CN116492334A - 2,2':5',2''-三噻吩-5-羧酸在制备降脂减肥药物中的应用 - Google Patents
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
本发明涉及2,2':5',2”‑三噻吩‑5‑羧酸在制备降脂减肥药物中的应用。本发明利用小鼠来源的原代脂肪细胞分化技术建立抗肥胖药物的细胞筛选模型进行筛选,首次发现2,2':5',2”‑三噻吩‑5‑羧酸具备显著的降脂减肥、抗肥胖活性。体内外实验表明,2,2':5',2”‑三噻吩‑5‑羧酸可以有效促进白色脂肪细胞棕色化,提高细胞产热程序关键基因的表达,提升小鼠的呼吸能力,显著降低小鼠体重,减少小鼠脂肪组织含量,增强小鼠适应性产热和能量消耗,从而改善小鼠肥胖。并且2,2':5',2”‑三噻吩‑5‑羧酸还能够缓解预防肥胖引发的肝脂肪变性,为临床提供了新的降脂减肥药物,具有较好的临床应用价值和广阔的应用前景。
Description
技术领域
本发明涉及2,2′:5′,2″-三噻吩-5-羧酸在制备降脂减肥药物中的应用,属于医药技术领域。
背景技术
肥胖是由于能量摄入和消耗之间的不平衡引起的。研究发现肥胖不仅能够诱发慢性疾病,包括心血管疾病、糖尿病、胰岛素抵抗、代谢综合征,还能增加患癌症的风险。因此,减肥治疗已成为迫切需要解决的问题。脂肪组织曾被认为是一个被动的脂质储存库。然而,现在人们已经很清楚地认识到,脂肪组织是一个活跃的代谢器官,其在调节全身能量稳态中起关键作用,能够影响包括食物摄入、葡萄糖代谢、胰岛素敏感性、产热以及免疫反应等众多进程。
一直以来,人们认为哺乳动物体内存在两种不同功能和形态的脂肪细胞—白色和棕色脂肪细胞。白色脂肪细胞含有大的单房脂滴和少量线粒体,而棕色脂肪细胞则有大量小的多房脂滴和大量具有高密度嵴结构的线粒体,表明它们具有巨大的产能潜力。冷刺激能够高度激活棕色脂肪细胞的产热活性,促进能量底物(如脂肪和糖)吸收,加快细胞代谢,尤其是线粒体代谢。此外,在成年小鼠中发现部分脂肪祖细胞和存在于白色脂肪组织中的白色脂肪细胞能够“变褐”(beiging)或“褐色化”(browning),即指响应冷刺激、儿茶酚胺(catecholamines)、运动等产生棕色样(brown-like)产热脂肪细胞的过程。这些米色脂肪细胞也能够产热,并且在形态和生化特征方面与棕色脂肪细胞有许多相似之处。功能上,产热脂肪组织在非颤栗性产热中起着关键作用,这是一种受冷暴露激活用以抵抗低温,且不涉及肌肉颤栗的生热过程,这一机制可将多余能量作为热量消耗以维持能量平衡。然而,棕色和米色脂肪在全身能量稳态中的生物学意义远不止是增强能量消耗,它们在调节糖脂代谢、胰岛素敏感性、以及脂肪组织稳态中也起着重要作用。因此,调节棕色/米色脂肪细胞的数量和功能正在成为调控人类能量代谢的一种策略,并有望被应用于肥胖症的治疗。
发明内容
针对现有技术的不足,本发明提供了2,2′:5′,2″-三噻吩-5-羧酸在制备降脂减肥药物中的应用。
本发明的技术方案如下:
本发明提供了2,2′:5′,2″-三噻吩-5-羧酸在制备降脂减肥药物中的应用。
所述2,2′:5′,2″-三噻吩-5-羧酸([2,2′:5′,2″-terthiophene]-5-carboxylicacid,Compound K)的结构式如下所示:
根据本发明优选的,所述2,2′:5′,2″-三噻吩-5-羧酸的合成方法如下:
