CN110981882B - 一类白屈菜碱一氧化氮供体衍生物及其制备方法和用途 - Google Patents

一类白屈菜碱一氧化氮供体衍生物及其制备方法和用途 Download PDF

Info

Publication number
CN110981882B
CN110981882B CN201911079950.7A CN201911079950A CN110981882B CN 110981882 B CN110981882 B CN 110981882B CN 201911079950 A CN201911079950 A CN 201911079950A CN 110981882 B CN110981882 B CN 110981882B
Authority
CN
China
Prior art keywords
chelidonine
nitric oxide
donor
pharmaceutically acceptable
derivative
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
CN201911079950.7A
Other languages
English (en)
Other versions
CN110981882A (zh
Inventor
续繁星
李达翃
华会明
黄雪妍
李占林
李昊楠
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.)
Shenyang Pharmaceutical University
Original Assignee
Shenyang Pharmaceutical 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 Shenyang Pharmaceutical University filed Critical Shenyang Pharmaceutical University
Priority to CN201911079950.7A priority Critical patent/CN110981882B/zh
Publication of CN110981882A publication Critical patent/CN110981882A/zh
Application granted granted Critical
Publication of CN110981882B publication Critical patent/CN110981882B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/153—Ortho-condensed systems the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

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

Abstract

本发明涉及天然药物及药物化学领域，涉及白屈菜碱一氧化氮供体衍生物及其制备方法和用途。具体涉及一系列具有抗肿瘤活性的白屈菜碱一氧化氮供体衍生物的制备方法和在制备抗肿瘤药物方面新用途。本发明所述的白屈菜碱一氧化氮供体衍生物及其药学上可接受的盐如通式所示。其中，n1、n2、n3和X如权利要求书和说明书中所述。

