CN117466816A - 一类青藤碱硫化氢供体衍生物及其制备方法和应用 - Google Patents
一类青藤碱硫化氢供体衍生物及其制备方法和应用 Download PDFInfo
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- CN117466816A CN117466816A CN202311420542.XA CN202311420542A CN117466816A CN 117466816 A CN117466816 A CN 117466816A CN 202311420542 A CN202311420542 A CN 202311420542A CN 117466816 A CN117466816 A CN 117466816A
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- Prior art keywords
- sinomenine
- hydrogen sulfide
- sulfide donor
- derivative
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- INYYVPJSBIVGPH-QHRIQVFBSA-N Sinomenine Chemical compound C([C@@H]1N(CC2)C)C3=CC=C(OC)C(O)=C3[C@@]32[C@@H]1C=C(OC)C(=O)C3 INYYVPJSBIVGPH-QHRIQVFBSA-N 0.000 title claims abstract description 49
- INYYVPJSBIVGPH-UHFFFAOYSA-N 14-episinomenine Natural products C1CN(C)C2CC3=CC=C(OC)C(O)=C3C31C2C=C(OC)C(=O)C3 INYYVPJSBIVGPH-UHFFFAOYSA-N 0.000 title claims abstract description 34
- RARWEROUOQPTCJ-RBUKOAKNSA-N cepharamine Natural products C1CC2=CC=C(OC)C(O)=C2[C@@]2(CCN3C)[C@]13C=C(OC)C(=O)C2 RARWEROUOQPTCJ-RBUKOAKNSA-N 0.000 title claims abstract description 34
- 229930002966 sinomenine Natural products 0.000 title claims abstract description 34
- 229910000037 hydrogen sulfide Inorganic materials 0.000 title claims abstract description 22
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 63
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 20
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 10
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 10
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- 125000003118 aryl group Chemical group 0.000 claims description 8
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- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000000460 chlorine Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- FVWDBVACVTXVJN-UHFFFAOYSA-L dipotassium;propan-2-one;carbonate Chemical compound [K+].[K+].CC(C)=O.[O-]C([O-])=O FVWDBVACVTXVJN-UHFFFAOYSA-L 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
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- 238000002474 experimental method Methods 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
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- 238000012512 characterization method Methods 0.000 description 10
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- PSWDQTMAUUQILQ-UHFFFAOYSA-N 2-[(6-methoxy-4-methylquinazolin-2-yl)amino]-5,6-dimethyl-1h-pyrimidin-4-one Chemical compound N1=C(C)C2=CC(OC)=CC=C2N=C1NC1=NC(=O)C(C)=C(C)N1 PSWDQTMAUUQILQ-UHFFFAOYSA-N 0.000 description 3
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- FCMCSZXRVWDVAW-UHFFFAOYSA-N 6-bromo-1-hexanol Chemical compound OCCCCCCBr FCMCSZXRVWDVAW-UHFFFAOYSA-N 0.000 description 3
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- WHQUHTXULUACFD-KRWDZBQOSA-N (3s)-4-[[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]methoxy-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1COP(O)(=O)C[C@@H](O)CC(O)=O WHQUHTXULUACFD-KRWDZBQOSA-N 0.000 description 2
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- BOOYHBPHFVNWNH-OAHLLOKOSA-N 1-tert-butyl-6-[[(1R)-1-(4-chlorophenyl)ethyl]amino]-5-[(4-fluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C[C@H](C1=CC=C(C=C1)Cl)NC2=NC3=C(C=NN3C(C)(C)C)C(=O)N2CC4=CC=C(C=C4)F BOOYHBPHFVNWNH-OAHLLOKOSA-N 0.000 description 1