步骤a:在0℃条件下,将2,2′:5′,2″-三噻吩溶于二氯甲烷中,再依次加入POCl3和DMF,然后在氩气保护,90℃下加热回流10h;反应体系冷却至室温,将反应混合物倒入冰水中,快速搅拌4h;分液保留有机层,旋干得2,2′:5′,2”-三噻吩-5-甲醛粗品,石油醚洗涤2,2′:5′,2”-三噻吩-5-甲醛粗品,得到2,2′:5′,2”-三噻吩-5-甲醛;
步骤b:在0℃条件下,将2,2′:5′,2”-三噻吩-5-甲醛溶解于四氢呋喃与叔丁醇的混合溶剂中,加入2-甲基-2-丁烯,搅拌5min;向反应体系中加入NaH2PO4和NaClO2的溶液,恢复室温继续搅拌4h,旋干溶剂,石油醚/乙酸乙酯柱层析纯化后,得到2,2′:5′,2”-三噻吩-5-羧酸。
根据本发明优选的,所述降脂减肥药物促进脂肪细胞产热,抑制体重增长。
根据本发明优选的,所述降脂减肥药物促进白色脂肪细胞棕色化。
根据本发明优选的,所述降脂减肥药物减少脂肪组织含量,缓解预防肥胖引发的肝脂肪变性。
根据本发明优选的,所述降脂减肥药物是以2,2′:5′,2″-三噻吩-5-羧酸作为活性成分的药物组合物。
进一步优选的,所述降脂减肥药物还包括药学上可接受的辅料。
根据本发明优选的,所述降脂减肥药物的有效剂量为5mg/kg/d~15mg/kg/d。
本发明利用小鼠来源的原代脂肪细胞分化技术建立抗肥胖药物的细胞筛选模型进行筛选,发现2,2′:5′,2″-三噻吩-5-羧酸可以促进白色脂肪细胞棕色化。高脂饮食小鼠体内相关指标的系统研究证实了2,2′:5′,2″-三噻吩-5-羧酸可以增强小鼠适应性产热和能量消耗,显著降低小鼠体重,从而改善小鼠肥胖;因此,本发明提供了2,2′:5′,2″-三噻吩-5-羧酸(Compound K)在制备降脂减肥药物中的新用途。
本发明的有益效果在于:
本发明提供了2,2′:5′,2″-三噻吩-5-羧酸在制备抗肥胖药物、降脂减肥药物中的应用。本发明首次发现2,2′:5′,2″-三噻吩-5-羧酸具备显著的降脂减肥、抗肥胖活性。体内外实验表明,2,2′:5′,2″-三噻吩-5-羧酸可以有效促进白色脂肪细胞棕色化,提高细胞产热程序关键基因的表达,提升小鼠的呼吸能力,显著降低小鼠体重,减少小鼠脂肪组织含量,增强小鼠适应性产热和能量消耗,从而改善小鼠肥胖。并且2,2′:5′,2″-三噻吩-5-羧酸还能够缓解预防肥胖引发的肝脂肪变性,为临床提供了新的降脂减肥药物,具有较好的临床应用价值和广阔的应用前景。
附图说明
图1为2,2′:5′,2”-三噻吩-5-甲醛在氘代氯仿(CDCl3)中的NMR谱图。
图2为2,2′:5′,2”-三噻吩-5-羧酸在氘代二甲基亚砜(DMSO-d6)中的NMR谱图。
图3为2,2′:5′,2″-三噻吩-5-羧酸(Compound K)诱导白色脂肪细胞棕色化;
其中,图3A为Compound K引起细胞中脂滴变小,即“褐化”现象的油红O染色结果;图3B为Compound K引起的脂肪细胞产热程序的关键基因;图3C为Compound K明显增加了细胞基础呼吸(basal respiration)和最大呼吸(maximal respiration)能力。
图4为2,2′:5′,2″-三噻吩-5-羧酸(Compound K)改善高脂饮食诱发的小鼠肥胖;
其中,图4A为小鼠体型比较,图4B为小鼠体重增长变化图,图4C为小鼠eWAT,iWAT,BAT组织形态大小图。
图5为2,2′:5′,2″-三噻吩-5-羧酸(Compound K)增加小鼠适应性产热能力,促进能量的消耗。
其中,图5A为基础条件下Compound K处理组小鼠代谢活动更强;5B、5C为冷刺激条件下,小鼠耗氧率(VO2)和能量消耗的检测结果。
