CN115068486A - 乳香酸类化合物作为ltb4受体抑制剂的用途 - Google Patents
乳香酸类化合物作为ltb4受体抑制剂的用途 Download PDFInfo
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- CN115068486A CN115068486A CN202110277275.XA CN202110277275A CN115068486A CN 115068486 A CN115068486 A CN 115068486A CN 202110277275 A CN202110277275 A CN 202110277275A CN 115068486 A CN115068486 A CN 115068486A
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- boswellic acid
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- carbonyl
- methanol
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明属于医药技术领域,公开了从乳香(Boswellia sacra Flueck)树脂中提取分离得到化合物11‑羰基‑β‑乙酰乳香酸和β‑乙酰乳香酸的方法;并对11‑羰基‑β‑乙酰乳香酸和β‑乙酰乳香酸进行了作用靶标研究,发现其在LTB4R抑制剂模型中具有显著抑制作用,因此本发明公开了11‑羰基‑β‑乙酰乳香酸和β‑乙酰乳香酸及其药学上可接受的盐和药物组合物在制备LTB4受体抑制剂中的应用,以及在制备治疗肥胖、胰岛素抵抗、糖耐量异常,高血脂,糖尿病及其并发症等疾病药物中的应用,其中糖尿病并发症包括糖尿病肾病、糖尿病心血管并发症、糖尿病性脑血管病、糖尿病眼部并发症和糖尿病足。
Description
技术领域
本发明属于医药技术领域,涉及从中药乳香中分离纯化乳香酸类化合物(包括11-羰基-β-乙酰乳香酸和β-乙酰乳香酸)的方法,及11-羰基-β-乙酰乳香酸(AKBA)和β-乙酰乳香酸在制备LTB4受体抑制剂中的应用;以及在制备治疗肥胖、胰岛素抵抗、糖耐量异常,高血脂,糖尿病及其并发症等疾病药物中的应用,其中糖尿病并发症包括糖尿病肾病、糖尿病心血管并发症、糖尿病性脑血管病、糖尿病眼部并发症和糖尿病足。
背景技术
糖尿病是以慢性高血糖为主要特征的一组内分泌代谢性疾病,可能导致身体各部位的并发症并会提升过早死亡的风险。近年来,随着我国经济的高速发展,人口社会的老龄化、环境污染、不良的生活方式以及过高的精神压力等因素的影响,糖尿病在我国日益恶化。糖尿病几乎无法完全治愈,其并发症会给患者带来生理伤害,精神痛苦,生活质量下降等,并且高昂持续的医疗费用会为患者及其家庭带来巨大经济负担。因此,糖尿病治疗研究迫在眉睫。
糖耐量异常(IGT)和空腹血糖受损(IFG)指血糖水平高于正常范围但还不到诊断标准,统称为糖调节受损,通常也被称为糖尿病前期。出现IGT和IFG的警示意义在于三方面:(1)发展为2型糖尿病的高风险;(2)心血管疾病风险增加;(3)提醒通过干预措施预防疾病发展。从IGT和IFG发展为2型糖尿病的风险受到年龄、体重等因素的影响,诊断IGT或IFG五年后发展为2型糖尿病的累积发生率分别约为26%和50%。肥胖、体力活动较少、血脂增高以及有糖尿病家族史和高胰岛素血症者,多为诱发糖耐量减低的危险因素。
所有2型糖尿病患者,几乎都要经过糖耐量减低这个阶段,故有人把糖耐量减低者视为糖尿病发病的高危人群,或者称“糖尿病前期”。糖耐量减低往往还同时伴有肥胖、高血压、高脂血症等情况。糖耐量异常者与正常人群比较,高血压、肥胖患病率要高2倍,而冠心病患病率则高8倍之多。
遏制糖尿病,须从防治糖耐量异常(IGT)着手。生活方式的改变包括饮食控制、运动增加、体重减轻、戒烟等是最基本的干预措施。相关研究报道,IGT者经过生活方式干预,3年后糖尿病发病率降低了58%,同时血压、体重较前亦明显下降,而未经任何干预措施的IGT者糖尿病发病率高达68%。最近对IGT人群的干预试验表明,药物干预IGT人群不仅显著降低糖尿病发病率,还可明显减少脑血管疾病(Cerebrovascular Disease,CVD)的危险性,其中新发生高血压降低34%,心肌梗死降低9%,任何心血管事件降低49%。因此,IGT患者诊断明确后,应主动就医,医生会根据病情选择恰当的治疗方案及药物,积极治疗高血糖及相关危险因素。
因此,早期采取针对性的IGT干预措施,有助于逆转IGT,降低IGT进展为糖尿病的风险,减少CVD的发生。
