CN102600126B - 异戊烯基黄酮化合物的应用 - Google Patents
异戊烯基黄酮化合物的应用 Download PDFInfo
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Abstract
本发明公开了异戊烯基黄酮化合物的新用途,具体涉及到异戊烯基黄酮化合物——脱水淫羊藿素和2"-羟基-3"-烯-脱水淫羊藿素作为活性成分在制备抗骨质疏松及促进骨修复药物中的应用,实验结果显示所述化合物具有较显著的抗骨质疏松作用,且毒性较低,安全性高,可作为抗骨质疏松类药物。
Description
技术领域
本发明涉及异戊烯基黄酮化合物----脱水淫羊藿素和2"-羟基-3"-烯-脱水淫羊藿素在制备抗骨质疏松,促进骨修复药物中的应用,属于医药技术领域。
背景技术
骨质疏松是一个日益受到全世界关注的健康问题。美国、欧洲和日本大约有7500万绝经后妇女患有骨质疏松,治疗骨质疏松继发骨折费用每年达230亿美元。骨质疏松患者骨折后的并发症包括:致残、瘫痪、呼吸动力学障碍、疼痛。社会负担远远超过了直接医疗费用。随着老龄化社会的不断临近,开发治疗骨质疏松药物就越发迫切。雌激素替代治疗虽然取得疗效,但长期应用可增加子宫内膜癌和乳腺癌的发病率,使其应用受到限制。开发具有组织特异性的雌激素样类似物,使之对骨、心脏和脑的功能有促进作用,且长期使用没有对子宫内膜和乳腺致癌的危险性,已成为治疗骨质疏松药物开发的黄金标准。近年来,在抗骨质疏松以及促进骨修复药物的研究中,中药因其药效好、不良反应少及资源丰富等特点,越来越受到人们的重视。
淫羊藿,小檗科多年草本生植物,又名仙灵脾、三枝九叶草等,是我国传统的补肾壮阳药,始载于《神农本草经》,具有补肾阳、强筋骨、祛风湿之功效。据统计,100味治疗骨质疏松症的常用中药中,淫羊藿的使用频率仅次于熟地而居第二位,在补阳药中则居首位。故淫羊藿是我国传统医学宝库中的一种温阳补肾,强肾坚骨药物。现代医学研究发现,淫羊藿的主要成分具有刺激成骨细胞增殖和分化的功效,还可改善免疫系统、心血管系统功能和抑制肿瘤细胞生长,既具有雌激素和生长因子的促进成骨细胞分裂和分化功能的生理作用,又克服了雌激素和生长因子导致肿瘤发病率升高的缺点。
60年代末,人们发现黄酮类化合物具有抗炎、抗病毒、利胆、强心、镇静、镇痛、抗氧化、抗衰老、免疫调节和抗肿瘤等作用,亦可作为植物雌激素,具有较强的防治骨质疏松的作用。淫羊藿总黄酮能促进大鼠颅盖骨成骨样细胞增殖和分化,显著提高成骨细胞中碱性磷酸酶(alkalinePhosPhatase,ALP)的活性、骨钙素分泌量和钙盐沉积量;另外,淫羊藿还能剂量依赖的抑制破骨细胞的凋亡,从而抑制大鼠骨量的丢失。
迄今为止,现有技术中没有本发明的异戊烯基黄酮化合物-----脱水淫羊藿素和2"-羟基-3"-烯-脱水淫羊藿素作为药物有效成分在治疗骨质疏松疾病方面的相关报道。
发明内容
本发明的目的在于提供一种异戊烯基黄酮化合物的新用途,即在制备抗骨质疏松及促进骨修复药物中的应用。
本发明中所述异戊烯基黄酮化合物为脱水淫羊藿素或2"-羟基-3"-烯-脱水淫羊藿素。
本发明所述的应用是以异戊烯基黄酮化合物---脱水淫羊藿素或2"-羟基-3"-烯-脱水淫羊藿素为活性成分在制备抗骨质疏松及促进骨修复药物中的应用。
本发明所述的应用还可是以异戊烯基黄酮化合物---脱水淫羊藿素或2"-羟基-3"-烯-脱水淫羊藿素为活性成分与其他活性成分配合使用制成药物抗骨质疏松组合物。
本发明所述的应用中还可以加入一种或多种药物上可接受的载体或辅料。所述药学上可接受的载体或辅料是指药学领域常规的药物载体或辅料,如:水或酒精等稀释剂、赋形剂,或者淀粉、蔗糖等填充剂,或者纤维素衍生物、藻酸盐、明胶或聚乙烯吡咯烷酮等粘合剂,或者甘油等湿润剂,或者琼脂、碳酸钙或碳酸氢钠等崩解剂,或者季铵化合物等吸收促进剂,或者十六烷醇等表面活性剂,或者皂土或高岭土等吸附载体,或者滑石粉、硬脂酸钙和硬脂酸镁、聚乙二醇等润滑剂,另外在组合物中可加入香味剂、甜味剂等其它辅剂。