Description

一类白屈菜碱一氧化氮供体衍生物及其制备方法和用途
技术领域
本发明涉及天然药物及药物化学领域，涉及白屈菜碱一氧化氮供体衍生物及其制备方法和用途。具体涉及一系列具有抗肿瘤活性的白屈菜碱一氧化氮供体衍生物的制备方法及其在制备抗肿瘤药物方面的用途。
背景技术
白屈菜作为传统中药，全草都可以入药，临床上主要用于治疗胃痛、腹痛、肠炎、痢疾、慢性支气管炎、百日咳、咳嗽、水肿、蛇虫咬伤等疾病。现代研究表明，白屈菜中生物碱为其主要活性成分，其中白屈菜碱为一种主要的生物碱，其主要的药理作用是镇痛、祛痰、止咳、消肿、抗炎、抗菌、抗肿瘤等。
本发明以白屈菜碱为先导化合物，设计并合成了白屈菜碱拼合呋咱类一氧化氮供体衍生物，并测试了合成衍生物在抗肿瘤方面的生物活性。
发明内容
发明要解决的技术问题是寻找抗肿瘤活性好的白屈菜碱一氧化氮供体衍生物及其药学上可接受的盐，并进一步提供一种药物组合物。
为解决上述技术问题，本发明提供如下技术方案：
本发明所述的白屈菜碱一氧化氮供体衍生物及其药学上可接受的盐具有如下的结构通式：
Figure BDA0002263650200000011
其中，n1、n2、n3为1-8的整数，X为-CH2-、-O-、-NH-、-C≡C-或-CH＝CH-。
优选地，n1、n2、n3为1-6的整数，X为-CH2-、-O-、-C≡C-或-CH＝CH-。
更优选地，n1、n2、n3为1-3的整数，X为-CH2-、-O-或-C≡C-。
进一步地，
本发明优选如下衍生物及其药学上可接受的盐：
Figure BDA0002263650200000021
本发明的衍生物可用下列方法制备得到：
Figure BDA0002263650200000022
呋咱类NO供体2在四氢呋喃中与二醇、30％NaOH溶液在0℃反应，得呋咱类NO供体衍生物3，再将其溶于二氯甲烷中，依次加入三乙胺、DMAP和酸酐，室温反应得到呋咱类供体衍生物4。
将NO供体衍生物4，溶于二氯甲烷中，依次加入EDCI、白屈菜碱1、DMAP，室温反应得到白屈菜碱呋咱类NO供体衍生物5。
本发明还提供了一种药物组合物，包含所述的白屈菜碱一氧化氮供体衍生物及其药学上可接受的盐和药学上可接受的载体。
药理试验证明，本发明的白屈菜碱一氧化氮供体衍生物及其药学上可接受的盐或药物组合物具有很好的抗肿瘤细胞增殖作用，可以用于进一步制备抗肿瘤药物。
具体实施方式：
实施例1
Figure BDA0002263650200000031
将100mg(0.27mmol)的呋咱类NO供体2溶解于四氢呋喃中，在0℃条件下，依次加入90μL的丙二醇(1mmol)、0.06ml的30％NaOH溶液，反应至化合物2斑点消失，蒸干溶剂，加10mL水使其悬浮，用二氯甲烷萃取三次，每次10mL，合并有机相，再用饱和食盐水洗两次，无水硫酸钠干燥，过滤、浓缩，硅胶柱层析(二氯甲烷:甲醇＝300:1)得化合物3。将30mg化合物3(0.10mmol)溶于约4mL二氯甲烷中，依次加入65μl的三乙胺(0.50mmol)、20mg的丁二酸酐(0.20mmol)、催化量DMAP，室温搅拌反应约4h，TLC监测反应，待反应完全，加入10％HCl溶液调pH至酸性，加入10mL蒸馏水，用二氯甲烷萃取三次，每次10mL，合并有机相，再用饱和食盐水洗两次，无水硫酸钠干燥，过滤、浓缩，得化合物4。将化合物4用二氯甲烷溶解，依次加入35mg的EDCI(0.18mmol)、21mg白屈菜碱1(0.06mmol)、催化量DMAP，室温反应10h，TLC监测反应至白屈菜碱1的斑点消失或不在减少，加入约15mL水，用二氯甲烷萃取三次，每次10mL，合并有机相，再用饱和食盐水洗两次，无水硫酸钠干燥，过滤、浓缩，硅胶柱层析(二氯甲烷:甲醇＝200:1)，得到淡黄色固体目标产物5a。产率38％。1H NMR(DMSO-d6,600MHz)δ(ppm):8.00(d,2H,J＝7.4Hz,Ar-H),7.86(t,1H,J＝7.7Hz,Ar-H),7.72(t,2H,J＝8.0Hz,Ar-H),7.22(d,1H,J＝8.4Hz,H-10),7.10(s,1H,H-1),6.75(d,1H,J＝8.4Hz,H-9),6.55(s,1H,H-4),5.88-5.95(m,4H,2×-OCH2O-),5.15(m,1H,H-11),4.46(t,2H,J＝6.1Hz,-CH2-),4.17(t,2H,J＝6.3Hz),4.11(d,1H,J＝4.4Hz,H-4b),3.58(d,1H,J＝17.6Hz,H-6),3.51(m,1H,H-10b),3.40(d,1H,J＝17.6Hz,H-6),2.72(m,2H,H-12),2.67(m,2H,-CH2-),2.62(m,2H,-CH2-),2.46(s,3H,N-CH3),2.09(m,2H,-CH2-)；13C NMR(DMSO-d6,150MHz)δ(ppm):172.0,171.4,158.8,146.5,146.4,144.8,143.6,137.1,136.2,130.0,130.0,129.0,128.4,128.4,126.9,126.2,121.3,116.3,111.5,108.2,107.3,106.4,100.9,100.8,72.1,68.2,60.6,60.4,54.9,44.7,41.0,32.0,30.6,28.6,27.4；HR(ESI)MS m/z calcd forC35H34N3O13S[M+H]+736.1768,found 736.1833。