临床上将糖尿病主要分为3种类型:1型、2型及妊娠糖尿病,其中2型糖尿病最为常见,约占85%-95%,甚至更高。2型糖尿病的主要特征是胰岛素抵抗。胰岛素抵抗是肝脏、肌肉和脂肪组织等周围靶组织细胞对胰岛素的敏感性降低导致葡萄糖摄取和利用效率下降而产生的一种慢性亚临床性的炎症过程。细胞内的炎症因子,分泌各种可能削弱胰岛素信号的因素,使胰岛素信号的传导受到阻碍,诱发了胰岛素抵抗。2型糖尿病患者炎症因子和胰岛素抵抗脂联素水平的实验研究表明,2型糖尿病患者存在慢性炎症状态。因此,改善炎症诱导的胰岛素抵抗,提高胰岛素敏感性,便成了治疗2型糖尿病患者的重大问题。
炎症因子白三烯B4(LTB4)是一种与炎症反应相关的白三烯类物质,由花生四烯酸经过5-脂氧合酶,5-脂氧合酶激活蛋白,白三烯A4水解酶有序催化产生。LTB4对巨噬细胞,嗜中性粒细胞和T细胞有强效的趋化性。LTB4可以通过活化和募集巨噬细胞,嗜酸性粒细胞,效应T细胞等,促进炎症的发生发展。同时能够诱导中性粒细胞中的溶酶体及活性氧类的形成与释放。
LTB4通过与G蛋白偶联受体Ltb4r1或Ltb4r2结合发挥趋化作用,调节促炎因子释放等生物学功能。Ltb4r1(也称为Blt1)是特异于LTB4的高亲和力受体,在炎症细胞及免疫细胞广泛表达,包括粒细胞,嗜酸性粒细胞,巨噬细胞,Th1细胞,Th2细胞,Th17细胞,CD8效应T细胞,树突状细胞及破骨细胞等。Ltb4r2(也称为Blt2)是低亲和力受体,表达更为广泛。LTB4-Ltb4r1系统在宿主急性感染期具有重要防御作用,降低炎症反应。慢性激活LTB4-Ltb4r1系统可以引起慢性炎症,包括动脉粥样硬化和关节炎等。近期一项研究表明,Ltb4r1基因敲除可以降低小鼠的炎症反应,改善胰岛素抵抗。这表明胰岛素敏感的表型是基于Ltb4r1基因缺失之上的。高胰岛素-正葡萄糖钳夹实验也证实,大多小鼠经Ltb4r1抑制剂处理后表现出更高的胰岛素敏感性。
肥胖是导致胰岛素抵抗的重要因素。流行病学研究亦表明,肥胖是糖尿病的重大危险因素。过度肥胖,巨噬细胞会被过度积累的脂肪激活,激活后的巨噬细胞释放LTB4以及其它炎性分子进而吸引更多的巨噬细胞。这一正向反馈调节机制会产生更多的LTB4。过多的LTB4会激活巨噬细胞以外的其它细胞,像肝细胞,脂肪细胞,肌肉细胞等这些细胞受到刺激从而对胰岛素产生了耐受。在肥胖受试者的内脏脂肪中,巨噬细胞可占总细胞数的40%,并分泌多种可能损害胰岛素信号转导的因子。通过使用巨噬细胞的跟踪技术,发现Ltb4r1抑制剂处理的小鼠巨噬细胞在脂肪组织的标记程度基本上较低。LTB4促进单核细胞迁移入脂肪组织,以剂量依赖的方式刺激巨噬细胞的趋化性,促进胰岛素抵抗。此外,其他免疫细胞类型,如淋巴细胞、嗜酸性粒细胞和中性粒细胞也有助于肥胖组织的炎症状态。这种与细胞因子无关的胰岛素抵抗机制为炎症和胰岛素敏感性降低之间的关系提供了新的机制。
从胰岛素抵抗发生的分子机制来看,能量代谢紊乱、内质网应激、氧化应激、线粒体功能受损、沉默信息调节因子信号通路下调、炎症反应以及中枢调控紊乱等都参与了胰岛素抵抗的发生。胰岛素信号传导通路的障碍作为胰岛素抵抗的本质。葡萄糖转运蛋白4(GLUT4)重要功用是在脂肪和肌肉组织中转送、运输葡萄糖。研究表明,LTB4通过对GLUT4的抑制,导致胰岛素抵抗。LTB4能增强肝二酰甘油(DAG)和神经酰胺的合成,诱导内质网应激和线粒体膜通透性增加,抑制胰岛素信号通路,降低胰岛素敏感性,诱导胰岛素抵抗。同时,DAG增加会提高脂毒性风险,也是导致胰岛素抵抗的重要机制之一。
因此,抑制LTB4的作用有可能成为治疗胰岛素抵抗性疾病的有效方案。及其药学上可接受的盐和药物组合物在治疗肥胖、糖耐量异常,高血脂,糖尿病及其并发症等疾病;和上述疾病所涉及慢性炎症、胰岛素抵抗、脑血管疾病和动脉粥样硬化的应用。
乳香为橄榄科(Burseraceae)乳香属(Boswellia)植物卡氏乳香树(Boswelliacarterii Birdw)、鲍达乳香树(Boswellia bhawdajiana Birdw)、弗里乳香树(Boswelliafereana)、纸乳香树(Boswellia papyrfera)、索科乳香树(Boswellia socotana)、齿叶乳香树(Boswellia serrate)、野乳香树(Boswellia neglecta M.Moor)皮部渗出或经刀割渗出的胶状树脂,主产于索马里、埃塞俄比亚、印度等地。乳香辛散温通,具有调气、活血、止痛、追毒之功效,主治气血凝滞、心腹疼痛、痈疮肿毒、跌打损伤、痛经、产后淤血刺痛等。
乳香在临床上广泛应用于风湿、类风湿性关节炎和骨关节炎的治疗,其药理作用主要有抗炎、抗肿瘤、抗氧化,且其发挥抗炎作用的主要成分为乳香酸类五环三萜化合物,尤其是熊果烷型乳香酸类化合物,该类化合物的优势在于抗炎活性强,毒副作用小。
发明内容
本发明解决的技术问题是提供一类熊果烷型三萜酸化合物11-羰基-β-乙酰乳香酸、β-乙酰乳香酸,该类化合物及其药学上可接受的盐和药物组合物在制备治疗肥胖、糖耐量异常,高血脂,糖尿病及其并发症等疾病药物中的应用,以及在制备预防或治疗上述疾病所涉及慢性炎症、胰岛素抵抗、脑血管疾病和动脉粥样硬化药物中的应用;并提供了一类熊果烷型三萜酸化合物11-羰基-β-乙酰乳香酸、β-乙酰乳香酸在制备LTB4受体抑制剂中的应用。
为解决上述技术问题,本发明提供了如下技术方案:
本发明技术方案的第一方面是提供了一类三萜乳香酸类化合物及其药学上可接受的盐在制备LTB4受体抑制剂中的应用,其特征在于,所述的乳香酸类化合物包括11-羰基-β-乙酰乳香酸、β-乙酰乳香酸;
熊果烷型三萜酸化合物11-羰基-β-乙酰乳香酸、β-乙酰乳香酸在LTB4R抑制剂模型中具有显著活性,表明其作用靶标为LTB4受体BLT1。
本发明技术方案的第二方面是提供了一类三萜乳香酸类化合物及其药学上可接受的盐在制备预防或治疗肥胖、胰岛素抵抗、糖耐量异常、高血脂、糖尿病及其并发症疾病药物中的应用,其特征在于,所述的乳香酸类化合物包括11-羰基-β-乙酰乳香酸、β-乙酰乳香酸;
所述的糖尿病并发症包括糖尿病肾病、糖尿病心血管并发症、糖尿病性脑血管病、糖尿病眼部并发症或糖尿病足本发明技术方案的第三方面是提供了一种从乳香中分离纯化11-羰基-β-乙酰乳香酸和β-乙酰乳香酸的方法,该方法步骤为:
(1)将乳香药材粉碎后以95%乙醇进行加热回流提取,每次提取3h,共提取三次。合并提取液,去除溶剂,得到乳香粗提物。
(2)将乳香粗提物进行硅胶柱层析,依次以石油醚两份、乙酸乙酯两份、95%乙醇两份进行洗脱,每份一个柱体积。得到粗段A-F。
(3)取粗段A进行硅胶柱层析,以石油醚乙酸乙酯梯度进行洗脱,体积比分别为1:0,20:1,4:1,1:1,0:1,每个梯度洗脱两个柱体积。
(4)取(3)中石油醚和乙酸乙酯体积比1:0洗脱的第一份A1,经反相C18硅胶柱层析,以甲醇-水梯度洗脱(60%-100%甲醇),每个梯度洗脱两个柱体积。100%甲醇洗脱流份经甲醇反复重结晶得到11-羰基-β-乙酰乳香酸,结晶母液经反相C18柱制备高效液相法制备,以甲醇和水97:3为流动相进行制备,得到β-乙酰乳香酸。
所得化合物11-羰基-β-乙酰乳香酸和β-乙酰乳香酸结构式分别为:
上述步骤中,步骤(1)乳香药材质量与每次使用的95%乙醇的比为1:3.5(kg/L)。
上述步骤中,步骤(1)中去除溶剂的方法为减压旋转蒸干。
上述步骤中,步骤(4)中反相C18硅胶柱层析使用的甲醇-水梯度体积比为60%甲醇,70%甲醇,80%甲醇,90%甲醇,100%甲醇。
上述步骤中,步骤(4)中C18柱制备高效液相法制备中流速为6ml/min,紫外检测波长为254nm。
本发明技术方案的第四方面是提供了一种药物组合物在制备LTB4受体抑制剂中的应用,所述的药物组合物含有治疗有效剂量的11-羰基-β-乙酰乳香酸、β-乙酰乳香酸及其药学上可接受的盐及药用载体。
本发明还涉及一种含有药物有效剂量所述的化合物和药效学上可接受的载体的药物组合物。用于此目的时,如果需要,可与一种或多种固体或液体药物赋形剂和/或辅剂结合,制成可作为人药使用的适当施用形式或剂量形式。
根据本发明,本发明化合物可以以异构体的形式存在,而且通常所述的“本发明化合物”包括该化合物的异构体。
本发明的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等。
本发明的药物组合物的给药途径可为注射给药。注射包括静脉注射、肌肉注射、皮下注射、皮内注射和穴位注射等。给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
本发明的组合物可以制成普通制剂、也可以是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将单位给药剂型制成片剂,可以广泛使用本领域公知的各种载体。关于载体的例子,例如稀释剂与吸收剂,如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化纳、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等;湿润剂与粘合剂,如水、甘泊、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素纳、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等;崩解剂,例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢纳与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等;崩解抑制剂,例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等;吸收促进剂,例如季铵盐、十二烷基硫酸纳等;润滑剂,例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成丸剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等;粘合剂,如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等;崩解剂,如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。
为了将给药单元制成栓剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如聚乙二醇、卵磷脂、可可脂、高级醇、高级醇的酶、明胶、半合成甘油酶等。
为了将给药单元制成胶囊,将有效成分与上述的各种载体混合,并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分制成微囊剂,混悬于水性介质中形成混悬剂,亦可装入硬胶囊中或制成注射剂应用。
例如,将本发明的组合物制成注射用制剂,如溶液剂、混悬剂溶液剂、乳剂、冻干粉针剂,这种制剂可以是含水或非水的,可含一种和/或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂或分散剂。如稀释剂可选自水、乙醇、聚乙二醇、1,3一丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酶等。另外,为了制备等渗注射液,可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油,此外,还可以添加常规的助溶剂、缓冲剂、pH调节剂等。这些辅料是本领域常用的。
此外如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
本发明药用组合物的给药剂量取决于许多因素,例如所要预防或治疗疾病的性质和严重程度,患者或动物的性别、年龄、体重、性格及个体反应,给药途径、给药次数等,因此本发明的治疗剂量可以有大范围的变化。一般来讲,本发明化合物使用剂量是本领域技术人员公知的。可以根据本发明药用组合物中最后的制剂中所含有的实际有效药物数量,加以适当的调整,以达到其治疗有效量的要求,完成本发明在治疗肥胖、糖耐量异常,高血脂,糖尿病及其并发症等疾病;和上述疾病所涉及慢性炎症、胰岛素抵抗、脑血管疾病和动脉粥样硬化的应用。
通常对体重约75公斤患者,所给本发明化合物的日剂量为0.001mg/kg体重~200mg/kg体重,优选1mg/kg体重~100mg/kg体重。上述剂量可以单一剂量形式或分成几个,例如二、三或四个剂量形式给药,这受限于给药医生的临床经验以及给药方案。本发明的化合物或组合物可单独服用,或与其它治疗药物或对症药物合并使用。
有益技术效果
本发明首次发现从乳香中分离纯化得到熊果烷型三萜酸化合物11-羰基-β-乙酰乳香酸、β-乙酰乳香酸具有显著抗糖尿病活性,且作用靶标为LTB4受体,上述化合物具有较好的制备抗糖尿病药物的应用前景。
附图说明
本申请的附图用来提供对本申请的进一步说明,本申请的示意性实施例及其说明用来解释本申请,并不构成对本申请的不当限定。
图1. 11-羰基-β-乙酰乳香酸的1H NMR
图2. 11-羰基-β-乙酰乳香酸的13C NMR
图3. 11-羰基-β-乙酰乳香酸的MS
图4.β-乙酰乳香酸的1H NMR
图5.β-乙酰乳香酸的13C NMR
图6.β-乙酰乳香酸的MS
图7. 11-羰基-β-乙酰乳香酸口服给药4周明显改善ob/ob小鼠糖耐量。(A)IPGTT(B)血糖曲线下面积(C)空腹血糖(D)体重。*P 0.05,**P 0.01,***P 0.001VS对照组
图8. 11-羰基-β-乙酰乳香酸腹腔给药2周明显改善ob/ob小鼠糖耐量。(A)IPGTT(B)血糖曲线下面积(C)空腹血糖(D)体重。*P<0.05,**P<0.01,***P<0.001VS对照组
图9. 11-羰基-β-乙酰乳香酸给药3周改善ob/ob小鼠胰岛素耐量。(A)ITT(B)血糖曲线下面积。*P 0.05,**P 0.01VS对照组
图10. 11-羰基-β-乙酰乳香酸改善ob/ob小鼠胰岛素抵抗。(A)血糖基化血红蛋白(HbA1c)(B)血胰岛素(C)胰岛素抵抗指数。*P 0.05,**P 0.01VS对照组
图11. 11-羰基-β-乙酰乳香酸给药4周对改善脂质紊乱。(A)血总胆固醇(B)低密度脂蛋白胆固醇(C)血甘油三酯(D)肝脏指数。*P<0.05,**P<0.01VS对照组
图12. 11-羰基-β-乙酰乳香酸给药4周对改善ob/ob小鼠肾功能。(A)心脏指数(B)血肌酐。*P<0.05,**P<0.01VS对照组
具体实施方式
为进一步阐述本发明,下面以具体实例对本发明进行详细说明,这些实施例完全是例证性的,旨在对本发明作具体描述,非意图限制根据本申请的示例性实施方式。
本申请的一种实施方式,提供了一种从乳香中分离纯化熊果烷型三萜酸化合物11-羰基-β-乙酰乳香酸、β-乙酰乳香酸的方法,步骤为:
(1)将乳香药材粉碎后以95%乙醇进行加热回流提取,每次提取3h,共提取三次。合并提取液,去除溶剂,得到乳香粗提物。
(2)将乳香粗提物进行硅胶柱层析,依次以石油醚两份、乙酸乙酯两份、95%乙醇两份进行洗脱,每份一个柱体积。得到粗段A-F。
(3)取粗段A进行硅胶柱层析,以石油醚乙酸乙酯梯度进行洗脱,体积比分别为1:0,20:1,4:1,1:1,0:1,每个梯度洗脱两个柱体积。
(4)取(3)中石油醚和乙酸乙酯体积比1:0洗脱的第一份A1,经反相C18硅胶柱层析,以甲醇-水梯度洗脱(60%-100%甲醇),每个梯度洗脱两个柱体积。100%甲醇洗脱流份经甲醇反复重结晶得到11-羰基-β-乙酰乳香酸,结晶母液经反相C18柱制备高效液相法制备,以甲醇和水97:3为流动相进行制备,得到β-乙酰乳香酸。
所得化合物11-羰基-β-乙酰乳香酸和β-乙酰乳香酸结构式分别为:
优选的,步骤(1)乳香药材质量与每次使用的95%乙醇的比为1:3.5(kg/L)。
优选的,步骤(1)中去除溶剂的方法为减压旋转蒸干。
优选的,步骤(4)中反相C18硅胶柱层析使用的甲醇-水梯度体积比为60%
甲醇,70%甲醇,80%甲醇,90%甲醇,100%甲醇。
优选的,步骤(4)中C18柱制备高效液相法制备中流速为6ml/min,紫外检测波长为254nm。
实施例1
11-羰基-β-乙酰乳香酸和β-乙酰乳香酸制备方法,步骤如下:
(1)取乳香药材19.0kg粉碎后以95%乙醇进行加热回流提取,固液比为1:3.5(kg/L),每次提取3h,共提取三次。合并提取液,减压旋转蒸干溶剂,得到乳香粗提物。
(2)将乳香粗提物进行硅胶柱层析,依次以石油醚两份、乙酸乙酯两份、95%乙醇两份进行洗脱,每份接收一个柱体积,约35L。得到粗段A-F。
(3)取粗段A进行硅胶柱层析,以石油醚乙酸乙酯梯度进行洗脱,体积比分别为1:0,20:1,4:1,1:1,0:1,每个梯度洗脱两个柱体积,每份接收一个柱体积,约5L。
(4)取(3)中石油醚和乙酸乙酯体积比1:0洗脱的第一份A1,经反相C18硅胶柱层析,依次用60%甲醇,70%甲醇,80%甲醇,90%甲醇,100%甲醇洗脱,每个梯度洗脱两个柱体积。100%甲醇洗脱流份经甲醇反复重结晶得到11-羰基-β-乙酰乳香酸,结晶母液经反相C18柱制备高效液相法制备,以MeOH/H2O(97:
3)为流动相进行制备,流速为6ml/min,检测波长为254nm,得到β-乙酰乳香酸。
结构鉴定:对分离得到的化合物通过核磁共振氢谱,核磁共振碳谱,质谱等方法确定了其结构。
11-羰基-β-乙酰乳香酸:无色针状结晶。mp 268-270℃;EI-MS m/z[M]+512,提示其分子式为C32H48O5。1H NMR(400MHz CDCl3)δH 5.55(1H,s,H-12),5.30(1H,brs,H-3),2.08(3H,s,CH3CO-),1.23(3H,s,CH3-23),1.14(3H,s,CH3-25),1.19(3H,s,CH3-26),1.34(3H,s,CH3-27),0.82(3H,s,CH3-28),0.79(3H,d,J=6.3Hz,CH3-29),0.94(3H,s,CH3-30).13C NMR(100MHz CDCl3)δC 34.6(C-1),23.5(C-2),73.0(C-3),46.5(C-),50.4(C-5),18.7(C-6),32.8(C-7),43.8(C-8),63.3(C-9),37.4(C-10),199.2(C-11),130.5(C-12),165.0(C-13),45.1(C-14),27.5(C-15),27.2(C-16),34.0(C-17),59.0(C-18),39.31(C-19),39.27(C-20),46.5(C-21),40.9(C-22),23.8(C-23),181.8(C-24),13.2(C-25),18.4(C-26),21.1(C-27),28.8(C-28),17.4(C-29),20.5(C-30),21.33(CH3CO-),170.2(CH3CO-).与参考文献(Wang F.,Li Z.L.,Cui H.H.Two new triterpenoids from the resin of Boswelliacarterii[J].J.Asian Nat.Prod.Res.,2011,13(3):193-197.)中报道的数据一致,确定化合物为11-羰基-β-乙酰乳香酸。
β-乙酰乳香酸:无色结晶。mp 268-270℃;EI-MS m/z[M]+498,提示其分子式为C32H50O4。1H NMR(400MHz CDCl3)δH 5.31(1H,t,J=2.4Hz,H-3),5.15(1H,t,J=3.6Hz,H-12),2.10(3H,s,CH3 CO-),1.24(3H,s,CH3-23),1.12(3H,s,CH3-27),1.05(3H,s,CH3-26),0.91(3H,s,CH3-25,30),0.81(3H,s,CH3-28,29)。13C NMR(125MHz CDCl3)δC 34.6(C-1),23.5(C-2),73.3(C-3),46.9(C-4),50.7(C-5),19.7(C-6),33.1(C-7),40.1(C-8),46.7(C-9),37.5(C-10),23.8(C-11),124.6(C-12),139.6(C-13),42.4(C-14),28.2(C-15),26.6(C-16),33.9(C-17),59.3(C-18),39.7(C-19),39.8(C-20),31.4(C-21),41.6(C-22),23.4(C-23),182.0(C-24),13.4(C-25),17.0(C-26),23.7(C-27),28.9(C-28),17.6(C-29),21.5(C-30),21.4(CH3 CO-),170.4(CH3 CO-);与文献(Wang F.,Li Z.L.,Cui H.H.Two newtriterpenoids from the resin of Boswellia carterii[J].J.Asian Nat.Prod.Res.,2011,13(3):193-197.)报道的数据一致,确定化合物为β-乙酰乳香酸。
实验例1药理学实验:测定熊果烷型三萜酸化合物11-羰基-β-乙酰乳香酸、β-乙酰乳香酸对LTB4R抑制剂模型的作用。
LTB4R是白三烯B4(LTB4)的受体,隶属于GPCR家族。当LTB4结合LTB4R时,LTB4R会募集对应的G-protein Gα16介导下游的信号通路,引起内质网中钙离子的释放到细胞质中。通过Fluo-8钙离子荧光螯合剂结合细胞质中的钙离子后发出荧光,可以在488/525nm下检测荧光信号,确定LTB4R信号通路的激活。当加入LTB4R的抑制剂时,该信号通路不激活,就不会看到荧光信号的变化。
我们用DMSO和化合物处理过表达LTB4R和Gα16的仓鼠卵巢癌细胞(CHO)。通过孵育Fluo-8使之进入细胞质,加入LTB4刺激后比较钙离子信号的上升程度。如果低于DMSO处理的细胞,说明化合物有一定的抑制效果。如果和DMSO接近,说明没有抑制效果。再通过cell-titer试剂盒确定化合物对细胞没有毒性,即可证明化合物对于LTB4R有抑制效果。
实验样品
被测样品溶液的配置:测试样品为11-羰基-β-乙酰乳香酸、β-乙酰乳香酸。准确称取适量样品,使用DMSO配制成0.1M的储存溶液,供药理活性测试。
细胞株:仓鼠卵巢癌细胞CHO细胞
[实验材料及试剂]:
试剂:胎牛血清,DMED培养基,DMSO,Fluo-8 NW检测试剂盒,化合物,LTB4,CP-105956
材料:黑色透明底96孔细胞培养板,6cm细胞培养皿
[实验仪器]
CO2培养箱,酶标仪(带有滴定功能)
1.实验方法
(1)LTB4R抑制剂模型建立:
1)选用对数生长期的贴壁CHO细胞,胰酶消化后用含10%胎牛血清的DMEM培养液,接种在6cm细胞培养皿中。待细胞汇合度达到70-80%,转染3ug LTB4R-pReceiver和1.5ugGα16-pReceiver质粒进细胞。
2)转染36小时后,胰酶消化收集细胞,并用含10%胎牛血清的DMEM培养液重悬按照每孔50,000个细胞铺入黑色透明底96孔细胞培养板中,37℃,5%CO2培养12h。
3)第二日,将培养基替换含0.5%胎牛血清的DMEM培养液,按照设计分别加入DMSO,不同浓度的11-羰基-β-乙酰乳香酸、β-乙酰乳香酸及阳性对照。37℃,5%CO2培养2h。
4)加入Fluo-8孵育30分钟。设置酶标仪,在488/525nm下读取6s静息状态下的钙信号后,滴加LTB4进细胞孔,滴加LTB4的终浓度为400nM,继续在488/525nm下读取45s受到刺激后钙离子信号的变化。
(2)实验分组:实验组加入不同浓度的11-羰基-β-乙酰乳香酸和β-乙酰乳香酸,对照组则加入等体积溶剂的DMSO,DMSO比例不超过1%.
(3)细胞毒性的检测方法:
1)通过LTB4R抑制剂模型建立中步骤1)的方法建立可以对LTB4响应的LTB4R和Gα16共表达的CHO细胞系。
2)转染36小时后,胰酶消化收集细胞,并用含10%胎牛血清的DMEM培养液重悬按照每孔50,000个细胞铺入白色透明底96孔细胞培养板中。
3)加入DMSO,11-羰基-β-乙酰乳香酸和β-乙酰乳香酸。其中11-羰基-β-乙酰乳香酸、β-乙酰乳香酸的终浓度为10uM,DMSO加入相同体积。37℃,5%CO2培养过夜。
4)加入新鲜配置的Cell-titer化学发光检测试剂,迅速通过酶标仪读取荧光值。如果细胞死亡,则荧光值降低
2.实验结果
[结果计算]
1)钙信号增长系数(Ca)=后45s钙信号最大值/前6s钙信号平均值
LTB4R抑制率(%)=(CaDMSO-Ca化合物)/(CaDMSO-Ca无LTB4)X 100%
2)化合物毒性计算:
化合物毒性=1-LUM化合物/LUMDMSO
11-羰基-β-乙酰乳香酸、β-乙酰乳香酸在10μΜ浓度下对CHO细胞毒性较低或无毒性,且均具有显著抑制作用。其中11-羰基-β-乙酰乳香酸抑制LTB4R效果最佳。
以上所述仅为本申请的优选示例,不用于限制本申请。在本申请的中心思想和原则内对本申请所作的任何修改、等同替换、改进等,均应包含在本申请保护范围内。
表1.化合物对LTB4R抑制剂模型中对CHO细胞的影响
实验例2 11-羰基-β-乙酰乳香酸小鼠体内药效总结
1.实验方法:
1.1动物分组及给药
ob/ob小鼠30只,根据空腹血糖、体重和胰岛素耐量40min血糖下降百分数等3个指标,将动物随机分为3组:对照组、阳性药罗格列酮组(3mg/kg)和11-羰基-β-乙酰乳香酸(300mg/kg),每组10只,按照0.1ml/10g体重口服灌胃给药,每日一次,连续给药4周,做腹腔注射葡萄糖耐量实验(IPGTT)。之后11-羰基-β-乙酰乳香酸剂量改为10mg/kg,每天一次按照0.2ml/10g体重腹腔注射,连续给药2周后,做腹腔注射葡萄糖耐量实验(IPGTT)。连续给药3周后做胰岛素耐量实验(ITT)。连续给药四周后取材,称重心脏、肝脏、测量血中总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、甘油三酯(TG)、糖基化血红蛋白(HbA1c)、胰岛素和肌酐,计算胰岛素抵抗指数。
1.2血糖检测
使用罗氏卓越型血糖仪ACCU-CHEK Performa及配套试纸条检测。
1.3 IPGTT
动物禁食6h(禁食5h时给药),测0min血糖,腹腔给予葡萄糖溶液(1g/kg),尾尖取血测糖负荷后15min,30min,60min,90min,120min血糖。
1.4 ITT
动物禁食6h(禁食5h时给药),测0min血糖,皮下注射胰岛素(0.4IU/kg),尾尖取血测注射胰岛素后15min,30min,60min,90min,120min血糖。
1.5 TC检测
取小鼠10倍稀释血样,按照试剂盒(中生北控生物科技股份有限公司)说明书测定。
1.6 LDL-C检测
取小鼠10倍稀释血样,然后按试剂盒(中生北控生物科技股份有限公司)说明书测定。
1.7 TG检测
取小鼠10倍稀释血样,按照试剂盒(中生北控生物科技股份有限公司)说明书测定。
1.8 HbA1c检测
取EDTA抗凝全血,然后按试剂盒(北京豪迈生物工程有限公司)说明书测定。
1.9胰岛素检测
小鼠血浆稀释2倍,然后按试剂盒说明书(ALPCO)测定。
1.10肌酐检测
取EDTA抗凝全血,然后按试剂盒(中生北控生物科技股份有限公司)说明书测定。
1.11胰岛素抵抗指数计算
HOMA-IR=空腹血糖(mmol/l)空腹胰岛素(uU/ml)/22.5。
2.实验结果
2.1如图7所示,口服给药4周后,阳性药罗格列酮显著改善ob/ob小鼠葡萄糖耐量,与对照组相比,11-羰基-β-乙酰乳香酸(300mg/kg)亦明显降低ob/ob小鼠空腹血糖以及糖负荷后血糖水平,改善葡萄糖耐量,血糖曲线下面积也明显降低,给药4周对小鼠体重无明显影响。
2.2如图8所示,腹腔注射给药2周后,与对照组相比,11-羰基-β-乙酰乳香酸(300mg/kg)亦明显降低ob/ob小鼠空腹血糖以及糖负荷后血糖水平,改善葡萄糖耐量,血糖曲线下面积也明显降低,给药2周对小鼠体重无明显影响。
2.3如图9所示,腹腔注射给药3周后,与对照组相比,11-羰基-β-乙酰乳香酸20mg/kg显著降低ob/ob小鼠空腹血糖,改善小鼠胰岛素耐量,血糖曲线下面积也明显降低。
2.4如图10所示,腹腔注射给药4周后,11-羰基-β-乙酰乳香酸明显降低糖基化血红蛋白水平,同时降低ob/ob小鼠的高胰岛素血症,明显降低ob/ob小鼠胰岛素抵抗指数。且这些作用与阳性药罗格列酮相当。
2.5如图11所示,阳性药罗格列酮明显增加ob/ob小鼠血总胆固醇(TC)和低密度脂蛋白胆固醇(LDL-C)水平,而11-羰基-β-乙酰乳香酸不增加LDL-C,降低TC。阳性药罗格列酮降低血甘油三酯(TG),但明显增加肝脏重量,提示增加肝脏脂质合成;而11-羰基-β-乙酰乳香酸在改善甘油三酯的同时还降低肝脏重量。
2.6如图12所示罗格列酮增加ob/ob小鼠的心脏指数,提示罗格列酮增加水肿和心脏肥大。而11-羰基-β-乙酰乳香酸不增加ob/ob小鼠的心脏指数。与罗格列酮相比,11-羰基-β-乙酰乳香酸还可明显降低ob/ob小鼠的血肌酐水平,提示11-羰基-β-乙酰乳香酸改善ob/ob小鼠肾功能。
3.实验结论
(1)11-羰基-β-乙酰乳香酸给药2-4周明显改善ob/ob小鼠胰岛素抵抗。改善葡萄糖耐量改善胰岛素耐量,降低ob/ob小鼠高胰岛素血症和胰岛素抵抗指数。
(2)11-羰基-β-乙酰乳香酸给药2-4周可明显降低糖尿病小鼠空腹血糖。
(3)11-羰基-β-乙酰乳香酸给药2-4周对体重没有明显影响。
(4)与阳性药罗格列酮不同,11-羰基-β-乙酰乳香酸可改善ob/ob小鼠脂质紊乱,降低胆固醇和甘油三脂。
(5)与阳性药罗格列酮不同,11-羰基-β-乙酰乳香酸不增加ob/ob心脏指数,还可改善糖尿病小鼠肾功能。
Claims (9)
3.根据权利要求2的应用,其特征在于,所述的糖尿病并发症包括糖尿病肾病、糖尿病心血管并发症、糖尿病性脑血管病、糖尿病眼部并发症或糖尿病足。
5.根据权利要求4的应用,其特征在于,所述的药物组合物选自片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂、及各种微粒给药系统。
6.一种从乳香中提取分离纯化得到权利要求1的11-羰基-β-乙酰乳香酸和β-乙酰乳香酸的制备方法,该方法包括以下步骤:
(1)将乳香药材粉碎后以95%乙醇进行加热回流提取,每次提取3h,共提取三次,合并提取液,去除溶剂,得到乳香粗提物;
(2)将乳香粗提物进行硅胶柱层析,依次以石油醚两份、乙酸乙酯两份、95%乙醇两份进行洗脱,每份一个柱体积,得到粗段A-F;
(3)取粗段A进行硅胶柱层析,以石油醚乙酸乙酯梯度进行洗脱,体积比分别为1:0,20:1,4:1,1:1,0:1,每个梯度洗脱两个柱体积;
(4)取(3)中石油醚和乙酸乙酯体积比1:0洗脱的第一份A1,经反相C18硅胶柱层析,以60%-100%甲醇-水梯度洗脱,每个梯度洗脱两个柱体积;100%甲醇洗脱流份经甲醇反复重结晶得到11-羰基-β-乙酰乳香酸,结晶母液经反相C18柱制备高效液相法制备,以甲醇和水97:3为流动相进行制备,得到β-乙酰乳香酸。
7.如权利要求6所述的方法,其特征是,步骤(1)乳香药材质量与每次使用的95%乙醇的比为1:3.5kg/L。
8.如权利要求6所述的方法,其特征是,步骤(4)中反相C18硅胶柱层析使用的甲醇-水梯度体积比为60%甲醇,70%甲醇,80%甲醇,90%甲醇,100%甲醇。
9.如权利要求6所述的方法,其特征是,步骤(4)中C18柱制备高效液相法制备中流速为6ml/min,紫外检测波长为254nm。
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