CN111529515B - 12,15-二氧-α-蛇床烯在制药中的应用 - Google Patents
12,15-二氧-α-蛇床烯在制药中的应用 Download PDFInfo
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Abstract
本发明提供12,15‑二氧‑α‑蛇床烯(PFC‑37)在制备预防和治疗神经退行性疾病和帕金森病的药物中的应用。PFC‑37对MPP+诱导的PC12损伤有显著的保护作用，可以用于制备预防和治疗帕金森病的药物组合物或膳食补充组合物。
Description
技术领域：
本发明属于医药技术领域，尤其涉及12,15-二氧-α-蛇床烯在制备预防和治疗神经退行性疾病的药物中的应用。
背景技术：
帕金森病(Parkinson’s disease)是中老年人常见的神经系统疾病。目前，主要采用左旋多巴替代疗法治疗帕金森病，但无法阻止帕金森病的进展，疗效在3～5年后就开始减退，不仅有早期不良反应(厌食、恶心、头晕、精神障碍及异动症等)，长期使用还会导致“开关现象”、剂末现象和肌张力运动障碍等[孙静,熊航,姚玉玺.帕金森病的治疗进展.医学综述,2020,26(2):1157-1160,1165.]。因此，寻找新的治疗药物和方法，是研究的热点和难点。
1-甲基-4-苯基吡啶离子(1-methyl-4-phenylpyridinium ion,MPP+)诱导的PC12细胞损伤模型，是目前公认的帕金森病治疗药物的筛选模型[a.Delavar MR,Baghi M,Safaeinejad Z,Kiani-Esfahani A,Ghaedi K,Nasr-Esfahani MH.Differentialexpression of miR-34a,miR-141,and miR-9in MPP+-treated differentiated PC12cells as a model of Parkinson’s disease.Gene,2018,662:54-65；b.Lin K-H,Li C-Y,Hsu Y-M,Tsai C-H,Tsai F-J,Tang C-H,Yang J-S,Wang Z-H,Yin M-C.Oridonin,anatural diterpenoid,protected NGF-differentiated PC12 cells against MPP+-andkainic acid-induced injury.Food and Chemical Toxicology,2019,133:110765]。迄今为止，现有技术中未见有倍半萜类化合物PFC-37具有对神经退行性疾病、帕金森病的活性的报道。
发明内容：
本发明在利用MPP+诱导的PC12细胞损伤模型筛选药理活性成分时，发现倍半萜类化合物PFC-37对MPP+诱导的PC12细胞损伤具有显著的保护作用，PFC-37的这种作用是首次报道。本发明的目的在于提供PFC-37在制备预防和治疗神经退行性疾病的药物中的应用，以及在制备预防和治疗帕金森病的药物中的应用。
为了实现本发明的上述目的，本发明提供了如下的技术方案：
预防和治疗神经退行性疾病的药物组合物，由12,15-二氧-α-蛇床烯和药学上可接受的载体所组成。
预防和治疗帕金森病的药物组合物，由12,15-二氧-α-蛇床烯和药学上可接受的载体所组成。
膳食补充组合物，由12,15-二氧-α-蛇床烯和食品辅料所组成。
12,15-二氧-α-蛇床烯在制备预防和治疗神经退行性疾病的药物中的应用。
12,15-二氧-α-蛇床烯在制备预防和治疗帕金森病的药物中的应用。
上面所述的药学上可接受的载体是指药学领域常规的药物载体，例如，水、葡萄糖、乳糖、阿拉伯胶等和适合在制备固体、半固体、液体或气溶胶形式的制剂中使用的其他载体。组合物可以另外含有稳定剂，增稠剂，和/或着色剂和香料。
本发明的化合物及其药学上可接受的载体制备而成的组合物可经口或不经过口给药，给药量因药物不同而各有不同，对成人来说，每天1～100mg较合适。
经口服给药时，首先使化合物与常规的药用辅剂如赋形剂、解剂、黏合剂、润滑剂、抗氧化剂、包衣剂、着色剂、芳香剂、表面活性剂等混合，将其制成颗粒剂、胶囊、片剂等形式给药：非经口给药时可以注射液、输液剂或栓剂等形式给药。制备上述制剂时，可使用常规的制剂技术。
本发明化合物12,15-二氧-α-蛇床烯用作药物或保健产品时，可以直接使用，或者以组合物的形式使用。该药物组合物含有0.1～99％，优选为0.5～90％的化合物，其余为药物学上可接受的，对人和动物无毒和惰性的可药用载体和/或赋形剂，或日用食品添加剂和基质。
具体实施方式：
下面用本发明的实施例来进一步说明本发明的实质性内容，但并不以此来限定本发明。
实施例1：
化合物PFC-37的制备过程：
干燥的中药沉香[即土沉香Aquilaria sinensis(Lour.)Spreng.的心材；2.9kg]粉碎，90％乙醇60℃超声提取30min，最后得浓缩粗提物浸膏(459.3g)。然后将浸膏悬浮于水中，依次用等体积石油醚、乙酸乙酯、正丁醇萃取，回收溶剂得石油醚萃取物0.7g，乙酸乙酯萃取物374.8g，以及正丁醇萃取物52.5g。