本发明化合物以组合物的形式通过口服、外用等给药的方式应用于需要这种治疗的患者。用于口服时,可将其制成常规的固体制剂如片剂、粉剂、粒剂、胶囊剂等,或者制成液体的水或油的悬浮剂或其它的糖浆、酏剂;用于外用给药时,可将其制成膜剂。
本发明药物组合物的各种剂型可以按照药学领域的常规生产方法制备。例如使活性成分与一种或多种载体或辅料混合后,按常规方法制成所需剂型。
本发明药物组合物优选含有质量比为0.1~99.5%的活性成分,最佳优选含有质量比为0.5~95%的活性成分。
本发明化合物的施用量可根据用药途径、患者年龄、体重、所治疗的疾病类型和严重程度等变化具体确定,其日剂量可以是0.01~10mg/kg体重,优选0.1~5mg/kg体重。可以一次或多次施用。
本发明中所述的异戊烯基黄酮化合物----脱水淫羊藿素(I)或2"-羟基-3"-烯-脱水淫羊藿素(II),是从干燥淫羊藿(Epimedium brevicornumMaxim)全草中分离出的两种具有促进成骨的活性成分,具有以下结构式:
本发明中所述的异戊烯基黄酮化合物是从淫羊藿全草中提取分离的,提取分离方法包括以下步骤:
A、将干燥淫羊藿全草粉碎后,按淫羊藿:丙酮水溶液=1:2~4的质量/体积(w/v)比,将淫羊藿放入浓度为75%的丙酮水溶液中,室温下浸泡15~30小时后,制得提取液,如此重复提取2~3次,合并提取液;
B、将上述A步骤所得提取液减压蒸馏至无丙酮味后,按提取液∶石油醚=1:1的体积比,于室温下,用石油醚对提取液进行2~3次的萃取,回收石油醚后,制得萃取液;
C、按萃取液∶乙酸乙酯=1∶1的体积比,于室温下,用乙酸乙酯对上述B步骤的萃取液进行2~3次的萃取,回收后得乙酸乙酯浸膏;
D、将上述C步骤的乙酸乙酯浸膏上硅胶柱进行层析分离,用氯仿:甲醇=40:1,20:1,10:1,8:1,5:1,4:1,0:1(体积比)的洗脱剂依次进行洗脱,收集氯仿:甲醇=8:1洗脱段溶液,浓缩后制得粗分离物;
E、将步骤D所得粗分离物上硅胶柱,用氯仿/甲醇=150:1-10:1溶液作为洗脱剂,洗脱2-5次,第一次洗脱后洗脱液浓缩物作为下一次洗脱的分离物,以此类推,最后制得精分离物;
F、精分离物用氯仿/甲醇=100-150:1溶液作为洗脱剂进行洗脱,收集洗脱液浓缩后得到异戊烯基黄酮化合物脱水淫羊藿素(I);E步骤所得精分离物用高效液相色谱分析后,用ZORBAX SB-C18柱半制备分离后制得2"-羟基-3"-烯-脱水淫羊藿素(II)。
通过上述方法获得的脱水淫羊藿素(I)为黄色粉末,分子式为C21H20O6,不饱和度为12,具体为3,5,7-三羟基-8-( 3"-甲基-2"-丁烯基)-4′-甲氧基黄酮,结构式如下:
通过上述方法获得的2"-羟基-3"-烯-脱水淫羊藿素(II)为黄色粉末,分子式为C21H20O7,不饱和度为12,具体为3,5,7-三羟基-8-(2"-羟基-3"-甲基-3"-丁烯基)-4′-甲氧基黄酮,结构式如下:
本发明中所述异戊烯基黄酮化合物,应用WST-8 [2-(2-甲氧基-4-硝苯基)-3-(4-硝苯基)-5-(2,4-二磺基苯)-2H-四唑单钠盐]实验表明其对小鼠前成骨细胞MC3T3-E1细胞作用72 h后不具有明显的细胞毒性作用,说明异戊烯基黄酮化合物的细胞毒性较低,安全性好。
本发明中所述的异戊烯基黄酮化合物,应用WST-8实验表明其对小鼠前成骨细胞MC3T3-E1细胞作用72 h后具有明显的促进细胞增殖的作用,在浓度为1.0×10-6mol/L时能显著提高细胞内ALP的水平,具有明显的促进成骨细胞分化从而修复骨缺损的作用。
本发明中所述的异戊烯基黄酮化合物,经试验研究发现其在促进小鼠前成骨细胞MC3T3-E1细胞增殖的最佳浓度1.0×10-6mol/L下,经14天作用后能显著促进细胞形成矿化结节,说明本发明的异戊烯基黄酮化合物具有明显的促进成骨细胞矿化从而修复骨缺损的作用。