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- KGPGFQWBCSZGEL-ZDUSSCGKSA-N GSK690693 Chemical compound C=12N(CC)C(C=3C(=NON=3)N)=NC2=C(C#CC(C)(C)O)N=CC=1OC[C@H]1CCCNC1 KGPGFQWBCSZGEL-ZDUSSCGKSA-N 0.000 description 1
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/28—Morphinans
-
- 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
-
- Y—GENERAL 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及天然药物及药物化学技术领域，涉及一类青藤碱硫化氢供体衍生物及其制备方法和应用。本发明以青藤碱为先导化合物，设计并合成了一系列青藤碱硫化氢供体衍生物，并测试了合成青藤碱衍生物在抗肿瘤方面的生物活性，药理试验证明本发明制备的目标衍生物具有抗肿瘤细胞增殖作用且对正常细胞具有良好的选择性，可以用于进一步制备抗肿瘤药物。
Description
技术领域
本发明涉及天然药物及药物化学技术领域，涉及一类青藤碱衍生物及其制备方法和应用，具体涉及一系列具有抗肿瘤活性的青藤碱衍生物、制备方法及其在抗肿瘤方面的用途。
背景技术
青藤碱作为中药清风藤的主要成分，其结构为吗啡烷型异喹啉类生物碱，在体外和体内具有各种重要生物学作用，包括镇痛、抗血管生成、抗惊厥、抗炎、免疫抑制和抗癌活性。青藤碱的抗癌潜力被不断发掘，对多种不同癌症表现抑制作用，如肺癌、肝癌、乳腺癌、骨肉瘤、结直肠癌和胃癌。青藤碱可以通过诱导细胞凋亡抑制多种肿瘤细胞株的生长，这使其成为药物开发的热点先导化合物之一。青藤碱衍生物应用于抗肿瘤药物的相关研究较少，对青藤碱的结构修饰、衍生物合成的研究越来越受到重视，以期得到更多具有抗肿瘤细胞增殖活性的衍生物应用于临床药物。
发明内容
为解决背景技术中的技术问题，本发明的目的在于提供一系列具有抗肿瘤活性的青藤碱衍生物、制备方法及其在抗肿瘤方面的用途。
为解决上述技术问题，本发明提供如下技术方案：
一类青藤碱硫化氢供体衍生物，其结构通式如式3、4所示：
其中，R为卤素、甲基、甲氧基或氢原子，含有4-12个碳原子的芳香环或卤代芳香环、芳杂环或卤代芳杂环，所述的芳杂环中包含1-3个N、O、或S的杂原子；n为1-10的整数。
基于上述技术方案，进一步地，R为卤素或氢原子，芳香环或卤代芳香环；n为1-10的整数。
基于上述技术方案，进一步地，R为溴、氯或氢原子；n为2-6的整数。
基于上述技术方案，进一步地，所述的青藤碱衍生物的结构式如下所示：
基于上述技术方案，进一步地，本发明的青藤碱衍生物可用下列方法制备得到：
a：NXS,X＝Cl,Br,二氯甲烷室温；
b：溴醇类试剂,EDCI，DMAP，二氯甲烷室温；
c：K2CO3，丙酮回流；
d：2a-e或2，EDCI，DMAP，二氯甲烷室温。
将青藤碱1溶于氯仿，与NCS室温反应得到化合物1a。然后用同样的方法加入NBS合成得到1b。将硫化氢供体2溶于二氯甲烷，加入EDCI、DMAP和对应溴代烷醇得到2a-e；2a-e加入到无水丙酮中，加入无水碳酸钾和青藤碱1或衍生物1a-b回流得到衍生物3a-o。将硫化氢供体2溶于二氯甲烷，在EDCI/DMAP条件下加入青藤碱1或衍生物1a-b得到目标化合物4a-4c。
其中：
本发明另一方面提供一种药物组合物，其包含前述青藤碱硫化氢供体衍生物中的一种或两种以上。
基于上述技术方案，进一步地，所述药物组合物含有治疗有销量的所述的青藤碱硫化氢供体衍生物和药学上可接受的载体。
本发明还提供前述青藤碱硫化氢供体衍生物、药物组合物在制备治疗肿瘤疾病的药物中的应用。
基于上述技术方案，进一步地，所述的肿瘤包括乳腺癌肿瘤、肺癌肿瘤、白血病或肝癌肿瘤。
本发明相对于现有技术具有的有益效果如下：
本发明以青藤碱为先导化合物，设计并合成了一系列青藤碱硫化氢供体衍生物，并测试了该合成衍生物在抗肿瘤方面的生物活性，药理试验证明，本发明制备的目标衍生物具有抗人乳腺癌细胞、人肺癌细胞、人慢性髓原白血病细胞、人宫颈癌细胞和人肝癌细胞增殖活性且对正常细胞具有良好的选择性，可以用于进一步制备抗肿瘤药物。
具体实施方式
下述非限定性实施例可以使本领域的普通技术人员更全面地理解本发明，但不以任何方式限制本发明。
实施例1
青藤碱衍生物3a的制备方法，主要包括以下步骤：
(1)将硫化氢供体2(100mg，0.485mmol)加入到无水二氯甲烷中，随后依次加入EDCI(302mg，1.576mmol)，DMAP(44mg，0.364mmol)，搅拌15分钟后滴加2-溴乙醇(60.6mg，0.485mmol)，室温反应8h，TLC监测，反应完全，将反应液浓缩，加水用二氯甲烷萃取3次，饱和食盐水洗2次，无水硫酸钠干燥，过滤，浓缩，粗产物经过硅胶柱色谱分离(石油醚：乙酸乙酯＝10：1)，得2a 80mg；
(2)将2a(0.161mmol)加入到无水丙酮中，随后加入无水碳酸钾，和青藤碱1(55mg，0.161mmol)，加热回流反应6h，TLC监测，反应完全，将反应液冷却到室温，浓缩，加入二氯甲烷，用水洗3次，无水硫酸钠干燥，过滤，浓缩，粗产物经过硅胶柱色谱分离得衍生物3a，淡黄色粉末，产率34％。
化合物3a表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.34–7.26(m,8H,Ar-H),7.26–7.18(m,2H,Ar-H),6.80(d,J＝2.6Hz,2H,Ar-H),5.44(d,J＝2.2Hz,1H,CH),4.47(t,J＝4.8Hz,2H,CH2),4.43–4.31(m,2H,CH2),4.18(d,J＝15.8Hz,1H,CH),3.93(s,1H,CH),3.84(s,1H,CH),3.79(s,3H,CH3),3.52(s,3H,CH3),3.32–3.25(m,1H,CH),3.18(d,J＝11.0Hz,1H,CH),2.76(s,3H,CH3),2.65(d,J＝15.8Hz,1H,CH),2.62–2.45(m,4H,2CH2),2.37–2.27(m,2H,CH2),2.14–2.08(m,1H,CH),1.78–1.69(m,2H,CH2)；
13C NMR(150MHz,CDCl3)δ:192.01,173.45,153.18,152.31,147.23,138.65,138.53,128.93(×2),128.87(×2),128.50(×2),128.47,127.85,126.96,126.93,125.20,123.37,112.41,110.64,69.72,63.82,58.46,55.79(×2),55.21(×2),48.29,48.11,44.36,42.58,41.30,39.39,36.38,35.12,34.53,34.43,34.08,28.78,26.20,25.00,24.71；
HR-ESIMS m/z calcd for C43H53NO6S2Na[M+Na]+766.3212,found 766.3189.
