CN108047271A - 一种槲皮素二聚体衍生物及其制备方法和应用 - Google Patents
一种槲皮素二聚体衍生物及其制备方法和应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
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Abstract
本发明公开了一种槲皮素二聚体衍生物或其药学可接受的水合物，包括其立体异构体或互变异构体。其制备步骤包括：槲皮素与溴丙炔在碱作用下制得7‑炔丙氧基槲皮素（II)；溴代醇与叠氮钠反应,制得叠氮醇（III)；（III)与磷酰二氯化合物作用制得（IV)；（II)和（IV)在CuSO4.5H2O/抗坏血酸钠作用下制得式（I)。本发明的槲皮素二聚体衍生物具有抗癌、抗氧化、消炎和抗突变作用。
Description
技术领域
本发明涉及槲皮素二聚体衍生物，及其在制药中的应用，属于医药技术领域。
背景技术
槲皮素，又名栎精，槲皮黄素，溶于冰醋酸，碱性水溶液呈黄色，几乎不溶于水，可作为药品，具有较好的祛痰、止咳作用和平喘作用。用于治疗慢性支气管炎。此外还有降低血压、增强毛细血管抵抗力、减少毛细血管脆性、降血脂、扩张冠状动脉，增加冠脉血流量等作用。对冠心病及高血压患者有辅助治疗作用。槲皮素能显著抑制促癌剂的作用、抑制离体恶性细胞的生长、抑制艾氏腹水癌细胞DNA、RNA和蛋白质合成。槲皮素有抑制血小板聚集和5-羟色胺(5-HT)的释放作用。槲皮素对ADP、凝血酶和血小板活化因子(PAF)诱导的血小板聚集均有明显抑制作用，其中对PAF的抑制作用最强，槲皮素也能明显抑制凝血酶诱导的兔血小板3H-5-HT释放。槲皮素不溶于水，限制了临床应用。以槲皮素为先导物，对其结构进行修饰、改造，以增强其药理作用，获得结构新颖的新药。
发明内容
本发明的目的在于提供一种槲皮素二聚体衍生物，其具有抗癌作用。
本发明的另一目的在于提供上述槲皮素二聚体衍生物的制备方法。
本发明的再一目的在于提供上述槲皮素二聚体衍生物的用途。
以下对本发明进行详细描述。
本发明提供的槲皮素二聚体衍生物或其药学可接受的水合物，包括其立体异构体或互变异构体，结构如下所示：
式中，R1，R2各自独立选取H，烷基，芳基，取代芳基，卤取代烷基，羟基取代的烷基，羧基取代的烷基，酯基取代的烷基；n各自独立选取1-8的整数。
所述化合物的典型实例结构包括：
所述化合物的制备方法包括以下步骤：
式中，R1，R2各自独立选取H，烷基，芳基，取代芳基，卤取代烷基，羟基取代的烷基，羧基取代的烷基，酯基取代的烷基；n各自独立选取1-8的整数。
所述的槲皮素二聚体衍生物或其药学可接受的水合物，包括其立体异构体或互变异构体，具有抗肿瘤作用。
通过以下实施例进一步举例说明本发明，但应注意本发明的范围并不受这些实施例的任何限制。
具体实施方式
实施例1
化合物（1）的制备
将3.0 g(10 mmol)槲皮素和1.68g(10 mmol)K2CO3加入盛有20mL无水DMF的反应器中，剧烈搅拌下缓慢加入1.18 g(10 mmol)溴丙炔，50-60℃反应5h。反应完毕，减压蒸除溶剂，剩余物加入20 mL水，过滤，滤饼用水洗涤，干燥，柱层析纯化，得7-炔丙氧基槲皮素（II），产率67%。
将1.25 g(10 mmol)2-溴乙醇和0.78g(12mmol) 的NaN3加入10mLDMSO中，加热至50-60℃，反应6h，加入50mLH2O，用10mLx3乙醚萃取，有机层用饱和食盐水洗涤3次，浓缩，得到化合物（III)，直接应用于下步反应。
将上述化合物（III)加入8mLCH2Cl2中，加入1.2mLEt3N, 0℃下加入1.3 g(5 mmol)的氮芥磷酰二氯的2mLCH2Cl2溶液，室温反应48h，加入15mLH2O，分层，干燥，浓缩，柱层析纯化（石油醚：乙酸乙酯=6:1），得到化合物（IV)，收率82%。