图6为2,2′:5′,2″-三噻吩-5-羧酸(Compound K)改善肥胖相关症状;
其中,图6A为小鼠肝脏图片;6B为小鼠血清总胆固醇(TC)、甘油三酯(TG)含量检测。
具体实施方式
为了更好的理解本发明的实质,下面结合实施例对本发明的内容作进一步说明,但不能视为对本发明的限制。
实施例1、2,2′:5′,2″-三噻吩-5-羧酸的制备
本发明中用到的2,2′:5′,2″-三噻吩-5-羧酸(Compound K)为本实验室通过以下方法(步骤a和b)合成获得,具体如下:
步骤a:2,2′:5′,2”-三噻吩-5-甲醛的合成
在0℃条件下,将2,2′:5′,2″-三噻吩(0.50g,2.0mmol,CAS No.1081-34-1,购买自毕得BD64212-25g)溶于二氯甲烷(50mL)中,再依次加入POCl3(170μL,2.2mmol)、DMF(105μL,2.2mmol),在氩气保护,90℃下加热回流10h;反应体系冷却至室温(20℃),将反应混合物倒入冰水中,快速搅拌4h;分液保留有机层,旋干得2,2′:5′,2”-三噻吩-5-甲醛粗品(棕色固体),石油醚(100mL×3)洗涤2,2′:5′,2”-三噻吩-5-甲醛粗品,得黄色固体为2,2′:5′,2”-三噻吩-5-甲醛(0.52g),产率94%;
步骤b:2,2′:5′,2″-三噻吩-5-羧酸(Compound K)的合成
在0℃条件下,将2,2′:5′,2”-三噻吩-5-甲醛(0.55g,2.0mmol)溶解于40mL四氢呋喃与20mL叔丁醇的混合溶剂中,加入4mL的2-甲基-2-丁烯(cas:513-35-9),搅拌5min;向反应体系中加入氧化剂溶液(1.9g,20mmol的NaH2PO4和1.44g,24mmol的NaClO2溶解于20mL水中),恢复室温(20℃)继续搅拌4h,旋干溶剂,石油醚/乙酸乙酯柱层析纯化后,得到黄色固体2,2′:5′,2”-三噻吩-5-羧酸(0.49)g,产率83%。
本方法所涉及的反应流程如下:
上述方法所制备的产物2,2′:5′,2”-三噻吩-5-甲醛和终产物2,2′:5′,2”-三噻吩-5-羧酸的核磁氢谱和碳谱分别见图1和图2。由图2可知,本发明成功制备得到了2,2′:5′,2”-三噻吩-5-羧酸。
所述2,2′:5′,2”-三噻吩-5-甲醛,其在400MHz下氘代氯仿(CDCl3)中的核磁谱图见图1。其中图1A为核磁氢谱,图1B为核磁碳谱。2,2′:5′,2”-三噻吩-5-甲醛的核磁数据如下:1H-NMR(400MHz,CDCl3)δ:9.86(1H,s),7.68(1H,d,J=4.0Hz),7.29(1H,d,J=4.0Hz),7.27(1H,d,J=3.8Hz),7.25(1H,d,J=3.9Hz),7.24(1H,d,J=3.9Hz,7.14(1H,d,J=3.9Hz),7.06(1H,dd,J=5.0,3.7Hz);13C-NMR(400MHz,CDCl3)δ:182.4,146.8,141.6,139.2,137.4,136.4,134.5,128.1,126.9,125.4,124.7,124.5,124.0。