实施例2
青藤碱衍生物3b的制备方法，实验步骤参照实施例1的合成方法，区别仅在于，步骤(1)中的2-溴乙醇替换为3-溴丙醇，硅胶柱色谱分离获得黄色粉末化合物3b，产率为35％。
化合物3b表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.34–7.27(m,8H,Ar-H),7.30–7.17(m,2H,Ar-H),6.79(d,J＝1.6Hz,2H,Ar-H),5.44(d,J＝2.0Hz,1H,CH),4.36–4.11(m,4H,2CH2),4.06(d,J＝15.8Hz,1H,CH),3.91(q,J＝4.4Hz,1H,CH),3.78(s,3H,CH3),3.68–3.58(m,6H,3CH2),3.51(s,3H,CH3),3.32–3.19(m,1H,CH),2.77(s,3H,CH3),2.65(d,J＝15.9Hz,1H,CH),2.61–2.44(m,4H,2CH2),2.27(dt,J＝26.3,7.6Hz,3H,CH,CH2),2.21–2.12(m,2H,CH2),2.14–2.03(m,1H,CH),1.77–1.68(m,2H),1.59–1.41(m,6H),1.43–1.29(m,2H)；
13C NMR(150MHz,CDCl3)δ:191.90,173.63,153.16,152.44,147.74,138.64,138.52,128.92,128.86(×2),128.51(×2),128.46(×2),126.98,126.94,125.09,123.14,112.31,110.76,68.82,61.27,58.48,55.71,55.20,48.27,44.34,42.46,41.31,39.32,36.39(×2),35.17,35.12,34.48,34.42,34.15,29.67,28.75,26.20,26.14,25.10,24.77；
HR-ESIMS m/z calcd for C44H56NO6S2[M+H]+758.3549,found 758.3558.
实施例3
青藤碱衍生物3c的制备方法，实验步骤参照实施例1的合成方法，区别仅在于，步骤(1)中的2-溴乙醇替换为4-溴-1-丁醇，硅胶柱色谱分离获得黄色粉末化合物3c，产率为52％。
化合物3c表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.34–7.23(m,8H,Ar-H),7.26–7.19(m,2H,Ar-H),6.72(q,J＝8.4Hz,2H,Ar-H),5.46(d,J＝2.3Hz,1H,CH),4.17(m,2H,CH2),4.17–4.05(m,2H,CH2),3.76(s,3H,CH3),3.65(d,J＝12.5Hz,5H,CH,2CH2),3.49(s,3H,CH3),3.25(s,1H,CH),3.10(s,1H,CH),3.00(d,J＝18.2Hz,1H,CH),2.81(dd,J＝18.2,5.1Hz,1H,CH),2.63–2.54(m,2H,CH2),2.47(m,3H,CH3),2.26(t,J＝7.6Hz,2H,CH2),1.96–1.81(m,4H,2CH2)；
13C NMR(150MHz,CDCl3)δ:193.49,173.70,152.64,151.61,147.83,138.65,138.53,129.32,128.91,128.86(×2),128.50(×2),128.46(×2),126.97,126.93,122.71,114.70,111.41,71.34,64.22,56.83,55.67,54.85,49.72,47.25,45.49,44.29,42.47,40.61,36.86,36.39,35.15,34.49(×2),34.43,34.22(×2),28.74,26.86,26.21,25.27,24.81,24.71；
HR-ESIMS m/z calcd for C45H58NO6S2[M+H]+772.3706,found 772.3697.
实施例4
青藤碱衍生物3d的制备方法，实验步骤参照实施例1的合成方法，区别仅在于，步骤(1)中的2-溴乙醇替换为5-溴-1-戊醇，硅胶柱色谱分离获得淡黄色粉末化合物3d，产率为26％。
化合物3d表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.34–7.27(m,8H,Ar-H),7.30–7.18(m,2H,Ar-H),6.71(m,2H,Ar-H),4.16–4.03(m,4H,2CH2),3.76(s,3H,CH3),3.65(m,5H,CH,2CH2),3.49(s,3H,CH3),3.21(t,J＝4.4Hz,1H,CH),3.05(s,1H,CH),3.02–2.96(m,1H,CH),2.78(dd,J＝18.1,5.2Hz,1H,CH),2.56(m,2H,CH2),2.45(s,3H,CH3),2.25(dd,J＝9.0,6.1Hz,2H,CH2),2.02(td,J＝11.7,3.5Hz,1H,CH),1.98–1.82(m,2H,CH2)；
13C NMR(150MHz,CDCl3)δ:193.61,173.71,151.59,147.95,138.65,138.53,129.76,129.61,128.91,128.86(×2),128.50(×2),128.45(×2),126.97,126.93,122.62,114.97,111.40,71.84,64.40,63.97,56.73,55.71,54.83,49.77,47.19,45.72,44.29,42.57,40.68,37.03,36.41,36.38,35.15,34.49,34.42,34.21,32.29,29.93,28.74,28.56,26.20,24.80,22.41；
HR-ESIMS m/z calcd for C46H60NO6S2[M+H]+786.3862,found 786.3868.