实施例2
Figure BDA0002263650200000041
参照实施例1的合成方法制备得化合物5b，淡黄色固体，产率29％。1H NMR(DMSO-d6,600MHz)δ(ppm):8.00(d,2H,J＝8.2Hz,Ar-H),7.88(t,1H,J＝7.4Hz,Ar-H),7.73(t,2H,J＝7.4Hz,Ar-H),7.23(d,1H,J＝8.6Hz,H-10),7.09(s,1H,H-1),6.75(d,1H,J＝8.6Hz,H-9),6.54(s,1H,H-4),5.88-5.94(m,4H,2×-OCH2O-),5.20(m,1H,H-11),4.38(t,2H,J＝6.1Hz,-CH2-),4.12(d,1H,J＝4.1Hz,H-4b),4.08(t,2H,J＝6.1Hz,-CH2-),3.58(d,1H,J＝17.9Hz,H-6),3.52(m,1H,H-10b),3.39(d,1H,J＝17.9Hz,H-6),2.74(dd,1H,J＝15.1,4.9Hz,H-12),2.67(m,1H,H-12),2.67(m,2H,-CH2-),2.62(t,2H,J＝6.1Hz,-CH2-),2.46(s,3H,N-CH3),1.80(m,2H,-CH2-),1.67(m,2H,-CH2-)；13C NMR(DMSO-d6,150MHz)δ(ppm):171.9,171.4,158.8,146.5,146.3,144.8,143.6,137.2,136.1,130.0,130.0,,128.9,128.3,128.3,126.9,126.2,121.3,116.3,110.4,108.1,107.3,106.4,100.9,100.8,72.1,71.0,63.6,60.6,54.9,44.7,41.0,32.0,30.6,29.1,24.6,24.5；HR(ESI)MS m/z calcdfor C36H36N3O13S[M+H]+750.1924,found 750.1978。
实施例3
Figure BDA0002263650200000042
参照实施例1的合成方法制备得化合物5c，淡黄色固体，产率47％。1H NMR(DMSO-d6,600MHz)δ(ppm):8.00(d,2H,J＝7.6Hz,Ar-H),7.88(t,1H,J＝7.0Hz,Ar-H),7.73(t,2H,J＝7.6Hz,Ar-H),7.24(d,1H,J＝8.2Hz,H-10),7.10(s,1H,H-1),6.77(d,1H,J＝8.2Hz,H-9),6.54(s,1H,H-4),5.89-5.95(m,4H,2×-OCH2O-),5.20(m,1H,H-11),4.35(t,2H,J＝6.4Hz,-CH2-),4.13(d,1H,J＝4.7Hz,H-4b),4.03(t,2H,J＝6.7Hz,-CH2-),3.58(m,1H,H-6),3.53(m,1H,H-10b),3.40(d,1H,J＝17.3Hz,H-6),2.74(dd,1H,J＝15.2,5.3Hz,H-12),2.68(m,1H,H-12),2.66(m,2H,-CH2-),2.61(m,2H,-CH2-),2.46(s,3H,N-CH3),1.99(m,2H,-CH2-),1.71(m,2H,-CH2-),1.57(m,2H,-CH2-),1.34(m,2H,-CH2-)；13C NMR(DMSO-d6,150MHz)δ(ppm):172.0,171.4,158.9,146.5,146.3,144.8,143.6,137.2,136.1,130.0,130.0,128.9,128.3,128.3,126.9,126.2,121.3,116.3,110.4,108.1,107.3,106.4,100.9,100.8,72.1,71.3,64.0,60.6,51.5,44.6,41.0,32.0,31.3,30.6,28.0,27.7,24.8,24.7；HR(ESI)MS m/z calcd for C38H40N3O13S[M+H]+778.2237,found 778.2279。
实施例4
Figure BDA0002263650200000051
