CN106562929A - 一种制备新颖脂质体包裹自旋靶向药用化合物l‑mpbn纳米粒的方法 - Google Patents
一种制备新颖脂质体包裹自旋靶向药用化合物l‑mpbn纳米粒的方法 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- 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)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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- Dispersion Chemistry (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开一种制备脂质体包裹新颖自旋靶向纳米粒(L‑MPBN)化合物的方法,可作为自旋结合探针,也能作靶向干预。合成流程:将4‑羟基苯甲醛、二溴代直链烷烃在碱性条件下进行消去反应,再与三苯基磷反应;在有机溶剂中,将化合物4、2‑硝基‑2‑甲基丙烷、4A分子筛和锌粉在溶剂中混合,滴加冰乙酸,室温搅拌反应,然后置于冰箱冷藏,再分离提纯,得MPBN捕捉剂,再做脂质体包裹,制备成纳米级自旋靶向药用化合物。本发明具有合成步骤较少,原料廉价,产物纯度高及较稳定的特点。
Description
技术领域
本发明涉及一种纳米级脂质体自旋靶向L-MPBN药用化合物的简便制备方法,本发明具有合成步骤较少,原料廉价,产物纯度和稳定性相对较高的特点。其功能可以进入细胞线粒体捕捉自旋信号,并可在体内靶向性进入应激病变脏器,通过对探针捕捉信息的捡测,可观察分析细胞氧化还原微环境的变化信息,并可对病变部位自旋靶向干预。从而可实现对病变部位的预警和对代谢性疾病的早期防治。
利用自旋捕捉技术制备由脂质体包裹的自旋探针类纳米粒,可实现对应激病变组织和肿瘤细胞的有效干预,这是本发明人研究成果的应用转化。
背景技术
机体中不停地产生含氧和含氮的自由基物质(ROS和RNS),它们在生命活动中扮演着极为重要的角色。在生理情况下体内自由基不断产生,也不断被清除,使自由基浓度保持在动态平衡之中。当某些因素导致这一平衡失调时,机体一些部位将出现病变,如癌变、血管硬化、发炎、衰老等。自由基的危害主要是损伤生物大分子。(1)自由基对DNA的损伤:研究证明,自由基引起的细胞内DNA氢链断裂,碱基降解和主链解旋。这些损伤可能是永久性的,也可以被修复,但修复后的DNA突变率远大于正常的DNA的突变率。(2)自由基对生物大分子的损伤:主要通过修饰氨基酸残基,引起结构和空间的构象变化,导致肽链断裂、聚合、变联。(3)自由基对其他大分子的毒性作用:已有研究证明自由基可损伤生物多糖,透明质酸.不饱和脂肪酸等。从而引起一系列疾病发生。
自旋捕捉剂因其与高反应活性的自由基结合生成稳定自由基的特性,自问世以来便在检测自由基,探索自由基及其生物机理的科学研究中大显身手。由于自旋捕捉剂具有一定清除自由基的作用,所以用于治疗自由基损伤引起的疾病应具有非常好的前景。硝酮类化合物在降低和预防生物体系中自由基引起损伤方面的治疗作用已在1990年由OliverC.,Starke-Read P.,Stadman E.,Liu G.,Carncy J.,Floyd R.Natl.Acad.USA(1990)87,5144-5147证明。
传统理论认为,机体内自由基最主要的产生场所位于线粒体内,因为线粒体是细胞能量的提供者。线粒体膜内带负电荷,膜外带正电荷,所以带正电荷的有机小分子可以在电场力的驱动下进入线粒体膜内。基于这种理论,Martin D.Brand等将季膦盐与自旋捕捉剂PBN连接在一起,用以靶向定位于线粒体膜内,干预其中的自由基情况。详见文献:Speroxide Activates Uncoupling Proteins by Generating Carbon-centeredRadicals and initiating Lipid Peroxidation-studies using a mitochondria-targeted spin trap derived fromα-phenyl-N-tert-butylnitron.2003;278(49):48534-48545.其使用的合成路线如式(I)所示。
但此路线需要用到碘代化合物,金属氢化物,存在原料昂贵,反应条件苛刻,制备程序繁琐,产率和产品纯度不高的缺点,这些都严重限制了该领域的研究。且尚未有脂质体处理成稳定的纳米粒可具对胞内氧化还原微环境探测和对病变部分进行有效靶向干预。本发明成功制订了新的简便的合成路线,并制备成稳定性好、毒性小、渗透率提高数十倍有望开发出自旋靶向系列纳米新药。
发明内容
本发明的目的是提供一种简便,成本低廉的高纯度的制备L-MPBN的方法。
即提供一种制备线粒体靶向定位和脂质体包裹的新颖自旋捕捉剂方法。
其步骤为:
1)将对羟基苯甲醛和二溴代直链烷烃在碱性条件下反应,得到式1结构的化合物
2)将式(I)结构的化合物与三苯基磷在溶剂中反应得到式2结构的季膦盐。
3)在溶剂中,冰浴条件下,将式(II)结构的季膦盐、2硝基-2烷基丙烷和锌粉按1/3/10的当量比混合,再加入4A分子筛,然后滴加冰乙酸,冰乙酸与季膦盐的当量比为5/1,1小时内滴加完成,加完后继续在冰浴下搅拌6小时,然后置于4摄氏度冰箱存放,再过柱分离。得式(III)。
4)将式(III)与卵磷脂、胆固醇以适量的溶剂溶解,于水浴减压蒸溜,除去溶剂成分,得到干燥的脂质膜。真空干燥后,加入PBS缓冲液,得乳白色的脂质体混悬液。将其放入恒温振荡箱中振荡一定时间,水化后,再超声适当时间即得L-MPBN目标产物。
步骤1)所述碱为有机碱或无机碱,有机碱为二乙胺、三乙胺、吡啶、二异丙基胺、2,4,6-三甲基吡啶、四丁基氟化铵;所述无机碱为碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾或氢化钠。
步骤1)所述的反应时间为10分钟—两周。
步骤2)反应的溶剂为乙醇、甲醇、苯、甲苯或者丙酮,反应时间为10分钟—两周。
步骤3)所述的冰箱存放时间为1小时—两周。
步骤4)所述目标物用脂质体处理制备成20-500纳米的自旋探针用于对细胞内氧化还原微环境的检测和干预。
步骤4)混和溶剂为乙醇、甲醇、乙腈、乙醚、氯仿或者丙酮。
步骤4)所述超声时间为5-60分钟
本发明原料价格低廉,反应条件温和,反应步骤较短,中间体纯化简便,产物纯度高,可应用于对病变部位预警和早期干预。本方法易于实现大量合成,可实现商品化生产。
附图说明
图1是L-MPBN对肿瘤细胞抑制试验流式细胞仪检测比较图A空白组,B游离自旋捕捉剂组,C脂质体包裹纳米粒
图2是L-MPBN合成流程图
图3是MPBN的核磁共振氢谱图。
图4是L-MPBN纳米粒的电镜图和粒径分布图,A电镜图,B粒径分布图
具体实施方式
实施例MitoPBN的合成
1)4—(4—溴丁氧基)苯甲醛的合成:在250mL反应瓶中加入对羟基苯甲醛2.0克(16.4mmol),4.5克(32.8mmol,2eq)无水碳酸钾,2.5mL的1,4-二溴丁烷及50毫升DMF,反应12小时后,反应液倒入150mL冰水中,用乙酸乙酯萃取(50mL×4),合并有机相,用100mL水洗一次。有机相用无水硫酸镁干燥后,过滤,减压蒸馏得浓缩粗产物。粗产物用硅胶柱色谱进行分离提纯(洗脱剂:乙酸乙酯/石油醚=1/3)。得产物3.1g,产率73%。1H NMR(400MHz,CDCl3):δ9.84(s,1H),7.78(d,J=5.6Hz,2H),6.95(d,J=3.2Hz,2H),4.04(t,2H),3.46(t,2H),2.01-2.05(m,2H),1.93-1.97(m,2H)。
2)季膦盐A的合成:
在100mL反应瓶中,加入4—(4—溴丁氧基)2.6克(10mmol),三苯基磷7.3g(30mmol,3eq),50mL乙腈,回流12小时。然后将反应液蒸干,加入5mL二氯甲烷溶解,随即倾入50mL乙酸乙酯,有白色沉淀析出,过滤得粗产品。用硅胶柱色谱纯化粗产品(洗脱剂:二氯甲烷/丙酮/甲醇=10/2/1),得纯的季膦盐A 4.3克,产率82.6%。
1H NMR(400MHz,CDCl3):δ9.82(s,1H),7.81-7.85(m,6H),7.74-7.77(m,5H),7.63-7.67(m,6H),6.91(d,J=2.6Hz,2H),4.19(t,J=4.2Hz,2H),3.95(t,J=8.4Hz,2H),2.22-2.27(m,2H),1.82-1.89(m,2H)。
3)MPBN捕捉剂的合成:50mL反应瓶中加入季膦盐A 0.5克(1mmol),活化锌粉0.65克(10mmol,10eq),2—硝基—2—甲基丙烷0.3克(3mmol,3eq),4A分子筛1克,无水乙醇10mL。滴液漏斗中加入5mL乙醇,0.3克冰乙酸,在冰浴下,1小时内将滴液漏斗中的溶液滴加至反应瓶中。冰浴下反应12小时,然后转移至4℃冰箱冷藏7天。过滤,滤渣用5mL无水乙醇洗涤,减压浓缩滤液得粗产物。粗产物用硅胶柱色谱纯化(洗脱剂:二氯甲烷/丙酮/甲醇=10/2/1),得纯的MPBN 0.27克,产率48%。1H NMR(400MHz,CDCl3):δ8.24(d,J=3.8Hz,1H),7.80-7.84(m,6H),7.75-7.76(m,3H),7.64-7.68(m,6H),7.49(s,1H),6.84(d,J=3.8Hz,2H),4.15(t,J=4.4Hz,2H),3.91(t,J=11.2Hz,2H),2.22-2.27(m,2H),1.8-1.88(m,2H),1.60(s,9H)。
4)L-MPBN脂质体纳米粒的制备:采用薄膜分散-超声法,取脂质50mg(卵磷脂、胆固醇质量比2:1)和5mg MPBN,溶于10ml氯仿中,于水浴减压蒸溜,除去溶剂成分,在瓶壁形成均匀的脂质薄膜。真空干燥后,加入10mlPBS缓冲液,旋转振摇搅拌,得均匀的乳白色的脂质体混悬液。将其放入恒温振荡箱中振荡2h,使其充分水化后,再超声20分钟,即得L-MPBN脂质体混悬液。
Claims (11)
1.制备脂质体包裹自旋靶向药用化合物L-MPBN纳米粒的方法,其特征在于包括以下步骤
2.根据权利要求1所述的方法,其特征在于步骤1)所述碱为有机碱或无机碱,有机碱为二乙胺、三乙胺、吡啶、二异丙基胺、2,4,6-三甲基吡啶、四丁基氟化铵;所述无机碱为碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾或氢化钠。
3.根据权利要求1所述的方法,其特征在于步骤1)所述的反应时间为10分钟—两周。
4.根据权利要求1所述的方法,其特征在于步骤2)反应的溶剂为乙醇、甲醇、乙腈、苯、甲苯或者丙酮。
5.根据权利要求1所述的方法,其特征在于步骤2)所述的反应时间为10分钟—两周。
6.根据权利要求1所述的方法,其特征在于步骤3)所述的冰箱存放时间为1小时—两周。
7.根据权利要求1所述的方法,其特征在于步骤4)把自旋探针MPBN经脂质体处理,使粒径做到20至500纳米,用于进入细胞捕捉自旋信号,改变细胞和组织氧化还原微环境。
8.根据权利要求1所述的方法,其特征在于步骤4)混合适量溶剂为乙醇、甲醇、乙腈、乙醚、氯仿或者丙酮。
9.根据权利要求1所述的方法,其特征在于步骤4)超声时间为5-60分钟。
10.根据权利要求1所述的方法,其特征在于步骤4)混合适量溶剂为乙醇、甲醇、乙腈、乙醚、氯仿或者丙酮。
11.根据权利要求1所述的方法,其特征在于步骤4)超声时间为5-60分钟。
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