实施例5
青藤碱衍生物3e的制备方法，实验步骤参照实施例1的合成方法，区别仅在于，步骤(1)中的2-溴乙醇替换为6-溴-1-己醇，硅胶柱色谱分离获得淡黄色粉末化合物3d，产率为53％。
化合物3e表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.34–7.23(m,8H,Ar-H),7.26–7.19(m,2H,Ar-H),6.75–6.67(m,2H,Ar-H),5.46(d,J＝2.2Hz,1H,CH),4.15(d,J＝16.0Hz,1H,CH),4.12–4.02(m,5H,CH,2CH2),3.76(s,3H,CH3),3.65(m,5H,CH,2CH2),3.49(s,3H,CH3),3.24(s,1H,CH),3.08(s,1H,CH),2.99(d,J＝18.1Hz,1H,CH),2.80(d,J＝17.6Hz,1H,CH),2.62–2.54(m,2H,CH2),2.56–2.46(m,4H,2CH2),2.47(s,3H,CH3),2.24(m,3H,CH,CH2),1.93–1.80(m,2H,CH2),1.78–1.60(m,5H),1.57–1.43(m,9H),1.46–1.24(m,4H)；
13C NMR(150MHz,CDCl3)δ:193.49,173.68,152.65,151.66,148.06,138.66,129.67,128.90(×2),128.85(×2),128.50(×2),128.45(×2),126.96,126.93,122.57,114.74,111.53,77.23,72.07,64.45,56.84,55.74,54.83,49.66,47.26,45.55,44.31,42.48,40.61,36.90,36.41,35.17,34.49,34.45,34.22,34.19,30.20,28.76,28.70,26.20,26.17,25.89,24.80,24.74；
HR-ESIMS m/z calcd for C47H62NO6S2[M+H]+800.4019,found 800.4020.
实施例6
青藤碱衍生物3f的制备方法：
将1g化合物青藤碱1(3.03mmol)用50mL氯仿溶解，在室温条件下加入480mg NCS(10.08mmol)，然后室温搅拌，过夜反应，TLC监测，反应完全，然后依次加入水、2N的NaOH溶液，室温搅拌2h后，抽滤，滤饼用二氯甲烷洗，将滤液浓缩得到化合物1a 800mg。将2(100mg，0.485mmol)加入到无水二氯甲烷中，随后依次加入EDCI(302mg，1.576mmol)，DMAP(44mg，0.364mmol)，搅拌15分钟，再滴加2-溴乙醇(60.6mg，0.485mmol)，室温反应8h，TLC监测，反应完全，将反应液浓缩，加水用二氯甲烷萃取3次，饱和食盐水洗2次，无水硫酸钠干燥，过滤，浓缩，粗产物经过硅胶柱色谱分离(石油醚：乙酸乙酯＝10：1)，得2a80mg；将2a(0.161mmol)加入到无水丙酮中，随后加入无水碳酸钾，和1a(60mg，0.161mmol)，加热回流反应6h，TLC监测，反应完全，将反应液冷却到室温，浓缩，加入二氯甲烷，用水洗3次，无水硫酸钠干燥，过滤，浓缩，粗产物经过硅胶柱色谱分离得衍生物3f，淡黄色粉末，产率26％。
化合物3f表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.34–7.26(m,8H,Ar-H),7.28–7.18(m,2H,Ar-H),6.81(s,1H,Ar-H),5.45(d,J＝2.0Hz,1H,CH),4.46(t,J＝4.9Hz,2H,CH2),4.40–4.34(m,1H,CH2),4.28–4.21(m,1H,CH2),4.14(d,J＝16.0Hz,1H,CH),3.75(s,3H,CH3),3.65(m,5H,CH,2CH2),3.48(s,3H,CH3),3.24(t,J＝4.6Hz,1H,CH),3.05–2.99(m,2H,CH2),2.64–2.53(m,1H,CH),2.55–2.45(m,4H,2CH2),2.42(s,3H,CH3),2.36–2.26(m,2H,CH2)；
13C NMR(150MHz,CDCl3)δ:193.44,173.47,152.60,151.50,146.02,138.65,138.53,131.71,128.91(×2),128.86(×2),128.50(×2),128.46(×2),127.69,127.53,126.97,126.93,114.91,112.37,69.63,63.89,55.89,55.86,54.89(×2),49.70,46.83,45.95,44.32,42.76,41.33,36.78,36.38,35.15,34.52,34.44,34.12,28.74,26.22,24.71,23.23；
HR-ESIMS m/z calcd for C43H53ClNO6S2[M+H]+778.3003,found 778.3010.
实施例7
青藤碱衍生物3g的制备方法，实验步骤参照实施例6的合成方法，区别仅在于，步骤(2)中的2-溴乙醇替换为3-溴丙醇，硅胶柱色谱分离得到淡黄色粉末化合物3g，产率为16％。
化合物3g表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.33–7.18(m,10H,Ar-H),6.80(s,1H,Ar-H),5.45(d,J＝2.1Hz,1H,CH),4.17(t,J＝6.2Hz,2H,CH2),4.09(m,3H,CH,CH2),3.75(s,3H,CH3),3.65(m,4H,2CH2),3.49(s,3H,CH3),3.25(t,J＝4.6Hz,1H,CH),3.01(s,1H,CH),2.61–2.49(m,4H,2CH2),2.49(q,J＝4.4,3.8Hz,2H,CH2),2.43(s,3H,CH3),2.26(t,J＝7.6Hz,2H,CH2),2.00–1.79(m,3H,CH,CH2)；
13C NMR(150MHz,CDCl3)δ:193.32,173.68,152.61,151.75,146.62,138.65,138.53,131.62,128.91(×2),128.50(×2),128.45(×2),127.34,126.97(×2),114.92,112.33,71.44,64.13,55.98,55.80,54.89(×2),49.79,46.86,45.75,44.28,42.72,41.16,36.98,36.39,35.15(×2),34.47,34.42(×2),34.20,28.73,26.81,26.20,25.25,24.80,23.25；
HR-ESIMS m/z calcd for C44H55ClNO6S2[M+H]+792.3159,found 792.3160.
实施例8
青藤碱衍生物3h的制备方法，实验步骤参照实施例6的合成方法，区别仅在于，步骤(2)中的2-溴乙醇替换为4-溴-1-丁醇，硅胶柱色谱分离得到淡黄色粉末化合物3h，产率为40％。
化合物3h表征数据如下：
1H NMR(600MHz,CDCl3)δ:7.61–7.55(m,2H,Ar-H),7.01–6.94(m,2H,Ar-H),6.77(s,1H,Ar-H),5.44(d,J＝2.1Hz,1H,CH),4.22(dt,J＝7.5,3.8Hz,1H,CH),4.17–4.09(m,4H,2CH2),3.77(s,3H,CH3),3.66(s,1H,CH),3.58(dt,J＝5.5,2.7Hz,1H,CH),3.51(s,3H,CH3),3.13(d,J＝19.3Hz,1H,CH),3.07–2.98(m,2H,CH2),2.69(s,3H,CH3),2.61(d,J＝15.8Hz,1H,CH),2.33(d,J＝8.1Hz,2H,CH2),2.07–1.96(m,6H,3CH2)；
13C NMR(151MHz,CDCl3)δ:192.52,162.41,152.97,152.19,147.81,134.00,128.41,123.00,119.34,115.25(×2),112.21,112.00,103.74,71.54,68.05,57.88,55.69,55.06,48.77,47.87,46.51,43.39,41.59,39.79,35.25,29.71,26.73,25.62,24.98；
HR-ESIMS m/z calcd for C45H56ClNO6S2Na[M+Na]+828.3135,found828.3129.
实施例9
青藤碱衍生物3i的制备方法，实验步骤参照实施例6的合成方法，区别仅在于，步骤(2)中的2-溴乙醇替换为5-溴-1-戊醇，硅胶柱色谱分离得到淡黄色粉末化合物3i，产率为19％。
化合物3i表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.34–7.26(m,8H,Ar-H),7.29–7.18(m,2H,Ar-H),6.80(s,1H,Ar-H),5.45(d,J＝2.1Hz,1H,CH),4.13–4.02(m,5H,CH,2CH2),3.75(s,3H,CH3),3.65(m,4H,2CH2),3.49(s,3H,CH3),3.06–2.98(m,2H,CH2),2.61–2.44(m,6H,3CH2),2.42(s,3H,CH3),2.25(t,J＝7.6Hz,2H,CH2),1.98–1.82(m,4H,2CH2)；
13C NMR(150MHz,CDCl3)δ:193.36,173.68,152.58,151.75,138.63,128.88(×2),128.84(×2),128.43(×2),127.33,126.91(×2),114.97,112.31,71.94,64.32,55.93,55.80(×2),54.87(×2),49.75,46.84,45.80,44.27(×2),42.73,41.15,37.00,36.37(×2),35.13(×2),34.46,34.40,34.18,29.85,28.71(×2),28.52,26.17,24.78,23.23,22.36；
HR-ESIMS m/z calcd for C46H59ClNO6S2[M+H]+820.3472,found 820.3468.
实施例10
青藤碱衍生物3j的制备方法，实验步骤参照实施例6的合成方法，区别仅在于，步骤(2)中的2-溴乙醇替换为6-溴-1-己醇，硅胶柱色谱分离得到黄色粉末化合物3j，产率为42％。
化合物3j表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.34–7.25(m,8H,Ar-H),7.26–7.18(m,2H,Ar-H),6.80(s,1H,Ar-H),5.45(d,J＝2.1Hz,1H,CH),4.15–4.00(m,5H,CH,2CH2),3.76(s,3H,CH3),3.65(m,4H,2CH2),3.49(s,3H,CH3),3.24(t,J＝4.4Hz,1H,CH),3.06–2.98(m,2H,CH2),2.61–2.44(m,5H,CH,2CH2),2.43(s,3H,CH3),2.24(t,J＝7.6Hz,2H,CH2),1.99–1.77(m,5H,CH,CH2)；
13C NMR(150MHz,CDCl3)δ:193.36,173.70,152.60,151.79,146.81,138.65,138.52,131.65,128.90(×2),128.86(×2),128.50(×2),128.45(×2),127.33,127.21,126.97,126.93,114.96,112.35,72.17,64.43,55.97,55.83,54.88,49.73,46.87,45.80,44.28,42.74,41.15,37.01,36.39,35.15,34.47,34.41,34.21,30.15,28.73,28.67,26.19,25.87,25.58,24.80,23.25；
HR-ESIMS m/z calcd for C47H61ClNO6S2[M+H]+834.3629,found 834.3621.
实施例11
青藤碱衍生物3k的制备方法：
将1g化合物青藤碱1(3.03mmol)用50mL氯仿溶解，在室温条件下加入640mg NBS(10.08mmol)，然后室温搅拌，过夜反应，TLC监测，反应完全，然后依次加入水、2N的NaOH溶液，室温搅拌2h后，抽滤，滤饼用二氯甲烷洗，将滤液浓缩得到化合物1b 800mg。将2(100mg，0.485mmol)加入到无水二氯甲烷中，随后依次加入EDCI(302mg，1.576mmol)，DMAP(44mg，0.364mmol)，搅拌15分钟，再滴加2-溴乙醇(60.6mg，0.485mmol)，室温反应8h，TLC监测，反应完全，将反应液浓缩，加水用二氯甲烷萃取3次，饱和食盐水洗2次，无水硫酸钠干燥，过滤，浓缩，粗产物经过硅胶柱色谱分离(石油醚：乙酸乙酯＝10：1)，得2a80mg；将2a(0.161mmol)加入到无水丙酮中，随后加入无水碳酸钾，和1b(70mg，0.161mmol)，加热回流反应6h，TLC监测，反应完全，将反应液冷却到室温，浓缩，加入二氯甲烷，用水洗3次，无水硫酸钠干燥，过滤，浓缩，粗产物经过硅胶柱色谱分离得衍生物3k，淡黄色粉末，产率26％。
化合物3k表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.34–7.25(m,8H,Ar-H),7.27–7.17(m,2H,Ar-H),6.99(s,1H,Ar-H),5.44(d,J＝2.4Hz,1H,CH),4.46(t,J＝4.9Hz,2H,CH2),4.42–4.34(m,1H,CH2),4.29–4.20(m,1H,CH2),4.14(d,J＝15.9Hz,1H,CH),3.76(s,3H,CH3),3.65(dd,J＝14.4,3.4Hz,6H,3CH3),3.49(s,3H,CH3),3.23(s,1H,CH),3.02–2.95(m,2H,CH3),2.61–2.53(m,1H,CH),2.55–2.44(m,4H,2CH2),2.43(s,3H,CH3),2.37–2.26(m,3H,CH,CH2)；
13C NMR(150MHz,CDCl3)δ:193.40,173.47,152.62,151.60,138.64,138.53,128.91,128.86,128.50,128.46,126.97,126.93,115.55,114.81,69.59,63.88,56.29,55.89,54.91,49.64,46.86,45.95,44.32,42.74,41.48,36.73,35.15,34.52,34.43,29.71,28.74,26.40,24.71；
HR-ESIMS m/z calcd for C43H53BrNO6S2[M+H]+822.2498,found 822.2495.
实施例12
青藤碱衍生物3l的制备方法，实验步骤参照实施例11的合成方法，区别仅在于，步骤(2)中的2-溴乙醇替换为3-溴丙醇，硅胶柱色谱分离得到黄色粉末化合物3l，产率为25％。
化合物3l表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.34–7.22(m,8H,Ar-H),7.25–7.18(m,2H,Ar-H),6.99(s,1H,Ar-H),5.44(t,J＝2.3Hz,1H,CH),4.30(m,2H,CH2),4.22–4.10(m,2H,CH2),4.03(dd,J＝16.0,1.8Hz,1H,CH),3.76(s,3H,CH3),3.65(m,5H),3.49(s,3H,CH3),3.25(s,1H,CH),3.06–2.95(m,2H,CH2),2.60–2.50(m,2H,CH2),2.53(s,2H,CH2),2.52–2.46(m,2H,CH2),2.44(s,3H,CH3),2.29(m,2H,CH2),2.16(m,2H,CH2)；
13C NMR(150MHz,CDCl3)δ:193.26,173.63,152.62,147.07,138.65,138.52,128.90(×2),128.86(×2),128.50(×2),128.46(×2),126.97,126.93,115.52,114.79,68.65,61.43,56.37,55.84,54.91,49.72,46.89,45.73,44.31,42.70,41.33,41.14,36.88,36.39,35.14,34.50,34.42,34.17,34.15,29.72,29.67.28.74,26.41,26.21,24.77,23.26；
HR-ESIMS m/z calcd for C44H55BrNO6S2[M+H]+836.2654,found 836.2659.
实施例13
青藤碱衍生物3m的制备方法，实验步骤参照实施例11的合成方法，区别仅在于，步骤(2)中的2-溴乙醇替换为4-溴-1-丁醇，硅胶柱色谱分离得到白色粉末化合物3m，产率为87％。
化合物3m表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.31(dd,J＝7.1,4.7Hz,2H,Ar-H),7.30–7.18(m,8H,Ar-H),6.98(s,1H,Ar-H),5.45(d,J＝2.2Hz,1H,CH),4.20–4.05(m,5H,CH,2CH2),3.76(s,3H,CH3),3.65(d,J＝13.1Hz,6H,3CH2),3.49(s,3H,CH3),3.24(s,1H,CH),2.99(d,J＝18.7Hz,2H,CH2),2.62–2.47(m,6H,3CH2),2.44(s,3H,CH3),2.26(m,3H,CH,CH2),1.96–1.81(m,3H,CH,CH2)；
13C NMR(150MHz,CDCl3)δ:193.28,173.68,152.62,151.86,147.21,138.65,138.52,128.90(×2),128.86(×2),128.51(×2),128.46(×2),126.97,126.93(×2),115.49,114.84,71.41,64.13,56.37,55.83,54.92,49.72,46.90,45.75,44.29,42.70,41.32,36.94,36.39(×2),35.15,34.48,34.43(×2),34.20,28.74,26.81,26.41,26.20,25.25,24.80；
HR-ESIMS m/z calcd for C45H57BrNO6S2[M+H]+850.2811,found 850.2812.
实施例14
青藤碱衍生物3n的制备方法，实验步骤参照实施例11的合成方法，区别仅在于，步骤(2)中的2-溴乙醇替换为5-溴-1-戊醇，硅胶柱色谱分离得到白色粉末化合物3n，产率为25％。
化合物3n表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.34–7.23(m,8H,Ar-H),7.26–7.18(m,2H,Ar-H),6.99(s,1H,Ar-H),5.44(d,J＝2.2Hz,1H,CH),4.13–4.03(m,5H,CH,2CH2),3.76(s,3H,CH3),3.65(d,J＝13.5Hz,4H,2CH2),3.49(s,3H,CH3),3.28(s,1H,CH),3.01(m,2H,CH2),2.61–2.44(m,5H,CH,2CH2),2.46(s,3H,CH3),2.25(t,J＝7.6Hz,2H,CH2),1.93–1.81(m,2H,CH2)；
13C NMR(150MHz,CDCl3)δ:193.20,173.70,152.67,138.65,138.52,128.90(×2),128.86(×2),128.50(×2),128.46(×2),126.97(×2),126.93,115.59,71.95,64.32,56.49,56.15,55.87,54.92,49.58,46.98,45.49,44.29,42.59,41.20,36.73,36.39(×2),35.15(×2),34.48,34.42,34.20,29.85,29.71,28.74,28.53,26.43,26.19,24.80,23.29,22.37；
HR-ESIMS m/z calcd for C46H59BrNO6S2[M+H]+864.2967,found 864.2965.
实施例15
青藤碱衍生物3o的制备方法，实验步骤参照实施例11的合成方法，区别仅在于，步骤(2)中的2-溴乙醇替换为6-溴-1-己醇，硅胶柱色谱分离得到白色粉末化合物3o，产率为72％。
化合物3o表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.34–7.22(m,8H,Ar-H),7.22(td,J＝8.7,8.3,3.7Hz,2H,Ar-H),6.98(s,1H,Ar-H),5.44(d,J＝2.3Hz,1H,CH),4.15–4.01(m,5H,CH,2CH2),3.76(s,3H,CH3),3.65(d,J＝13.1Hz,4H,2CH2),3.49(s,3H,CH3),3.26(s,2H,CH2),3.01(m,2H,CH2),2.61–2.54(m,2H,CH2),2.51(m,6H,3CH2),2.45(s,3H,CH3),2.24(m,4H,2CH2)；
13C NMR(150MHz,CDCl3)δ:193.27,173.70,152.64,151.95,138.65,138.52,128.90(×2),128.86(×2),128.50(×2),128.46(×2),126.97(×2),126.93(×2),117.69,115.57,72.16,64.42,56.43,55.87,54.91,49.61,46.94,44.28,42.66,41.25,36.86,36.39(×2),35.15(×2),34.47,34.41,34.21,30.14,28.73,28.67,26.42,26.19,25.87,25.58,24.80(×2)；
HR-ESIMS m/z calcd for C47H61BrNO6S2[M+H]+878.3124,found 878.3122.
实施例16
青藤碱衍生物4a的制备方法，主要包括以下步骤
将100mg硫化氢供体2(0.32mmol)用5mL无水二氯甲烷溶解，依次加入185mg EDCI(0.96mmol)和23mg DMAP(0.19mmol)搅拌15min，然后加入55mg青藤碱1(0.32mmol)，室温搅拌22h，TLC监测，反应基本完全，然后加入20mL蒸馏水，二氯甲烷萃取3次，饱和食盐水洗1次，无水硫酸钠干燥，过滤，浓缩，得粗产物，硅胶柱色谱分离(石油醚：乙酸乙酯＝2：1)，得到目标化合物4a，产率为21％。
化合物4a表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.34–7.26(m,8H,Ar-H),7.29–7.19(m,2H,Ar-H),6.90(d,J＝8.4Hz,1H,Ar-H),6.74(d,J＝8.4Hz,1H,Ar-H),5.47(d,J＝2.3Hz,1H,CH),3.84(d,J＝16.0Hz,1H,CH),3.70(s,3H,CH3),3.48(s,3H,CH3),3.08–2.99(m,2H,CH2),2.75(dd,J＝18.2,5.4Hz,1H,CH),2.66–2.55(m,2H,CH2)2.57–2.46(m,4H,2CH2),2.44(s,3H,CH3),2.16–2.08(m,1H,CH)；
13C NMR(100MHz,CDCl3)δ:192.29,171.59,152.50,149.84,138.66,129.94,129.69,128.92(×2),128.87(×2),128.51(×2),128.47(×2),126.98,126.94,125.36,114.84,110.87,56.46,55.96,54.87(×2),50.08,46.69,45.81,44.34,44.31,42.66,40.55,37.09,36.38,35.16,34.51,34.43,34.34,28.76,26.16,24.67,24.25；
HR-ESIMS m/z calcd for C41H50NO5S2[M+H]+700.3130,found 700.3126.
实施例17
青藤碱衍生物4b的制备方法，实验步骤参照实施例16的合成方法，区别仅在于，步骤中的青藤碱1替换为1a，硅胶柱色谱分离得到白色粉末化合物4b，产率为53％。
化合物4b表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.34–7.25(m,8H,Ar-H),7.23(m,2H,Ar-H),6.85(s,1H,Ar-H),5.44(d,J＝2.2Hz,1H,CH),3.82(s,1H,CH),3.69(s,3H,CH3),3.48(s,3H,CH3),3.27(t,J＝4.7Hz,1H,CH),3.07(d,J＝18.9Hz,1H,CH),3.03–2.99(m,1H,CH)2.65–2.56(m,2H,CH2),2.43(s,3H,CH3),2.05(d,J＝13.7Hz,1H,CH),1.88(td,J＝12.7,4.5Hz,1H,CH),1.75(m,2H,CH2)；
13C NMR(150MHz,CDCl3)δ:191.98,171.44,162.52,152.52,150.12,138.57(×2),131.84,130.38,128.89(×2),128.49(×2),127.29,126.97(×2),114.57,112.05,56.09(×2),55.80(×2),54.94(×2),49.97,46.40,45.64,44.28,42.68,40.94,36.65(×2),35.15,34.45,34.26(×2),28.75(×2),26.12,24.61,22.98；
HR-ESIMS m/z calcd for C41H48ClNO5S2Na[M+Na]+756.2560,found756.2539.