参照实施例1的合成方法制备得化合物5d，淡黄色固体，产率46％。1H NMR(DMSO-d6,600MHz)δ(ppm):8.01(d,2H,J＝7.7Hz,Ar-H),7.87(t,1H,J＝7.7Hz,Ar-H),7.72(t,2H,J＝7.3Hz,Ar-H),7.23(d,1H,J＝8.4Hz,H-10),7.10(s,1H,H-1),6.76(d,1H,J＝8.4Hz,H-9),6.54(s,1H,H-4),5.88-5.95(m,4H,2×-OCH2O-),5.19(m,1H,H-11),4.50(m,2H,-CH2-),4.18(m,2H,-CH2-),4.13(d,1H,J＝4.6Hz,H-4b),3.80(m,2H,-CH2-),3.70(m,2H,-CH2-),3.58(d,1H,J＝17.3Hz,H-6),3.52(m,1H,H-10b),3.40(d,1H,J＝17.3Hz,H-6),2.74(dd,1H,J＝15.4,5.0Hz,H-12),2.67(m,1H,H-12),2.67(m,2H,-CH2-),2.61(t,2H,J＝5.4Hz,-CH2-),2.47(s,3H,N-CH3)；13C NMR(DMSO-d6,150MHz)δ(ppm):172.0,171.3,158.9,146.5,146.3,144.8,143.5,137.2,136.1,130.0,130.0,129.0,128.3,128.3,126.9,126.1,121.3,116.2,110.5,108.1,107.3,106.5,100.9,100.8,72.1,70.8,68.4,67.7,63.5,60.6,55.8,44.6,41.0,32.0,30.6,29.6；HR(ESI)MS m/z calcd for C36H36N3O14S[M+H]+766.1873,found 766.1906。
实施例5
Figure BDA0002263650200000052
参照实施例1的合成方法制备得化合物5e，淡黄色固体，产率29％。1H NMR(DMSO-d6,600MHz)δ(ppm):8.00(d,2H,J＝7.9Hz,Ar-H),7.89(t,1H,J＝7.5Hz,Ar-H),7.74(t,2H,J＝7.5Hz,Ar-H),7.23(d,1H,J＝8.2Hz,H-10),7.10(s,1H,H-1),6.77(d,1H,J＝8.2Hz,H-9),6.55(s,1H,H-4),5.88-5.94(m,4H,2×-OCH2O-),5.22(s,2H,-CH2-),5.22(m,1H,H-11),4.84(s,2H,-CH2-),4.13(d,1H,J＝4.2Hz,H-4b),3.60(d,1H,J＝17.2Hz,H-6),3.54(m,1H,H-10b),3.40(d,1H,J＝17.6Hz,H-6),2.76(dd,1H,J＝15.2,4.8Hz,H-12),2.69(m,1H,H-12),2.68(m,2H,-CH2-),2.67(m,2H,-CH2-),2.47(s,3H,N-CH3)；13C NMR(DMSO-d6,150MHz)δ(ppm):171.3,171.2,158.0,146.5,146.3,144.8,143.5,136.9,136.2,130.0,130.0,129.0,128.4,128.4,126.9,126.2,121.3,116.3,110.7,108.1,107.3,106.5,100.9,100.8,84.0,79.4,72.2,68.5,60.7,59.0,54.9,44.7,41.0,32.1,30.6,29.6；HR(ESI)MSm/z calcd for C36H32N3O13S[M+H]+746.1611,found746.1663。
实施例6
Figure BDA0002263650200000061
参照实施例1的合成方法制备得化合物5f，淡黄色固体，产率36％。1H NMR(DMSO-d6,600MHz)δ(ppm):8.02(d,2H,J＝7.9Hz,Ar-H),7.89(t,1H,J＝7.5Hz,Ar-H),7.74(t,2H,J＝7.5Hz,Ar-H),7.20(d,1H,J＝8.2Hz,H-10),7.10(s,1H,H-1),6.74(d,1H,J＝8.2Hz,H-9),6.57(s,1H,H-4),5.89-5.95(m,4H,2×-OCH2O-),5.22(m,1H,H-11),4.47(t,2H,J＝5.9Hz,-CH2-),4.16(t,2H,J＝6.3Hz,-CH2-),4.11(d,1H,J＝4.2Hz,H-4b),3.60(d,1H,J＝17.0Hz,H-6),3.52(m,1H,H-10b),3.41(d,1H,J＝17.0Hz,H-6),2.78(dd,1H,J＝15.3,4.8Hz,H-12),2.69(m,1H,H-12),2.45(s,3H,N-CH3),2.42(m,2H,-CH2-),2.38(t,2H,J＝7.5Hz),2.11(m,2H,-CH2-),1.80(m,2H,-CH2-)；13C NMR(DMSO-d6,150MHz)δ(ppm):172.5,171.8,158.8,146.4,146.3,144.8,143.5,137.2,136.2,130.0,130.0,129.0,128.3,128.3,127.0,126.4,121.2,116.3,110.5,108.2,107.4,106.4,100.9,100.8,71.7,68.3,60.6,60.2,54.9,45.0,41.0,33.0,32.0,30.6,27.4,19.8；HR(ESI)MS m/z calcd forC36H36N3O13S[M+H]+750.1924,found 750.1963。