将6.8g (20 mmol)化合物（II)和3.6g(10 mmol)化合物（IV）加入60 mL体积比为1：1的叔丁醇和水的混合溶剂，搅拌下依次加入39.6mg(0.2 mmol)抗坏血酸钠和25mg(0.1mmol)CuSO4·5H2O，50℃剧烈搅拌下反应5h。将反应体系降至室温，加入50mL的CH2Cl2和10mL2mol/L的HCl，分层，有机相用水洗涤2次，干燥，抽滤，减压浓缩得粗品。柱层析纯化，得化合物（1），收率为83%。1HNMR(DMSO-d6,400MHz)δ:12.47 (s, 2H), 9.56 (s, 2H), 9.33(s, 2H), 9.27 (s, 2H), 7.65 (s, 2H),7.52 (d,J=8.6Hz, 2H), 6.87 (d,J=8.5Hz,2H), 6.38 (s, 2H),6.17 (s, 2H),4.77(d,J = 2.0 Hz, 4H), 4.16 (m, 4H), 3.57 (t,J=5.0Hz, 4H), 3.53 (d,J=5.15Hz, 4H),2.71(m, 4H), 2.61(s, 2H)。
实施例2
用0.98 g(5 mmol)的氯乙胺基磷酰二氯代替1.3 g(5 mmol)的氮芥磷酰二氯，其它操作同实施例1，制得化合物（2），收率81%。1HNMR(DMSO-d6,400MHz)δ:12.47 (s, 2H), 9.56(s, 2H), 9.33 (s, 2H), 9.27 (s, 2H), 7.65 (s, 2H),7.52 (d,J=8.6Hz, 2H), 6.87(d,J=8.5Hz, 2H), 6.38 (s, 2H),6.17 (s, 2H),4.77(d,J = 2.0 Hz, 4H), 4.16 (m,4H), 3.58 (t,J=5.0Hz, 2H), 3.54 (d,J=5.1Hz, 2H),2.71(m, 4H), 2.61(s, 2H)。
实施例3
用1.02 g(5 mmol)的丙氨酸磷酰二氯代替1.3 g(5 mmol)的氮芥磷酰二氯，其它操作同实施例1，制得化合物（3），收率79%。1HNMR(DMSO-d6,400MHz)δ:12.47 (s, 2H), 9.56(s, 2H), 9.33 (s, 2H), 9.27 (s, 2H), 7.65 (s, 2H),7.52 (d,J=8.6Hz, 2H), 6.87(d,J=8.5Hz, 2H), 6.38 (s, 2H),6.17 (s, 2H),4.77(d,J = 2.0 Hz, 4H), 4.17 (m,4H), 3.85 (m, 1H),2.71(m, 4H), 2.61(s, 2H), 0.98 (m, 3H)。
实施例4
用1.41 g(5 mmol)的苯丙氨酸甲酯磷酰二氯代替1.3 g(5 mmol)的氮芥磷酰二氯，其它操作同实施例1，制得化合物（4），收率84%。1HNMR(DMSO-d6,400MHz)δ:12.47 (s, 2H),9.56 (s, 2H), 9.33 (s, 2H), 9.27 (s, 2H), 7.65 (s, 2H),7.52 (d,J=8.6Hz, 2H),7.12 (m, 5H), 6.87 (d,J=8.5Hz, 2H), 6.38 (s, 2H),6.17 (s, 2H),4.77(d,J = 2.0Hz, 4H), 4.16 (m, 4H), 3.84 (m, 1H), 3.67 (s, 3H), 3.29(m, 1H), 3.04 (m, 1H),2.71(m, 4H), 2.61(s, 2H)。
实施例5
用0.95 g(5 mmol)的乙醇胺磷酰二氯代替1.3 g(5 mmol)的氮芥磷酰二氯，其它操作同实施例1，制得化合物（5），收率78%。1HNMR(DMSO-d6,400MHz)δ:12.47 (s, 2H), 9.56(s, 2H), 9.33 (s, 2H), 9.27 (s, 2H), 7.65 (s, 2H),7.52 (d,J=8.6Hz, 2H), 6.87(d,J=8.5Hz, 2H), 6.38 (s, 2H),6.17 (s, 2H),4.77(d,J = 2.0 Hz, 4H), 4.17 (m,4H), 3.51(t, 2H), 2.71(m, 4H), 2.63 (t, 2H), 2.61(s, 2H)。
实施例6
用1.39 g(10 mmol)3-溴丙醇代替1.25 g(10 mmol)2-溴乙醇，用0.89 g(5 mmol)的二乙胺磷酰二氯代替1.3 g(5 mmol)的氮芥磷酰二氯，其它操作同实施例1，制得化合物（6），收率77%。1HNMR(DMSO-d6,400MHz)δ:12.47 (s, 2H), 9.56 (s, 2H), 9.33 (s, 2H),9.27 (s, 2H), 7.65 (s, 2H),7.52 (d,J=8.6Hz, 2H), 6.87 (d,J=8.5Hz, 2H), 6.38(s, 2H),6.17 (s, 2H),4.77(d,J = 2.0 Hz, 4H), 4.17 (m, 4H), 2.72(m, 4H), 2.62(t, 4H),2.61(s, 2H), 1.63 (m, 2H), 0.98 (m, 6H)。
实施例7
对腹水型S180肿瘤的抑制
将接种7天，生长良好的荷S180肿瘤细胞小鼠脱椎处死，于干净工作台腹部碘酒消毒，酒精脱碘后抽取腹水瘤，用生理盐水以l：4(腹水：生理盐水)的比例稀释为细胞悬液（细胞密度2×109/L）。每只小鼠右腋窝碘酒消毒后皮下接种该肿瘤细胞液0.2ml。于接种次日将小鼠随机分为阴性对照组、5-氟尿嘧啶组、槲皮素阳性对照组和槲皮素二聚体衍生物组。各组均连续灌胃给药10天。于末次给药后次日将小鼠脱椎处死，剥取瘤组织，称瘤重及体重(除瘤后)。将实验结果进行统计学处理，计算抑瘤率（表1）。结果显示，与阳性对照组相比，槲皮素二聚体衍生物对荷腹水型S180肿瘤小鼠有显著的抑制作用。
抑癌率(％)=(对照组平均瘤重-治疗组平均瘤重)/对照组平均瘤重×100％
Claims (4)
1.一种槲皮素二聚体衍生物或其药学可接受的水合物，包括其立体异构体或互变异构体，如下式所示：
tu1
式中，R1，R2各自独立选取H，烷基，芳基，取代芳基，卤取代烷基，羟基取代的烷基，羧基取代的烷基，酯基取代的烷基；n各自独立选取1-8的整数。
2.根据权利1所述的槲皮素二聚体衍生物或其药学可接受的水合物，包括其立体异构体或互变异构体，其特征在于，所述化合物的典型实例结构包括：
tu2。
3.根据权利要求1所述的槲皮素二聚体衍生物或其药学可接受的水合物，包括其立体异构体或互变异构体，其制备方法包括以下步骤：
tu3
式中，R1，R2各自独立选取H，烷基，芳基，取代芳基，卤取代烷基，羟基取代的烷基，羧基取代的烷基，酯基取代的烷基；n各自独立选取1-8的整数。
4.根据权利要求1所述的槲皮素二聚体衍生物或其药学可接受的水合物，包括其立体异构体或互变异构体，具有抗肿瘤。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1302295A (zh) * | 1997-10-09 | 2001-07-04 | 马尔斯公司 | 多酚的合成方法 |
| CN101912386A (zh) * | 2010-05-25 | 2010-12-15 | 大理学院 | 槲皮素二聚体黄酮用于制备抗氧化药物的用途 |
| CN102000059A (zh) * | 2010-10-27 | 2011-04-06 | 大理学院 | 一种槲皮素二聚体黄酮用于制备糖苷酶抑制剂的药物用途 |
| EP2468741A1 (en) * | 2010-12-16 | 2012-06-27 | Bel/Novamann International s.r.o. | Novel quercetin derivatives, their preparation, pharmaceutical compositions containing them and their use |
| FR3004341A1 (fr) * | 2013-04-10 | 2014-10-17 | Biochimie Appliquee Soc | Compositions cosmetiques comportant le dimere de quercetine a titre de principe actif |
| CN106674180A (zh) * | 2017-01-05 | 2017-05-17 | 石家庄学院 | 一种槲皮素衍生物及其制备方法和应用 |
| CN106727309A (zh) * | 2016-12-20 | 2017-05-31 | 广州中大南沙科技创新产业园有限公司 | 含有槲皮素的聚合物胶束溶液及其制备方法和应用 |
| CN106854223A (zh) * | 2017-01-05 | 2017-06-16 | 石家庄学院 | 氮芥槲皮素衍生物及其制备方法和用途 |
-
2017
- 2017-12-06 CN CN201711279265.XA patent/CN108047271B/zh active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1302295A (zh) * | 1997-10-09 | 2001-07-04 | 马尔斯公司 | 多酚的合成方法 |
| CN101912386A (zh) * | 2010-05-25 | 2010-12-15 | 大理学院 | 槲皮素二聚体黄酮用于制备抗氧化药物的用途 |
| CN102000059A (zh) * | 2010-10-27 | 2011-04-06 | 大理学院 | 一种槲皮素二聚体黄酮用于制备糖苷酶抑制剂的药物用途 |
| EP2468741A1 (en) * | 2010-12-16 | 2012-06-27 | Bel/Novamann International s.r.o. | Novel quercetin derivatives, their preparation, pharmaceutical compositions containing them and their use |
| FR3004341A1 (fr) * | 2013-04-10 | 2014-10-17 | Biochimie Appliquee Soc | Compositions cosmetiques comportant le dimere de quercetine a titre de principe actif |
| CN106727309A (zh) * | 2016-12-20 | 2017-05-31 | 广州中大南沙科技创新产业园有限公司 | 含有槲皮素的聚合物胶束溶液及其制备方法和应用 |
| CN106674180A (zh) * | 2017-01-05 | 2017-05-17 | 石家庄学院 | 一种槲皮素衍生物及其制备方法和应用 |
| CN106854223A (zh) * | 2017-01-05 | 2017-06-16 | 石家庄学院 | 氮芥槲皮素衍生物及其制备方法和用途 |
Non-Patent Citations (4)
| Title |
|---|
| ANH PHAM. ET AL: ""Rapid dimerization of quercetin through an oxidative mechanism in the presence of serum albumin decreases its ability to induce cytotoxicity in MDA-MB-231 cells"", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》 * |
| ISABELLE F. ET AL: ""Dimerization of quercetin, Diels-Alder vs. radical-coupling approach: a joint thermodynamics, kinetics, and topological study"", 《J MOL MODEL》 * |
| 翟广玉等: ""槲皮素及其衍生物的抗肿瘤活性研究进展"", 《化学试剂》 * |
| 贾景景等: ""槲皮素衍生物的合成及其抗肿瘤活性研究"", 《中国药学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109776575A (zh) * | 2019-03-12 | 2019-05-21 | 石家庄学院 | 川芎嗪一叶萩碱二聚体及其制备方法与应用 |
| CN109776575B (zh) * | 2019-03-12 | 2021-07-09 | 石家庄学院 | 川芎嗪一叶萩碱二聚体及其制备方法与应用 |
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