附图说明
图1是本发明化合物I和II对小鼠前成骨细胞MC3T3-E1的毒性作用和增殖作用结果示意图,图中数据以Mean±SEM方式表示,其中A为化合物I对细胞增殖的影响,B为化合物II对细胞增殖的影响,*为 p < 0.05, **为p < 0.01。
图2是本发明化合物I和II对小鼠前成骨细胞MC3T3-E1内碱性磷酸酶ALP合成的影响结果示意图,图中con为空白,os为阳性对照, 1为化合物I, 2为化合物II。
图3是本发明化合物I和II对小鼠前成骨细胞MC3T3-E1矿化结节形成的影响结果示意图,其中A为空白对照,B为阳性对照,C为化合物I对细胞矿化的影响,D为化合物II对细胞矿化的影响。
图4是本发明化合物I和II对小鼠前成骨细胞MC3T3-E1矿化结节形成的影响结果示意图, 数据以Mean±SEM方式表示,图中***为p < 0.001,con为空白,os为阳性对照,1为化合物I,2为化合物II。
图5为本发明的工艺流程示意图。
具体实施方式
下面通过附图和实施例对本发明作进一步详细说明,但本发明保护范围不局限于所述内容,本实施例中试剂如无特殊说明的,均为常规市售试剂或按常规方法制备的试剂。
实施例1:异戊烯基黄酮化合物---脱水淫羊藿素(I)和2"-羟基-3"-烯-脱水淫羊藿素(II)的制备,具体步骤如下:
取干燥淫羊藿(Epimedium brevicornumMaxim)全草12 kg粉碎后,按淫羊藿∶丙酮水溶液=1∶3的质量/体积比,用浓度为75%丙酮水溶液在室温下浸提淫羊藿3次,每次丙酮水用量为36 L,浸泡时间24小时,合并3次提取液后,减压蒸馏至无丙酮味;按提取液∶石油醚=1∶1的体积比,先用石油醚于室温下对提取液萃取三次,每次石油醚用量10 L,回收石油醚后,得萃取液;按萃取液∶乙酸乙酯=1∶1的体积比,再用乙酸乙酯于室温下对萃取液萃取三次,每次乙酸乙酯用量8 L,得乙酸乙酯浸膏 178 g;将乙酸乙酯浸膏用粒度为100-200目的400 g硅胶拌样后,上硅胶柱进行层析粗分离,硅胶柱为内装有2 kg(粒度为200-300目)硅胶、体积为120×1500 mm的玻钢硅胶柱,之后用氯仿:甲醇分别为40:1,20:1,10:1,8:1,5:1,4:1,0:1(体积比)的七个洗脱剂,依次对层析分离物进行洗脱后,收集氯仿:甲醇=8:1洗脱段溶液(Fr4),浓缩后制得粗分离物;
将氯仿:甲醇= 8:1洗脱剂洗脱段粗分离物20 g用硅胶拌样后,上硅胶柱(300 g硅胶)层析,经氯仿:甲醇=100:1体积比的洗脱剂进行洗脱得到204.4 mg分离物,该分离物再次上硅胶柱层析(0.2 g硅胶拌样,上6 g硅胶柱),并用氯仿:甲醇=120:1体积比的洗脱剂洗脱后,得26.6 mg精分离物;将该精分离物用硅胶柱以氯仿/甲醇120:1作为洗脱剂洗脱得到脱水淫羊藿素12 mg;另外,上述精分离物质经Agilent 1200 HPLC(高效液相色谱)分析(流动相为70%甲醇/水,柱温40℃,停留时间t = 8.2 min)后,用ZORBAX SB-C18柱半制备分离得2"-羟基-3"-烯-脱水淫羊藿素20.3 mg。(见图5)
实施例2:以异戊烯基黄酮化合物为活性成分制备的片剂,片剂组分及含量如下:
活性成分---异戊烯基黄酮化合物(I或II) 10mg
乳糖 156mg
玉米淀粉 55mg
硬脂酸钙 4mg
制备方法:将活性成分、乳糖、玉米淀粉混合,用水均匀湿润至能捏之成团,压之易散的软材,经60-80℃干燥、过筛后,加入硬脂酸钙,混合均匀后,压制成片,每片重225mg,活性成分含量为10mg。
实施例3:以异戊烯基黄酮化合物为活性成分制备的喷雾剂,其组分及含量如下:
活性成分异戊烯基黄酮化合物 (I或II) 8mg
氯化钠 9mg
EDTA 0.5mg
磷酸钠缓冲液(PH6.5) 10mg
蒸馏水加至2ml
制备方法:将各固体成分依次加入蒸馏水中完全溶解后,经微孔滤膜过滤灭菌后,装瓶。