实施例7
Figure BDA0002263650200000062
参照实施例6的合成方法制备得化合物5g，淡黄色固体，产率45％。1H NMR(DMSO-d6,600MHz)δ(ppm):8.00(m,2H,Ar-H),7.88(t,1H,J＝7.5Hz,Ar-H),7.73(t,2H,J＝8.0Hz,Ar-H),7.20(d,1H,J＝8.3Hz,H-10),7.09(s,1H,H-1),6.74(d,1H,J＝8.3Hz,H-9),6.56(s,1H,H-4),5.88-5.95(m,4H,2×-OCH2O-),5.22(m,1H,H-11),4.41(t,2H,J＝6.2Hz,-CH2-),4.11(m,1H,H-4b),4.09(t,2H,J＝6.4Hz,-CH2-),3.59(d,1H,J＝17.2Hz,H-6),3.52(m,1H,H-10b),3.39(d,1H,J＝17.2Hz,H-6),2.77(dd,1H,J＝15.5,5.1Hz,H-12),2.68(m,1H,H-12),2.44(s,3H,N-CH3),2.43(m,2H,-CH2-),2.36(t,2H,J＝7.5Hz,-CH2-)1.80(m,4H,2×-CH2-),1.69(m,2H,-CH2-)；13C NMR(DMSO-d6,150MHz)δ(ppm):172.5,171.9,158.8,146.4,146.3,144.8,143.6,137.2,136.1,130.0,130.0,,129.0,128.3,128.3,127.0,126.4,121.2,116.3,110.5,108.2,107.4,106.4,100.9,100.8,71.7,71.0,63.4,60.6,54.9,45.0,41.0,32.3,30.8,29.0,24.6,24.5,19.9；HR(ESI)MS m/z calcd for C37H38N3O13S[M+H]+764.2081,found 764.2145。
实施例8
Figure BDA0002263650200000071
参照实施例6的合成方法制备得化合物5h，淡黄色固体，产率35％。1H NMR(DMSO-d6,600MHz)δ(ppm):8.00(d,2H,J＝7.7Hz,Ar-H),7.88(t,1H,J＝7.9Hz,Ar-H),7.74(t,2H,J＝8.0Hz,Ar-H),7.20(d,1H,J＝8.2Hz,H-10),7.09(s,1H,H-1),6.75(d,1H,J＝8.0Hz,H-9),6.57(s,1H,H-4),5.89-5.95(m,4H,2×-OCH2O-),5.22(m,1H,H-11),4.36(t,2H,J＝5.7Hz,-CH2-),4.11(br s,1H,H-4b),4.03(t,2H,J＝6.1Hz,-CH2-),3.59(d,1H,J＝17.5Hz,H-6),3.52(br s,1H,H-10b),3.40(m,1H,H-6),2.78(m,1H,H-12),2.68(m,1H,H-12),2.45(s,3H,N-CH3),2.42(m,2H,-CH2-),2.35(m,2H,-CH2-),1.79(m,2H,-CH2-),1.73(m,2H,-CH2-),1.58(m,2H,-CH2-),1.35(m.2H,-CH2-),1.23(m,2H,-CH2-)；13C NMR(DMSO-d6,150MHz)δ(ppm):172.5,171.8,158.9,146.4,146.3,144.8,143.5,137.2,136.2,130.0,130.0,129.0,128.3,128.3,127.0,126.4,121.2,116.3,110.4,108.2,107.4,106.4,100.9,100.8,71.7,71.4,63.8,60.6,52.0,45.5,41.0,33.0,30.8,29.0,28.0,27.7,24.9,24.7,19.9；HR(ESI)MS m/z calcd for C39H42N3O13S[M+H]+792.2394,found 792.2469。
实施例9
Figure BDA0002263650200000081
参照实施例6的合成方法制备得化合物5i，淡黄色固体，产率33％。1H NMR(DMSO-d6,600MHz)δ(ppm):8.01(d,2H,J＝7.9Hz,Ar-H),7.87(t,1H,J＝7.6Hz,Ar-H),7.72(t,2H,J＝7.5Hz,Ar-H),7.20(d,1H,J＝8.2Hz,H-10),7.09(s,1H,H-1),6.74(d,1H,J＝8.2Hz,H-9),6.55(s,1H,H-4),5.88-5.94(m,4H,2×-OCH2O-),5.21(m,1H,H-11),4.51(m,2H,-CH2-),4.18(m,2H,-CH2-),4.10(d,1H,J＝3.1Hz,H-4b),3.81(m,2H,-CH2-),3.70(m,2H,-CH2-),3.59(d,1H,J＝16.9Hz,H-6),3.52(m,1H,H-10b),3.40(d,1H,J＝17.1Hz,H-6),2.76(m,1H,H-12),2.67(m,1H,H-12),2.44(s,3H,N-CH3),2.41(m,2H,-CH2-),2.34(t,2H,J＝7.1Hz,-CH2-),1.78(m,2H,-CH2-)；13C