乙酸乙酯萃取部位(374.8g)用等量的80～100目硅胶拌样，经正相硅胶柱层析划段，洗脱剂为石油醚-乙酸乙酯体系(50:1，30:1，20:1，10:1，5:1，3:1，2:1，1:1，0:1，v/v)进行梯度洗脱，接着用乙酸乙酯-甲醇体系进行洗脱(5:1，3:1，2:1，1:1，0:1，v/v)，经TLC检测合并相同组分，得到5个部分(Fr.Y-1～Fr.Y-5)。
Fr.Y-1(2.5g)经中压RP-18反相硅胶柱层析(甲醇-水，10％→100％)，经TLC检测合并相同馏分，得到4个部分(Fr.Y-1-1～Fr.Y-1-4)。Fr.Y-1-1(138.1mg)经Sephadex LH-20凝胶柱色谱(甲醇)得到化合物PFC37(130.2mg)。12,15-二氧-α-蛇床烯(PFC-37)的化学结构式中下所示：
化合物PFC-37的波谱数据：
化合物PFC-37，其化学名称为12,15-二氧-α-蛇床烯[(5R,7R,10R)-12,15-dioxo-α-selinene]，无色油状，分子式C15H20O2，CAS号76235-89-7；[α]D 22-47.7(c 0.12,MeOH)；ECD(c 0.027,MeOH)λmax(Δε)312(+0.40),222(-2.84)nm；1H NMR(CDCl3,500MHz)δH 9.50(1H,s,H-12),9.39(1H,s,H-15),6.70(1H,dd,J＝4.8,2.5Hz,H-3),6.25(1H,s,H-13),5.96(1H,s,H-13),2.59(1H,tt,J＝12.0,4.0Hz,H-7a),1.55–1.43(3H,m,H-8b,H-9),1.36(2H,m,H-1),1.21(1H,m,H-6b),0.83(3H,s,H-14)；13C NMR(CDCl3,125MHZ)δC 194.9(CH,C-13),194.6(CH,C-15),154.8(C,C-11),153.3(C,C-4),142.0(CH,C-3),133.4(CH2,C-12),43.4(CH2,C-9),39.6(CH2,C-1),37.0(CH,C-7),36.4(C,C-10),32.1(CH,C-5),27.0(CH2,C-6,C-8),26.3(CH3,C-14),15.8(CH2,C-2)；ESIMS m/z 255[M+Na]+,487[2M+Na]+。其波谱数据跟文献[Bohlmann,F.；Zdero,C.；Cuatrecasas,J.；King,R.M.,Robinson,H.Neue sesquiterpeneund norditerpene aus vertretern der gattung Libanothamnus.Phytochemistry,1980,19(6):1145-1148]中的数据基本一致。
实施例2：
化合物PFC-37的神经保护活性测试方法如下：
1.PC12低分化细胞采用DMEM高糖+10％FBS+100U/mL双抗的培养基进行培养，培养箱温度37℃，5％CO2；
2.当PC12低分化细胞长至合适数量时，胰酶消化，制成细胞悬液；
3.将细胞悬液吸至15mL离心管中，800rpm，5min；
4.离心结束后，离心管用酒精消毒后拿进超净台，将上清倒入废液缸；
5.加入新的完全培养基5mL，用移液器吹打十次，尽量吹散细胞，但不能太用力；
6.取0.02mL细胞悬液，加入到细胞计数板中，计数；
7.将细胞浓度调整至1×105cells/mL，加入96孔板，每孔0.1mL，放入细胞培养箱培养；
8. 23小时后，将原培养基吸出，然后加入新的培养基(同1中配方)，加入待测化合物，1小时后，加入MPP+(MPP+在体系中终浓度750μM)；
9.实验设计：各组设计各做3个重复。
空白组：只有培养基；
模型组(MPP+)：培养基加终浓度750μM MPP+；
阳性对照组(维生素E)：培养基加终浓度0.2μM维生素E，再加终浓度750μM MPP+。
化合物组(第一组至第五组)：培养基分别加终浓度为5、2、1、0.2、0.1μM的化合物PFC-37，再加终浓度750μM MPP+。
10.加入MPP+24小时后，加入MTS，2小时后，读值检测。
实施例3：
化合物PFC-37的神经保护活性的效果：
化合物PFC-37的神经保护活性数据如表1所示，在化合物浓度为1μM和2μM时，对MPP+诱导的PC12细胞损伤均具有显著的保护活性(P<0.001)。
表1.化合物PFC-37对MPP+诱导的PC12细胞损伤的保护作用
表1注释：跟模型组比较，**P<0.01，***P<0.001。
实施例4：
制备治疗神经系统疾病的药物，按以下的重量百分比进行混合：PFC-37占20～80％，分散剂2～20％，崩解剂3～5％，乳化剂3～8％，粘结剂0.2～2％，润湿剂0.5～10％，其余为填料。然后按常规药物制备方法制得有效成分为PFC-37的神经系统疾病的治疗药物。
实施例5：
口服液制剂的制备：
以PFC-37为活性成分，按常规口服液制法制成口服液。
实施例6：
胶囊剂、颗粒剂、或冲剂的制备：
按PFC-37与赋形剂重量比为5:1的比例加入赋形剂，制成胶囊或颗粒剂或冲剂。
实施例7：
膳食补充组合物的制备：按以下的重量百分比进行混合：PFC-37占20～80％，常用食品辅料80～20％。
Claims (1)
1. 12,15-二氧-α-蛇床烯在制备通过神经保护作用预防和治疗帕金森病的药物中的应用。
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