实施例4:异戊烯基黄酮化合物的抗骨质疏松、促成骨作用实验,具体内容如下:
1.1 细胞培养
小鼠前成骨细胞MC3T3-E1在含10%胎牛清的α-MEM培养基 (Gibco, Paisley, UK) 中,传代后接种于24孔培养板中。共分为三组,空白组(无药物和成骨诱导液处理)、成骨诱导液处理的阳性对照组(成骨诱导液的组成是在含10%胎牛清的α-MEM培养基中加入50 μg/ml 抗坏血酸,10 mM β-甘油磷酸酯,和50 nM 地塞米松)、化合物I和II(分别设置1×10-5,1×10-6 和1×10-7 mol/L三个浓度)处理组,每组各5个平行,37 ℃,5% CO2条件下培养。
化合物I和II对小鼠前成骨细胞的毒理学评价实验
应用WST-8检测方法对进行评价,取对数生长期小鼠前成骨细胞MC3T3-E1细胞接种于96孔培养板中,6000个细胞/孔/100μL,37℃,5% CO2条件下培养24 h后,分别设置步骤1.1中的三个实验组(空白组、阳性对照组和处理组)在37℃,5% CO2条件下继续培养72 h后,再加10 μL WST-8(2-(2-甲氧基-4-硝苯基)-3-(4-硝苯基)-5-(2,4-二磺基苯)-2H-四唑单钠盐)继续培养2 h,用酶联免疫检测仪于450 nm处测定各孔吸光值(OD值)。
实验结果显示:用浓度分别为1×10-5,1×10-6 和1×10-7 mol/L的化合物I和II处理MC3T3-E1细胞72 h后,与空白对照相比,细胞活率没有显著差异,说明化合物I和II对
MC3T3-E1细胞不具有细胞毒性作用,并具有促进细胞增殖的作用(见图1)。
化合物I和II对小鼠前成骨细胞内碱性磷酸酶(ALP)水平的影响
取培养7天的三组(空白组、阳性对照组和处理组)细胞的上清液各100 μL,按照ELISA检测试剂盒的程序操作,测定细胞内碱性磷酸酶(ALP)的量。
实验结果显示:空白组MC3T3-E1细胞培养7天后,分泌的ALP水平分别为12.235±2.671 nmol/min/protein。经成骨诱导液处理7天后ALP的分泌显著增加,达到20.762±0.975 nmol/min/protein。当加入化合物I和II(1×10-6 mol/L)分泌的ALP显著增加,分别达到28.079±2.163和21.083±1.077 nmol/min/protein(见图2)。与空白对照组相比,1×10-6 mol/L化合物I或II处理的细胞其细胞内ALP水平增加显著(p<0.05)。
1.4化合物I和II对小鼠前成骨细胞MC3T3-E1矿化结节形成的影响
取对数生长期小鼠前成骨细胞MC3T3-E1细胞接种于24孔培养板中,10000个细胞/孔/500μL,37℃,5% CO2条件下培养24h,分别设置与步骤1.1中三个实验组相同的实验组(空白组、阳性对照组和处理组)在37℃,5% CO2条件下继续培养,每2-3天换液一次,处理到第14天,取三组细胞,每组6孔,进行矿化结节染色,即PBS漂洗一次,95%乙醇固定10min,蒸馏水漂洗三次,滴加0.1%茜素红-Tris-HCL(pH=8.3)在37℃染色30min,蒸馏水漂洗,干燥,拍摄染色照片。取3组染色后的细胞,用含5% SDS 的0.5 N HCl 溶解茜素红染色的细胞,室温处理30min后,用紫外分光光度计于415nm 检测吸光度值。
MC3T3-E1细胞处理14天后,经茜素红染色,化合物I和II(1×10-6 mol/L)处理的细胞比空白对照组和阳性对照组的细胞相比,形成了更多的矿化结节(见图3)。对矿化结节定量的检测,结果同染色结果一致,即其吸光度值显著的高于空白组和阳性对照组(p<0.01)(见图4)。
Claims (1)
1.异戊烯基黄酮化合物2"-羟基-3"-烯-脱水淫羊藿素在制备抗骨质疏松及促进骨修复药物中的应用。
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