NMR(DMSO-d6,150MHz)δ(ppm):172.4,171.8,158.9,146.4,146.3,144.8,143.5,137.2,136.1,130.0,130.0,129.0,128.3,128.3,127.0,126.3,121.2,116.3,110.5,108.1,107.4,106.4,100.9,100.8,71.7,70.8,68.4,67.7,63.1,60.6,54.9,45.0,41.0,32.3,30.8,29.6,19.8；HR(ESI)MS m/z calcd for C37H38N3O14S[M+H]+780.2030,found 780.2059。
实施例10
Figure BDA0002263650200000082
参照实施例6的合成方法制备得化合物5j，淡黄色固体，产率44％。1H NMR(DMSO-d6,600MHz)δ(ppm):8.01(d,2H,J＝7.8Hz,Ar-H),7.89(t,1H,J＝7.4Hz,Ar-H),7.74(t,2H,J＝7.6Hz,Ar-H),7.21(d,1H,J＝8.3Hz,H-10),7.10(s,1H,H-1),6.75(d,1H,J＝8.3Hz,H-9),6.57(s,1H,H-4),5.88-5.95(m,4H,2×-OCH2O-),5.24(s,2H,-CH2-),5.22(m,1H,H-11),4.84(s,2H,-CH2-),4.11(d,1H,J＝3.8Hz,H-4b),3.60(d,1H,J＝17.0Hz,H-6),3.53(m,1H,H-10b),3.40(d,1H,J＝17.0Hz,H-6),2.79(dd,1H,J＝15.3,4.7Hz,H-12),2.69(m,1H,H-12),2.45(s,3H,N-CH3),2.41(m,4H,2×-CH2-),1.80(m,2H,-CH2-)；13C NMR(DMSO-d6,150MHz)δ(ppm):171.82,171.79,158.0,146.43,146.35,144.8,143.5,136.9,136.2,130.0,130.0,129.0,128.4,128.4,127.0,126.4,121.2,116.3,110.7,108.2,107.4,106.4,100.9,100.8,84.1,79.3,71.7,68.5,60.6,59.0,54.9,45.0,41.0,32.4,30.8,29.6,19.7；HR(ESI)MS m/z calcd for C37H34N3O13S[M+H]+760.1786,found 760.1772。
下面是本发明部分化合物的药理实验结果：
实验设备与试剂
仪器超净工作台(苏净集团安泰公司)
恒温培养箱(Thermo electron Corporation)
酶标仪(BIO-RAD公司)
倒置生物显微镜(重庆光学仪器厂)
试剂细胞培养基RPMI-1640、DMEM(高糖)(GIBCO公司)
胎牛血清(杭州四季清有限公司)
CCK-8(Biosharp公司产品)
台盼蓝(Solarbio公司产品)
DMSO(Sigma公司)
细胞株人肝癌细胞株HepG2和Bel-7402、人乳腺癌细胞MCF-7、人结肠癌细胞HCT116、人慢性髓系白血病细胞K562、人正常肝细胞L-02、外周血单个核细胞PMBC
实验方法
细胞抑制活性实验方法
细胞在37℃、5％CO2饱和湿度的培养箱中常规培养。培养液为含10％热灭活胎牛血清，青霉素100U/mL和链霉素100U/mL的RPMI1640细胞培养基。48h更换培养液，细胞贴壁后，用0.25％胰蛋白酶消化传代。实验用细胞均处于对数生长期，台盼蓝拒染法表明细胞活力>95％。
取处于对数生长期状态良好的细胞一瓶，加入消化液(0.125％胰蛋白酶+0.01％EDTA)消化，计数2～4×104cell/mL，制成细胞悬液接种于96孔板上，100μL/孔，置恒温CO2培养箱中培养24小时。换液，加入受试药物，100μL/孔，培养72小时。将CCK-8加入96孔板中，50μL/孔，培养箱中孵育4小时。吸去上清液，加DMSO，200μL/孔，平板摇床上震荡10分钟。受试物考察0.001至100μM以十倍浓度递增的6个浓度，用酶联免疫监测仪在波长为450nm处测定每孔的吸光度，分别计算各浓度下的细胞抑制率。
抑制率计算方法：
Figure BDA0002263650200000091
Figure BDA0002263650200000101
药敏孔相对OD值＝药敏孔绝对OD值﹣空白对照孔绝对OD值
实验结果
表1实施例对5种人类癌细胞株和2种人类正常细胞抗增殖活性的IC50值(μM)
Figure BDA0002263650200000102
药理试验证明，本发明的目标衍生物具有更好的抗肿瘤细胞增殖活性，并且对肿瘤细胞和正常细胞具有一定的选择性，可以用于进一步制备抗肿瘤药物。

