CN116120337B - 一种双氢青蒿素衍生物、药物及其在制备治疗预防脑血管病药物中的应用 - Google Patents
一种双氢青蒿素衍生物、药物及其在制备治疗预防脑血管病药物中的应用 Download PDFInfo
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Abstract
本发明提供了一种新的双氢青蒿素衍生物，以该双氢青蒿素衍生物为活性成分可制备成预防、治疗缺血性脑卒中的药物，而且所述药物更容易通过血脑屏障，具有更高的脑组织药物浓度。
Description
技术领域
本发明涉及一种双氢青蒿素衍生物，并涉及其药物用途。
背景技术
随着我国老龄化进程，脑血管病已成为致死致残第一病因。主要病因是由于脑血管栓塞或者血栓形成所导致的血流中断，而造成神经细胞缺血缺氧死亡，病情严重程度与脑组织梗死体积密切相关。
神经干细胞(Neural Stem Cells，NSCs)主要存在于侧脑室壁的室管膜下区和海马的齿状回区，是一群可以自我更新、干性维持和分化为有功能神经元的特殊细胞。由于神经元为终末分化细胞，无法自我更新，其缺血死亡后只能通过神经干细胞增殖分化予以修复功能，而脑血管病研究中如何激活内源性神经干细胞快速增殖以修复梗死脑组织一直是热点领域。
本课题组一直致力于青蒿素及其在治疗神经性相关疾病的应用。
CN104523679A提供了双氢青蒿素在治疗、脑血管病的用途。虽然双氢青蒿素被发现对神经干细胞增殖有促进作用，体外可诱导神经干细胞增殖，体内可以减少脑梗塞的缺血灶。但是，研究表明长期低剂量的双氢青蒿素可能导致骨髓抑制、外周血红细胞减少和脾脏髓外造血等副反应，而减少剂量可以有效避免相关副反应的发生[尹纪业.两种青蒿素衍生物毒理学再评价及其心脏毒性机制研究[D].中国人民解放军军事医学科学院,2014.]。另外随着研究的深入发现，双氢青蒿素属于水溶性药物，虽可通过血脑屏障，但透过率有限，需要较高的血药浓度才能达到神经保护所需的脑组织浓度[Yepu He et al,Synergistic integration of dihydro-artemisinin withγ-aminobutyric acidresults in a more potential anti-depressant.Bioorg Chem.2021.110:104769.]。综上，寻找一种双氢青蒿素衍生物可达到更高的血脑屏障通透率，对减少其治疗脑血管病中产生的副反应具有重要临床意义。
发明内容
基于此问题，经过潜心研究，本发明的目的在于提供了一种新的双氢青蒿素衍生物，具备治疗预防脑血管病功能，改善了双氢青蒿素血脑屏障透过率低的问题，提高了脑组织中的药物浓度。
本发明的目的是通过以下措施实现的：
一种双氢青蒿素衍生物，其结构式为：
本发明还提供了一种药物。
一种药物，包括上述双氢青蒿素衍生物。所述药物还可以包括一种或多种药理学上可接受的辅料，所述辅料包括药学领域中常规的稀释剂、赋形剂、填充剂、湿润剂、吸收促进剂、表面活化剂、润滑剂或稳定剂等。所述药物优选制成水溶液或粉剂等适用于注射用的药物形式；更优选为水溶液，药物浓度为150mg/kg。所述药物在使用时可静脉滴注或肌肉注射，一般1天应用1次，每次40mg，14天为一个疗程。较双氢青蒿素常规剂量(60mg)减少30％用量。
本发明的另一目的在于提供上述双氢青蒿素衍生物的用途。
上述双氢青蒿素衍生物在治疗、预防脑血管病药物中的应用。进一步的，所述双氢青蒿素衍生物在制备治疗、预防缺血性脑卒中药物中的应用。更进一步的，所述双氢青蒿素衍生物在制备减轻或消除脑梗塞缺血灶药物中的应用。
上述双氢青蒿素衍生物在制备促进神经干细胞增殖药物中的应用。进一步地，所述双氢青蒿素衍生物促进大脑室管膜下区(Subventricular Zone，SVZ)神经干细胞(Neural Stem Cells，NSCs)增殖的应用。
所述双氢青蒿素衍生物对神经干细胞增殖有促进作用；体外可诱导神经干细胞增殖；体内可有效减少脑梗塞的缺血灶梗死灶并改善脑卒中造成的神经功能缺损。以所述双氢青蒿素衍生物为活性成分可制备成治疗缺血性脑卒中的药物，而且所述药物更容易通过血脑屏障，具有更高的脑组织药物浓度。
有益效果
1.脑缺血发生后，由于神经元对血氧的特殊依耐性，短期内就会有大量的有功能神经细胞死亡，给预后带来极其不利的影响。本发明所提供的双氢青蒿素衍生物，其保持了双氢青蒿素治疗神经性相关疾病的相关功能，具体而言，可促进内源性NSCs在缺血区神经细胞受到损伤后激活、增殖、分化为神经前体细胞(Neuroblasts)并向损伤灶迁移，在损伤的神经网络系统中重新整合，修复损伤的神经网络结构并可替代坏死神经元发挥相应的神经功能。所述双氢青蒿素衍生物通过早期激活(图2)神经干细胞内源性NSCs的增殖替代缺血灶周围坏死神经元而发挥功能，可用于脑梗塞的治疗。
