
或者,所述双氢青蒿素衍生物为式Ⅰ化合物的药学上可接受的无机盐或有机盐。
2.根据权利要求1所述的双氢青蒿素衍生物,其特征是,R2为溴。
3.根据权利要求1所述的双氢青蒿素衍生物,其特征是,所述双氢青蒿素衍生物为以下化合物之一:
Figure QLYQS_2
4.一种如权利要求1所述的双氢青蒿素衍生物,其特征是,所述双氢青蒿素衍生物为式Ⅰ化合物的药学上可接受的无机盐或有机盐。
5.一种如权利要求1-3任一项所述的双氢青蒿素衍生物的制备方法,其特征是,将双氢青蒿素和
Figure QLYQS_3
反应,n为3-12,R2为卤素,得到中间体,中间体的结构式如下:
Figure QLYQS_4
,中间体和三苯基膦反应,得到双氢青蒿素衍生物。
6.如权利要求5所述的制备方法,其特征是,所述双氢青蒿素和
Figure QLYQS_5
反应的溶剂为二氯甲烷,催化剂为三氟化硼乙醚。
7.如权利要求5所述的制备方法,其特征是,中间体和三苯基膦反应的溶剂为乙氰,反应体系中还加入有碳酸盐。
8.一种药物组合物,其特征在于,所述的药物组合物包括如权利要求1-4任一项所述的双氢青蒿素衍生物,还包括药学上可接受的赋形剂或载体。
9.一种如权利要求1-4任一所述的双氢青蒿素衍生物在制备抗肿瘤药物中的用途。
10.根据权利要求9所述的应用,其特征在于,所述肿瘤为肺癌、膀胱癌或卵巢癌。
CN202111626019.3A 2021-12-28 2021-12-28 一种双氢青蒿素衍生物、制备方法、药物组合物和其在制备抗肿瘤药物中的应用 Active CN114380864B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202111626019.3A CN114380864B (zh) 2021-12-28 2021-12-28 一种双氢青蒿素衍生物、制备方法、药物组合物和其在制备抗肿瘤药物中的应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202111626019.3A CN114380864B (zh) 2021-12-28 2021-12-28 一种双氢青蒿素衍生物、制备方法、药物组合物和其在制备抗肿瘤药物中的应用

Publications (2)

Publication Number Publication Date
CN114380864A CN114380864A (zh) 2022-04-22
CN114380864B true CN114380864B (zh) 2023-06-23

Family

ID=81198020

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202111626019.3A Active CN114380864B (zh) 2021-12-28 2021-12-28 一种双氢青蒿素衍生物、制备方法、药物组合物和其在制备抗肿瘤药物中的应用

Country Status (1)

Country Link
CN (1) CN114380864B (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114014872B (zh) * 2021-11-29 2023-05-23 桂林医学院 青蒿琥酯衍生物及其制备方法和应用
CN115340571B (zh) * 2022-07-05 2024-09-27 中国中医科学院中药研究所 一种新型青蒿素类衍生物、脂质体的制备方法和应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022541881A (ja) * 2019-06-27 2022-09-28 サントル ナショナル ドゥ ラ ルシェルシュ シアンティフィック アルテミシニン-誘導体n-ヘテロ環状カルベン金(i)ハイブリッド錯体
CN111072699B (zh) * 2019-12-30 2022-05-24 广州中医药大学(广州中医药研究院) 一种羟基自由基比率式荧光探针及其制备方法和应用
CN114014872B (zh) * 2021-11-29 2023-05-23 桂林医学院 青蒿琥酯衍生物及其制备方法和应用

Also Published As

Publication number Publication date
CN114380864A (zh) 2022-04-22

Similar Documents

Publication Publication Date Title
CN114380864B (zh) 一种双氢青蒿素衍生物、制备方法、药物组合物和其在制备抗肿瘤药物中的应用
US20140235568A1 (en) Gemcitabine amide derivative and preparation method and use thereof
CN107955042B (zh) 具有抗癌活性的铂类配合物、制备方法及应用
CN103739616B (zh) 含噻唑基雷帕霉素类衍生物及其应用
CN116143842A (zh) 氧化异阿朴菲生物碱与n-杂环卡宾的环金属铱配合物及其合成方法和应用
CN110283162B (zh) 一种表皮生长因子受体抑制剂及其应用
CN102190658A (zh) 一类抗肿瘤海洋天然产物ecteinascidins的结构类似物
CN107286220B (zh) 1,2,4-三氮唑偶联的二氢杨梅素衍生物及其制备方法和应用
CN110981882B (zh) 一类白屈菜碱一氧化氮供体衍生物及其制备方法和用途
CN107383015B (zh) 烷硫端基寡PEG修饰的氨基吡唑并[3,4-d]嘧啶衍生物及抗非小细胞肺癌的应用
CN108017608B (zh) 一类黄酮衍生物及其制备方法和用途
WO2022142160A1 (zh) Icetexane型松香烷二萜在制备结直肠癌治疗药物中的应用
CN110590778B (zh) 3,10二对甲氧基苯基6,12二氮杂四高立方烷类化合物及合成方法和药物组合物
CN105121447A (zh) 长春碱类衍生物及其制备方法和应用
CN107456457B (zh) 2-(3, 4-二羟苯基)-5, 7-二羟苯基-8-(1, 4氧氮己烷-4-亚甲基)-4h-色烯-4-酮化合物在制备治疗癌症药物中的应用
CN115043878B (zh) 具有肿瘤靶向的生物素化金(i)配合物及其制备方法和应用
CN112694507B (zh) 四氢蒽醌糖苷类化合物及其在制备抗肿瘤药物中的应用
TWI852583B (zh) 一類二氘代喜樹鹼衍生物及製備方法
CN116854704B (zh) 具有抗肝癌活性的瑞香烷二萜衍生物及其制备方法和用途
CN111285900B (zh) 基于紫檀芪和香荚兰乙酮的偶联分子dcz0847类化合物、其制备方法及用途
CN112010791B (zh) 含苯磺酰胺结构单元的新型苯乙酸紫草宁酯类衍生物及其合成方法和应用
CN109824642B (zh) 一种具有抗肺癌活性的白杨素苯丙氨酸衍生物
EP1758904B1 (en) Flavopereirine derivatives for cancer therapy
CN115974890A (zh) 石蒜碱衍生物及其制备方法和在制备抗肿瘤药物中的应用
CN117466816A (zh) 一类青藤碱硫化氢供体衍生物及其制备方法和应用

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant