CN105693769A - 迷迭香酸衍生物及制备方法及应用 - Google Patents
迷迭香酸衍生物及制备方法及应用 Download PDFInfo
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- CN105693769A CN105693769A CN201610143489.7A CN201610143489A CN105693769A CN 105693769 A CN105693769 A CN 105693769A CN 201610143489 A CN201610143489 A CN 201610143489A CN 105693769 A CN105693769 A CN 105693769A
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- rosmarinic acid
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5442—Aromatic phosphonium compounds (P-C aromatic linkage)
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了迷迭香酸衍生物及制备方法及应用,迷迭香酸衍生物具有式(I)或式(II)所示结构:
Description
技术领域
本发明涉及一种迷迭香酸衍生物及制备方法及用途,属于医药领域。
背景技术
近年来,由于放射治疗和和核医学的迅猛发展,电离辐射已经越来越多的走进人们的生活,难免会有不少人因为意外接触到电离辐射,从而对身体产生一定的危害,其危害分为直接损伤和间接损伤,间接损伤作为一种主要的损伤,其原理是因为电离辐射产生的大量自由基对人体的大分子蛋白质,脂质和核酸产生损伤,这些大分子生物功能的障碍或者缺失会导致机体功能障碍或者疾病。传统的观点认为电离辐射是因为射线电离细胞内的水并产生自由基,自由基损伤生物大分子造成电离辐射损伤,但是,电离水产生的自由基寿命极其短暂,几分钟后就会消失,电离损伤导致机体内的自由基在一定时间内会呈现增长趋势,并在24h达到高峰。
线粒体作为细胞内的氧化呼吸的场所,也是细胞内唯一可能产生自由基的亚细胞结构,研究表明,电离辐射导致线粒体结构功能障碍,并持续不断的产生自由基对细胞产生损伤。并且在衰老或者是由于外界某些理化因素导致的线粒体功能损伤也会产生同样的自由基,因此保护线粒体不被损伤和清除损伤、衰老的线粒体内的自由基成为线粒体功能障碍疾病的首要任务。
迷迭香酸是从唇形科植物迷迭香中分离得到的一种水溶性的天然酚酸类化合物,分布较为广泛,主要存在于唇形科、紫草科、葫芦科、椴树科、伞形科的多种植物中,尤以唇型科和紫草科植物中含量最高。迷迭香酸是一种天然抗氧化剂,具有较强的抗氧化活性,其抗氧化活性强于维生素E,咖啡酸,绿原酸,叶酸等,有助于防止自由基造成的细胞受损,因此降低了癌症和动脉硬化的风险。迷迭香酸具有较强的抗炎活性,同时迷迭香酸还具有抗菌、抗病毒、抗肿瘤的活性,而具有抑制急慢性感染、抗紫外线、抑制弹性蛋白降解等特性已使迷迭香酸成为化妆品的添加剂。目前,迷迭香酸在制药、食品、化妆品等领域中已体现出其重要的应用价值。由于体内自由基的产生主要是线粒体功能障碍,而且迷迭香酸不能特定的聚集在线粒体内,达到清除自由基的目的。因此我们将其结构加以改造,制备迷迭香酸衍生物,以达到减轻线粒体损伤,提高清除自由基的目的。
发明内容
本发明的目的是克服现有技术的不足,提供一种迷迭香酸衍生物。
本发明的第二个目的是提供一种迷迭香酸衍生物的制备方法。
本发明的第三个目的是提供一种迷迭香酸衍生物的应用。
本发明的技术方案概述如下:
迷迭香酸衍生物,具有式(I)或式(II)所示结构:
其中:R1为钾或钠;R2为钾或钠;R3为钾或钠;R4为钾或钠。
上述一种迷迭香酸衍生物的制备方法,包括如下步骤:
(1)将三苯基膦(Ⅲ)与3-卤丙醇(Ⅳ)反应生成(3-羟丙基)三苯基卤化磷(Ⅴ);
(2)将(3-羟丙基)三苯基卤化磷(Ⅴ)与迷迭香酸(Ⅵ),在1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和1-羟基苯并三唑催化下反应,得到式(I)所示的迷迭香酸衍生物;
(3)将式(I)所示迷迭香酸衍生物与NaOH或KOH反应得到通式(II)所示的迷迭香酸衍生物,反应式如下:
其中:R1为钾或钠;R2为钾或钠;R3为钾或钠;R4为钾或钠。
卤为溴、氯或碘。
上述迷迭香酸衍生物在制备治疗阿尔兹海默病药物的应用。
上述迷迭香酸衍生物在制备治疗帕金森氏病药物的应用。
上述迷迭香酸衍生物在制备辐射防护药物的应用。
本发明的优点:
实验证明,本发明的迷迭香酸衍生物能有效清除电离辐射所产生的活性氧(ROS),因此在自由基导致的相关疾病,诸如阿尔兹海默病和电离损伤疾病治疗方面有用途。本制备方法简单,产品易得,无污染。
附图说明
图1为迷迭香酸衍生物能明显增加照射后细胞的存活率。
图2为迷迭香酸衍生物清除自由基能力明显增加。
图3为迷迭香酸衍生物保护DNA双链能力有所增加。
具体实施方式
测定仪器:核磁共振用VARIANINOVA500MHz型核磁共振仪。质谱用Waters3100四级杆质谱仪。
下面结合具体实施例对本发明作进一步的说明,本发明的实施例是为了使本领域的技术人员能够更好地理解本发明,但并不对本发明作任何限制。
实施例1
一种迷迭香酸衍生物(I)的制备方法,包括如下步骤:
(1)将2.8g(0.02mol)3-溴丙醇(Ⅳ-1)和5.3g(0.02mol)三苯基膦(Ⅲ)混合加入15mlN,N-二甲基甲酰胺(DMF)100℃回流反应过夜,待反应结束后,冷却反应体系会析出大量白色固体,减压过滤,然后用冷的DMF洗涤白色固体,50℃干燥过夜,得到白色粉末状固体(3-羟丙基)三苯基溴化磷(Ⅴ-1);
(2)将0.36g(0.001mol)迷迭香酸(Ⅵ)和0.4g(0.001mol)(3-羟丙基)三苯基溴化磷(Ⅴ-1)混合加入20mlDMF,再混合加入0.23g(0.0012mol)1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)、0.14g(0.0012mol)1-羟基苯并三唑(HOBT)搅拌均匀,氮气保护下室温反应过夜,充分反应后加入饱和的NaHCO3水溶液,析出淡黄色固体,减压过滤,40℃真空干燥过夜,得到式(I)所示的迷迭香酸衍生物粗品,硅胶柱层析分离,展开剂(二氯甲烷:乙酸乙酯:甲酸=8:1:0.2)。
1HNMR(500MHz,DMSO-d6)δ=8.41(s,4H,),δ=7.91–7.70(m,15H),δ=7(d,J=15.8Hz,1H),δ=7.11(s,1H,benzene),δ=6.90(d,J=8.1Hz,1H),δ=6.73(d,J=8.1Hz,1H),δ=6.68(s,1H),δ=6.55(d,J=8.0Hz,1H),δ=6.43(d,J=8.1Hz,1H),δ=6.22(d,J=15.8Hz,1H),δ=5.12(dd,J=6.9,5.7Hz,1H),δ=4.16(t,J=5.5Hz,2H),δ=3.54(dd,J=6.3Hz,2H),δ=3.00–2.90(m,2H),1.81(d,J=7.3Hz,2H).13CNMR(500MHz,DMSO-d6):δ=18.365,22.157,36.783,64.520,73.569,115.913,116.298,116.729,117.733,118.427,119.110,120.582,122.265,125.408,127.048,130.882,131.065,134.171,134.251,135.712,135.735,145.234,146.107,146.920,147.370,150.445,166.875,170.102.MassC39H36O8P+663.5.
实验证明,用等摩尔的3-氯丙醇(Ⅳ-2)或3-碘丙醇(Ⅳ-3)替代本实施例步骤(1)中的3-溴丙醇(Ⅳ-1),其它同本实施例,制备式(I)所示的迷迭香酸衍生物粗品。
迷迭香酸衍生物(I)的化学名为:(E)-(3-(3-(3,4二羟基苯基)-2-(3-(3,4-二羟基苯基)丙烯酰基)氧基)氧)丙基三苯基
实施例2
一种迷迭香酸衍生物(II)的制备方法,包括如下步骤:
(1)-(2)同实施例1的(1)-(2);
(3)将0.74g(0.001mol)式(I)所示迷迭香酸衍生物加入到0.16g(0.004mol)NaOH的水溶液中10ml,充分溶解后,减压除去溶剂,得到淡黄色固体,40℃真空干燥过夜。得到式(II)所示的迷迭香酸衍生物。
反应式如下:
本实施例的R1,R2,R3,R4均为钠。
用0.004mol的KOH替代本实施例的NaOH,其它同本实施例,制备(II)所示的迷迭香酸衍生物,其R1,R2,R3,R4均为钾。
实验例1
中性红法测定细胞存活率
1、细胞培养
CHO-K1细胞(国家实验细胞共享资源平台购得)于体积浓度为5%CO2的37℃培养箱中培养,含双抗的10%胎牛血清的RPMI1640培养液培养至对数期。
2、测定细胞存活率
将培养至对数期的CHO-K1细胞以每孔4000个铺在96孔板内,培养贴壁过夜,照射前30min分别给式(I)所示迷迭香酸衍生物和式(II)所示迷迭香酸衍生物药液(1μmol/L,溶剂为含血清和双抗的RPMI1640培养基)每孔100μL,置于培养箱中培养30min,用3Gyγ射线照射,然后于培养箱中继续培养24小时,移去培养液,然后每孔加入100μL饱和的中性红培养液于培养箱中培养2h,使细胞充分摄取中性红,吸出中性红培养液,用150μL磷酸缓冲液(PBS)洗涤2次,洗去未吸收的残留中性红,甩干PBS,加入150μL中性红溶解液(乙酸:乙醇:水的体积比=1:50:49),震荡3min,用酶标仪在544nm测定吸光度。
实验结果:迷迭香酸衍生物能明显增加照射后细胞的存活率(见图1)。
实验例2
ROS清除效果测定
1.同实验例1步骤1;
2.将培养至对数期的CHO-K1细胞,铺在6孔板内,每孔1x104个,分别设置一组对照组和三组加药组,加药组在照射前30min,分别加入迷迭香酸、式(I)所示迷迭香酸衍生物和式(II)所示迷迭香酸衍生物药液(1μmol/L,溶剂为含血清和双抗的RPMI1640培养基)每孔1mL,对照组在照射前30min只加入等量的新鲜含血清和双抗的RPMI1640培养基,四组同时置于培养箱中培养30min。然后用3Gyγ射线照射,再在培养箱中培养24小时,移去培养液,加入2',7'-二氯二氢荧光素二乙酯(DCFH-DA)(sigma购得)(5μM,培养基溶解)培养液1ml,避光37℃孵育20min,移去DCFH-DA培养液,用PBS洗涤3次,用胰酶消化收集细胞,酶标仪在488nm激发波长,525nm发射波长条件下测定荧光强度。
实验结果:迷迭香酸衍生物清除自由基能力明显增加(见图2)。
实验例3
DNA双链断裂测定
1.同实验例1步骤1;
2.将培养至对数期的CHO细胞,分别设置一组未照射组和四组照射组,四组照射组照射前30min,分别给迷迭香酸、式(I)所示迷迭香酸衍生物、式(II)所示迷迭香酸衍生物药液(1μmol/L,溶剂为含血清和双抗的RPMI1640培养基)和新鲜的含血清和双抗的RPMI1640培养基每孔500μL,未照射组加入等量的新鲜的含血清和双抗的RPMI1640培养基,四组照射组分别用3Gyγ射线照射。照射后的四组细胞和未照射组同时在培养箱中培养1小时,移去培养液,加入500μL质量分数4%多聚甲醛水溶液,固定15min,PBS洗涤3次,用500μL质量分数0.2%,Triton-X100溶液,(Triton-X100溶液的溶剂为PBS)破细胞膜15min,用PBS洗涤3次,羊血清工作液封闭2h,200μL兔多克隆γ-H2AX(abcom购得,1:1000山羊血清稀释)孵化4℃过夜,PBS洗涤3次,200μL羊抗兔荧光二抗(abcom购得,1:2000PBS稀释),避光室温孵育1h,PBS洗3次,DAPI(索莱宝购得)染色5min,PBS洗涤3次,抗淬灭剂封片(索莱宝购得),用AMGevo荧光显微镜拍照,ImageProPlus6.0软件焦点计数。
实验结果:迷迭香酸衍生物保护DNA双链能力有所增加。(见图3)。
在我们日常正常的生命活动中,机体具有自由基清除系统,包括超氧化物歧化酶,过氧化氢酶,谷胱甘肽还原酶等清除自由基的生物大分子。但是,一方面由于人们自身衰老导致自由基清除系统的衰退,从而使自由基,尤其是活性氧自由基的大爆发,导致体内氧化应激,从而产生帕金森病和阿尔兹海默病等与活性氧相关的疾病;另一方面由于受到电离辐射的作用,人体内也会大量的产生活性氧自由基,从而损害具有功能的生物大分子,进而导致人体的自由基清除系统障碍,使细胞氧化应激。由此可见,在这种条件下我们外源性的摄入活性氧自由基清除药物能有效的防治这些和活性氧自由基相关的疾病和功能障碍症。而本研究由于迭香酸衍生物能有效地清除体内的活性氧自由基,因此该类化合物可以作为帕金森病、阿尔兹海默病的治疗药,同时还能够作为肿瘤放射治疗临床和核事故应急救治时的辐射损伤防护药物。
迷迭香酸衍生物(I)或迷迭香酸衍生物(II)的盐,包合物,共晶、多晶或含有上述衍生物的固体剂型、液体剂型或者半固体剂型都属于本发明的保护范围。
固体剂型可以是片剂(包括普通片、分散片、泡腾片、咀嚼片等);
液体剂型可以是溶液剂(包括真溶液或者胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(粉针、水针剂);
半固体剂型可以是糊剂等。
迷迭香酸衍生物(I)或迷迭香酸衍生物(II)制成普通制剂、缓释制剂、控释制剂以及各种微粒给药系统。
Claims (6)
1.迷迭香酸衍生物,其特征是具有式(I)或式(II)所示结构:
其中:R1为钾或钠;R2为钾或钠;R3为钾或钠;R4为钾或钠。
2.权利要求1的一种迷迭香酸衍生物的制备方法,其特征是包括如下步骤:
(1)将三苯基膦(Ⅲ)与3-卤丙醇(Ⅳ)反应生成(3-羟丙基)三苯基卤化磷(Ⅴ);
(2)将(3-羟丙基)三苯基卤化磷(Ⅴ)与迷迭香酸(Ⅵ),在1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和1-羟基苯并三唑催化下反应,得到式(I)所示的迷迭香酸衍生物;
(3)将式(I)所示迷迭香酸衍生物与NaOH或KOH反应得到通式(II)所示的迷迭香酸衍生物,反应式如下:
其中:R1为钾或钠;R2为钾或钠;R3为钾或钠;R4为钾或钠。
3.权利要求2所述的方法,其特征是所述卤为溴、氯或碘。
4.权利要求1的迷迭香酸衍生物在制备治疗阿尔兹海默病药物的应用。
5.权利要求1的迷迭香酸衍生物在制备治疗帕金森氏病药物的应用。
6.权利要求1的迷迭香酸衍生物在制备辐射防护药物的应用。
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CN107216352A (zh) * | 2017-06-11 | 2017-09-29 | 中国医学科学院放射医学研究所 | 线粒体靶向二氢吡啶衍生物及制备方法及应用 |
CN107216352B (zh) * | 2017-06-11 | 2019-05-17 | 中国医学科学院放射医学研究所 | 线粒体靶向二氢吡啶衍生物及制备方法及应用 |
CN108997422A (zh) * | 2018-06-22 | 2018-12-14 | 中国人民解放军第四军医大学 | 线粒体靶向辐射防护剂的制备及其在辐射损伤防护中的应用 |
CN114939118A (zh) * | 2022-05-09 | 2022-08-26 | 天津大学 | 具有减毒增效作用的防治阿尔茨海默症的药物组合物及应用 |
CN117488458A (zh) * | 2023-10-25 | 2024-02-02 | 普宁市新栩纺织有限公司 | 一种抑菌透气面料 |
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