Claims (7)

1.通式所示的白屈菜碱一氧化氮供体衍生物及其药学上可接受的盐：
Figure 927532DEST_PATH_IMAGE001
其中，n1、n2、n3为1-3的整数，X为-CH2-、-O-或-C≡C-。
2.如下所述的白屈菜碱一氧化氮供体衍生物及其药学上可接受的盐，选自：
Figure 703727DEST_PATH_IMAGE003
。
3.一种药物组合物，含有治疗有效量的权利要求1或2所述的衍生物及其药学上可接受的盐和药学上可接受的载体。
4.如权利要求1所述的通式所示的白屈菜碱一氧化氮供体衍生物及其药学上可接受的盐的制备方法，其特征在于：
呋咱类NO供体2在四氢呋喃中与二醇、NaOH溶液反应，得呋咱类NO供体衍生物3，再将其溶于二氯甲烷中，依次加入三乙胺、DMAP和酸酐，室温反应得到呋咱类供体衍生物4；
将NO供体衍生物4，溶于二氯甲烷中，依次加入EDCI、白屈菜碱1、DMAP，室温反应得到白屈菜碱呋咱类NO供体衍生物5；
Figure 217885DEST_PATH_IMAGE005
其中，n1、n2、n3、X如权利要求1所述。
5.权利要求1所述的通式所示的白屈菜碱一氧化氮供体衍生物及其药学上可接受的盐在制备治疗肿瘤疾病的药物中的应用。
6.权利要求3所述的药物组合物在制备治疗肿瘤疾病的药物中的应用。
7.如权利要求5或6所述的应用，其特征在于，所述的肿瘤为白血病、肝癌、乳腺癌、结肠癌。
CN201911079950.7A 2019-11-07 2019-11-07 一类白屈菜碱一氧化氮供体衍生物及其制备方法和用途 Active CN110981882B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201911079950.7A CN110981882B (zh) 2019-11-07 2019-11-07 一类白屈菜碱一氧化氮供体衍生物及其制备方法和用途

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201911079950.7A CN110981882B (zh) 2019-11-07 2019-11-07 一类白屈菜碱一氧化氮供体衍生物及其制备方法和用途

Publications (2)

Publication Number Publication Date
CN110981882A CN110981882A (zh) 2020-04-10
CN110981882B true CN110981882B (zh) 2021-06-01

Family

ID=70083295

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201911079950.7A Active CN110981882B (zh) 2019-11-07 2019-11-07 一类白屈菜碱一氧化氮供体衍生物及其制备方法和用途

Country Status (1)

Country Link
CN (1) CN110981882B (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114957243B (zh) * 2021-02-25 2024-02-02 沈阳药科大学 一类β-卡波林NO供体衍生物及应用
CN113549085B (zh) * 2021-07-16 2022-11-22 湖北科技学院 一种天然产物6-hhc的合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101775059A (zh) * 2010-02-04 2010-07-14 中国药科大学 新的甘草次酸衍生物、其制备方法及其医药用途
CN102000072A (zh) * 2009-09-01 2011-04-06 奇复康药物研发(苏州)有限公司 偶联有一氧化氮供体的抗肿瘤天然药物及其医药用途
WO2014149494A1 (en) * 2013-03-15 2014-09-25 Lixte Biotechnology, Inc. Sanguinarine analog pp2c inhibitors for cancer treatment

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102000072A (zh) * 2009-09-01 2011-04-06 奇复康药物研发(苏州)有限公司 偶联有一氧化氮供体的抗肿瘤天然药物及其医药用途
CN101775059A (zh) * 2010-02-04 2010-07-14 中国药科大学 新的甘草次酸衍生物、其制备方法及其医药用途
WO2014149494A1 (en) * 2013-03-15 2014-09-25 Lixte Biotechnology, Inc. Sanguinarine analog pp2c inhibitors for cancer treatment

Also Published As

Publication number Publication date
CN110981882A (zh) 2020-04-10

Similar Documents

Publication Publication Date Title
CN108864024B (zh) 一类灯盏乙素苷元氮芥类衍生物及其制备方法和用途
CN111072682A (zh) 白屈菜碱呋咱类一氧化氮供体衍生物及其制备方法和用途
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
CN110981881B (zh) 白屈菜碱一氧化氮供体衍生物及其制备方法和用途
CN113717138B (zh) 一类氮芥类色原酮衍生物与应用
CN110028477B (zh) 一类布雷菲德菌素a的4-位拼合氮芥衍生物的制备方法和用途
CN108276424B (zh) 一类延命草素型贝壳杉烷二萜拼合氮芥衍生物及其制备方法和用途
RU2686459C1 (ru) Таксановое соединение, а также способ его получения и его применение
CN110964033B (zh) 冬凌草甲素14-位硫化氢供体衍生物及其制备方法和用途
CN110950883A (zh) 1-位氧化冬凌草甲素硫化氢供体衍生物及其用途
CN110981886A (zh) 一类二萜二聚体的硫化氢供体衍生物及其制备方法和用途
RU2686675C1 (ru) Таксановые соединения, а также способ их получения и их применения
CN108658957B (zh) 一种取代色烯醇酯类化合物及其在制备抗癌药物中应用
CN113292629A (zh) 薯蓣皂苷元羟肟酸类衍生物及其制备方法和应用
CN113788809B (zh) 一类色原酮的3位拼合氮芥衍生物与应用
CN112812145B (zh) 一种苯并咪唑衍生物bi293及其制备方法和应用
CN112920241B (zh) 一种苯并咪唑衍生物bi308及其制备方法和应用
CN113563330B (zh) 一类β-卡波林的3位衍生物及其制备方法和用途
CN110964032B (zh) 毛栲利素硫化氢供体衍生物及其制备方法和用途
CN109400595A (zh) 一类含噻吩环的抗癌化合物
CN109810119B (zh) 一类延命草素型二萜衍生物及其制备方法和用途
CN111635396B (zh) 螺内酯型二萜拼合硫化氢供体衍生物及其制备方法和用途
CN109776411B (zh) 氮芥喹诺酮衍生物及其制备方法和应用
CN111635395B (zh) 一类螺内酯型二萜衍生物、制备方法及其抗肿瘤用途
CN109761995B (zh) 延命草素型二萜氨基酸酯衍生物及其制备方法和用途

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