实施例18
青藤碱衍生物4c的制备方法，实验步骤参照实施例16的合成方法，区别仅在于，步骤(2)中的青藤碱1替换为1c，硅胶柱色谱分离得到黄色粉末化合物4c，产率为32％。
化合物4c表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.34–7.23(m,8H,Ar-H),7.23(m,2H,Ar-H),7.04(s,1H,Ar-H),5.44(d,J＝2.2Hz,1H,CH),4.12(q,J＝7.1Hz,1H,CH),3.87–3.80(m,2H,CH2),3.70(s,3H,CH3),3.50(d,J＝1.3Hz,1H,CH),3.49(s,3H,CH3),3.28(s,2H,CH2),3.03(m,3H,CH,CH2),2.65–2.56(m,3H,CH,CH2),2.44(s,3H,CH3),2.04(s,2H,CH2),1.75(m,4H,2CH2)；
13C NMR(150MHz,CDCl3)δ:191.95,171.15,152.53,150.25,139.07,138.64,138.51,132.00,128.92,128.87,128.51,128.47,126.98,126.95,121.02,115.24,114.42,60.40,56.19,56.13,55.83,54.96,46.43,44.30,44.27,42.61,41.06,40.88,36.40,35.22,35.15,34.53,34.49,34.44,34.27,28.76,26.16,26.12,24.68,24.61,23.00；
HR-ESIMS m/z calcd for C41H49BrNO5S2[M+H]+778.2236,found 778.2239.
实施例19
本实施例是对实施例1-18制备的化合物的药理活性进行评价。
实验设备与试剂
表1本实施例实验过程使用的仪器、试剂和细胞株
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实验方法
细胞生长抑制活性实验方法
通过CCK-8法检测目标化合物在六种癌细胞(人肺癌细胞系A549，人慢性骨髓性白血病细胞系K562，人乳腺肿瘤细胞系MCF-7，人肝癌细胞系HepG2、Bel-7402和人三阴性乳腺癌细胞系MDA-MB-231)和一种正常细胞系(外周血单个核细胞PMBC)中的抗增殖活性。所有细胞系均来自中国南京KeyGEN Biotech公司，所有细胞培养均采用标准DMEM培养基或RPMI1640培养基。在5％ CO2的湿润环境中于37℃下孵育24h后，将对数生长的细胞种植到96孔板中，在37℃和5％ CO2下孵育24h。然后，将目标化合物或阳性对照(taxol)添加到不同细胞系中，培养48h。给药后小心吸弃培养液，于每个孔中加入含10％ CCK-8的无血清培养基孵育1h，然后在酶标仪上测量每个孔的OD值，波长为450nm，计算目标化合物的IC50值。
实验结果
表2目标化合物对不同细胞系的抗增殖作用
aIC50：通过CCK-8测定法测量的一半抑制浓度，上述数值均为三个独立实验的平均值±标准偏差。
药理试验证明，本发明制备的目标衍生物在抗人乳腺癌细胞、人肺癌细胞、人慢性骨髓性白血病细胞、和人肝癌细胞具有增殖活性，部分目标衍生物具有极好的抗人乳腺癌细胞、人肺癌细胞、人白血病细胞和人肝癌细胞增殖活性且对正常细胞具有良好的选择性，可以用于进一步制备抗肿瘤药物。
最后应说明的是：以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (9)
1.一类青藤碱硫化氢供体衍生物，其特征在于，其结构通式如通式3或4所示：
其中，R为卤素、甲基、甲氧基或氢原子，含有4-12个碳原子的芳香环或卤代芳香环、芳杂环或卤代芳杂环，所述的芳杂环中包含1-3个N、O、或S的杂原子；n为1-10的整数。
2.根据权利要求1所述的青藤碱硫化氢供体衍生物，其特征在于，R为卤素或氢原子，芳香环或卤代芳香环；n为1-10的整数。
3.根据权利要求1或2所述的青藤碱硫化氢供体衍生物，其特征在于，R为溴、氯或氢原子；n为2-6的整数。
4.根据权利要求1所述的青藤碱硫化氢供体衍生物，其特征在于，所述青藤碱硫化氢供体衍生物的结构式如下所示：
5.权利要求4所述的青藤碱硫化氢供体衍生物的制备方法，其特征在于，所述制备方法的制备路线如下所示：
a：NXS,X＝Cl,Br,二氯甲烷室温；
b：溴醇类试剂,EDCI，DMAP，二氯甲烷室温；
c：K2CO3，丙酮回流；
d：2a-e或2，EDCI，DMAP，二氯甲烷室温。
6.一种药物组合物，其特征在于，其包含权利要求1-4任一项所述的青藤碱硫化氢供体衍生物中的一种或两种以上。
7.根据权利要求7所述的药物组合物，其特征在于，所述药物组合物含有治疗有效量的所述的青藤碱硫化氢供体衍生物和药学上可接受的载体。
8.权利要求1-4任一项所述的青藤碱硫化氢供体衍生物、权利要求6-7任一项所述的药物组合物在制备治疗肿瘤疾病的药物中的应用。
9.根据权利要求8所述的应用，其特征在于，所述的肿瘤包括乳腺癌肿瘤、肺癌肿瘤、白血病或肝癌肿瘤。
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