2.本发明所提供的双氢青蒿素衍生物，不仅具有所述药效，而且更优的是较双氢青蒿素具有更优的血脑屏障透过率(图4)，可以对于中枢神经系统疾病具有更高的药物浓度，能够有效的减少药物用量，提高药物疗效，并进一步降低毒、副作用。
附图说明
图1实施例1中双氢青蒿素衍生物(Dihydroartemisinin derivatives，DD)制备中化学结构变化
图2实施例2免疫荧光结果显示：DD组的NSC增殖数量(Nestin/Ki67双染)较对照组明显增加；
图3实施例3中MCAO动物手术72h后的MRI照片，可见DD组动物脑梗死灶较对照组与双氢青蒿素(Dihydroartemisinin,DHA)组显著缩小
图4实施例4中MCAO动物手术72h后的高效液相色谱法测定血浆与脑组织药物浓度；A.血浆中DHA测定色谱图；B.脑组织中DD测定色谱图；C.血浆中浓度对比两组无显著差异；D.脑组织中浓度对比DD显著高于DHA。
具体实施方式
下面结合附图和实施例对本发明做进一步详细说明。以下实施例仅限于说明本发明而不用于限制本发明的范围。
在整个说明书中，除非另有特别说明，本文使用的术语应理解为如本领域中通常所使用的含义。因此，除非另有定义，本文使用的所有技术和科学术语具有与本发明所属技术人员的理解相同的含义。若存在矛盾，本说明书优先。
下面将结合实施例对本发明的实施方式进行详细描述，实施例中未注明具体条件的，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商的，为可以通过商购获得的常规产品。
实施例1一种双氢青蒿素衍生物(Dihydroartemisinin derivatives，DD)的制备
1.10β-(2-溴乙氧基)双氢青蒿素的制备
将3.103g(24毫摩尔)2-溴乙基醇和100mL四氢呋喃加入到250mL的圆底烧瓶中，然后在冰浴条件下加入4mL BF3.Et2O(C4H10BF3O，三氟化硼乙醚溶液，商业购买)，再加入5.690g(20毫摩尔)的双氢青蒿素(C15H24O5)。该混合物在冰浴中搅拌反应1.5小时。反应过程用TLC监测。反应完成，分别加入饱和NaHCO3溶液和50mL EtOAc(CH3COOC2H5)，萃取分层后，将水层用EtOAc(30mL×2)萃取，然后将有机层合并。将有机层用40mL饱和盐水溶液洗涤，无水固体Na2SO4干燥，过滤后，减压旋转蒸馏有机溶剂。将所得到的粗产物重结晶(将石油醚滴加到溶解有样品EtOAc中)，静置，过滤，真空干燥，得白色晶体。
2.双氢青蒿素衍生物的制备
10β-(2-溴乙氧基)双氢青蒿素，CH3CN，KI，K2CO3和呋喃苄胺(Sigma-Aldrich公司商业购买)分别加入到一个100mL的圆底烧瓶中，该混合物反应在受控的温度下(50℃)加热反应。反应过程通过TLC监测。然后加入15mL二氯甲烷和20mL饱和NaCl溶液。萃取分层后，水层用二氯甲烷(10mL×2)萃取，然后将有机层合并。将有机层用20mL饱和盐水溶液洗涤，无水固体Na2SO4干燥；过滤后，减压旋转蒸馏二氯甲烷。硅胶柱色谱法(石油醚混合EtOAc)后，获得纯的产物。化合物结构变化过程如图1。
在Agilent核磁共振仪600MHz和151MHz条件下分别得到1H谱和13C谱，利用WatersSYNPAT G2仪器完成高分辨质谱测定所述化合物，谱图信息如下：1H NMR(600MHz,DMSO)d7.75(s,1H),6.57(s,1H),6.52(s,1H),5.40(s,1H),4.71(s,1H),4.20(s,2H,),3.89(s,1H),3.55(s,1H),3.08(s,2H),2.42(s,1H),2.18(s,1H),2.01(s,1H),1.80(s,1H),1.66(m,2H),1.54(s,1H),1.32(m,6H),1.14(s,1H),0.88(m,7H).13C NMR(151MHz,DMSO)d 146.84,143.96,111.41,110.87,103.43,101.06,86.89,80.34,63.65,51.90,45.75,43.83,42.83,36.46,36.01,34.09,30.27,25.62,24.22,23.95,20.11,12.62.HRMS m/z[M+H]+:408.2375(Calcd for C22H33NO6:407.230788)。
实施例2一种双氢青蒿素衍生物(DD)在离体条件下对神经干细胞增殖的影响
选取孕14.5d SD大鼠，5％水合氯醛腹腔麻醉，打开腹膜，取出胚胎，去除头皮、头骨和硬膜，剥离鼠脑。在解剖显微镜下，以嗅球为中心矢状位纵切，于室管膜下区取材。加入增殖培养基(DMEM/F12，bFGF 20ng/mL，EGF 20ng/mL，2％B27)，经200目滤网过滤后，台盼蓝染色后细胞计数，调整细胞数为1×106/ml，转入培养瓶，放入5％CO2、37℃恒温孵箱中培养，三天传代一次。
取对数期生长的NSCs，0.25％EDTA胰蛋白酶消化2min，10％DMEM/F12终止消化后，调整细胞数至8000/100μL，接种于的96孔板，置于5％CO2、37℃恒温培育箱中。24h后贴壁生长，弃上清，设置空白对照组、800nmol/L DD组共两组。每组6个复孔，孵育72h后取出。PBS缓冲液清洗3次，75％乙醇固定30min，PBS缓冲液清洗3次，加入0.5％的Triton X-100，静置20min，缓冲液洗3次，BSA封闭20min，分别加入Ki67一抗(细胞增殖标志物)与Nestin一抗(NSC标志物)。4℃过夜，缓冲液洗3次，加入相应的荧光二抗，37℃下反应lh，用缓冲液洗3次，复染DAPI，甘油封片。在相差倒置显微镜下观察Ki67与Nestin双阳性细胞并拍照计数。双氢青蒿素衍生物(DD)组Ki67与Nestin双阳性率明显高于对照组(p＜0.05)。
实施例3一种双氢青蒿素衍生物对大脑中动脉闭塞模型大鼠缺血灶的影响
大鼠大脑中动脉线栓法建立大鼠MCAO模型。实验动物5％水合氯醛腹腔注射全麻，经颈前正中切口、暴露并分离右侧颈总动脉及颈动脉分叉，眼科剪直视下于颈总动脉剪一小口，将栓线经此小口置入颈总动脉内向前推进至大脑中动脉分叉发出处，梗阻大脑中动脉血流。设置阴性对照组(术后每日腹腔注射生理盐水150mg/kg，Control组)，阳性对照组(术后每日腹腔注射双氢青蒿素水溶液(Dihydro artemisinin,DHA),150mg/kg，DHA组)和实验组(术后每日腹腔注射双氢青蒿素衍生物水溶液(DD)150mg/kg，DD组)。每组六只动物。72h后行小动物7.0T头颅MR检查，检查结果如图4。并做柱状图分析发现：DD组动物脑梗死体积显著低于Control组(p＜0.05)，且DD组动物脑梗死体积明显低于DHA组，但无统计学差异(p＞0.05)。说明同样剂量治疗脑梗死，双氢青蒿素衍生物(DD)较双氢青蒿素具有更好效果。
以上三组动物在注射药物后，活动正常，无明显毒性呈现，连续观察14天无动物发生死亡，三组间无明显的毒性差异。
实施例4一种双氢青蒿素衍生物透过血脑屏障的对比研究
大鼠大脑中动脉线栓法建立大鼠大脑中动脉阻塞模型。实验动物5％水合氯醛腹腔注射全麻，经颈前正中切口、暴露并分离右侧颈总动脉及颈动脉分叉，眼科剪直视下于颈总动脉剪一小口，将栓线经此小口置入颈总动脉内向前推进至大脑中动脉分叉发出处，梗阻大脑中动脉血流。设置阴性对照组(术后每日腹腔注射生理盐水150mg/kg)，阳性对照组(术后每日腹腔注射双氢青蒿素水溶液(Dihydroartemisinin,DHA),150mg/kg)和实验组(术后每日腹腔注射双氢青蒿素衍生物水溶液(DD)150mg/kg)，每组六只动物。72h后取小鼠脑组织匀浆与血浆标本，利用高效液相色谱法检测匀浆脑组织与血浆标本中分别所含注射药物的浓度。双氢青蒿素衍生物组血浆药浓度与双氢青蒿素组对比无显著差异(p＞0.05)。双氢青蒿素衍生物组脑组织药浓度明显高于等剂量双氢青蒿素组(p＜0.05)。同样剂量DD较DHA增加40％的血脑屏障通透率，据此测算，较DHA，DD达到同样神经保护效应，可减少30％用药量。
Claims (8)
1.一种双氢青蒿素衍生物在制备治疗、预防缺血性脑卒中药物中的应用，所述双氢青蒿素衍生物的结构式为：
2.如权利要求1所述应用，所述药物包括所述的双氢青蒿素衍生物。
3.如权利要求2所述应用，所述药物还包括一种或多种药理学上可接受的辅料，所述辅料包括药学领域中常规的稀释剂、赋形剂、填充剂、湿润剂、吸收促进剂、表面活化剂、润滑剂或稳定剂。
4.如权利要求1或2所述应用，所述药物为注射剂。
5.如权利要求4所述应用，所述注射剂为水溶液，药物浓度为150mg/kg。
6.如权利要求1所述应用，所述药物为减轻或消除脑梗塞缺血灶药物。
7.如权利要求1所述应用，所述药物为促进神经干细胞增殖药物。
8.如权利要求1所述应用，所述药物为促进大脑室管膜下区神经干细胞增殖药物。
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