所述2,2′:5′,2”-三噻吩-5-羧酸,其在400MHz下氘代二甲基亚砜(DMSO-d6)中的核磁谱图见图2。其中图1A为核磁氢谱,图1B为核磁碳谱。2,2′:5′,2”-三噻吩-5-羧酸的核磁数据如下:1H-NMR(400MHz,DMSO-d6)δ:7.65(1H,d,J=3.9Hz),7.58(1H,d,J=5.1Hz),7.46(1H,d,J=4.0Hz),7.40(1H,d,J=3.7Hz),7.37(1H,d,J=4.0Hz,7.33(1H,d,J=4.0Hz),7.13(1H,dd,J=5.1,3.7Hz);13C-NMR(400MHz,DMSO-d6)δ:163.2,146.8,142.4,137.5,136.1,135.0,134.4,129.0,127.3,126.7,125.6,125.3,125.1。
实施例2、Compound K促进白色脂肪细胞棕色化
测试原理:具有增殖分化能力的前体脂肪细胞能够在成脂条件下转变为成熟脂肪细胞,包括向白色脂肪细胞或向棕色脂肪细胞方向分化。其本质是分化液中特定成分的诱导,启动前体细胞分化,通过增强特定基因的表达,引起脂肪代谢基因表达模式和细胞形态的转变。脂肪组织血管基质(SVF,Stromal Vascular Fraction)中存在的前体脂肪细胞,具有多向分化潜能,是研究脂肪细胞增殖分化的主要细胞模型。
测试方法:以3~4周龄的雄性C57BL/6J小鼠(购自北京维通利华实验室)为材料,从小鼠脂肪组织血管基质SVF中获得大量具有增殖分化能力的前脂肪细胞,在成脂条件下诱导分化为成熟脂肪细胞,并分为三组,第一组添加终浓度为20μM的Compound K;第二组添加终浓度为40μM的Compound K;第三组添加等体积DMSO作为对照。按照以上分组处理后进行以下实验:①、通过油红O染色观察脂滴变化;②、qPCR观察产热相关基因变化;③、Seahorse XF能量代谢检测系统检测线粒体耗氧率。
测试结果:由图3可知,在诱导小鼠腹股沟原代脂肪细胞分化的筛选实验中,通过明场拍照及油红O染色,发现20μM的Compound K可以促进白色脂肪细胞脂滴变小,即发生“褐化”现象(图3A);20μM和40μM的Compound K处理原代脂肪细胞48h后,均能引起细胞产热程序相关的关键基因水平的显著升高(图3B),所述细胞产热程序相关的关键基因包括解偶联蛋白1(Ucp1)、碘甲腺原氨酸脱碘酶Ⅱ(DiO2)、过氧化物酶体增殖物激活受体γ辅激活因子1α(PGC1α)、PRDM锌指转录因子(Prdm16)等。线粒体压力测试线粒体耗氧率(OCR)的结果表明,20μM的Compound K处理明显上升了基础呼吸(basal respiration)和最大呼吸(maximal respiration)能力(图3C)。这些结果均说明2,2′:5′,2″-三噻吩-5-羧酸能够有效促进白色脂肪细胞棕色化,提高脂肪细胞产热程序关键基因的表达,提升小鼠的呼吸能力,具备显著的降脂减肥、抗肥胖活性,可以用于制备抗肥胖药物、降脂减肥药物。
实施例3、Compound K治疗改善高脂饮食诱发的小鼠肥胖
测试方法:8周龄雄性C57BL/6J小鼠(购自北京维通利华实验室),60%高脂饲料(ResearchDiets;D12492)喂养,构建高脂饮食(HFD)小鼠。将小鼠随机分为两组,即实验组和对照组,每组10只。实验组小鼠以10mg/kg/d的剂量口服Compound K,对照组小鼠以0.3%CMC-Na口服给药,然后利用呼吸代谢系统研究Compound K对HFD小鼠全身能量消耗的影响。每周固定三天记录小鼠体重,12周后对老鼠进行安乐死,解剖各脂肪组织保存备用。
测试结果:由图4可知,Compound K处理组小鼠体重明显轻于对照组小鼠(图4A),且体重增长缓慢,维持在30g左右(图4B);Compound K处理组小鼠皮下白色脂肪组织(eWAT)、腹股沟白色脂肪组织(iWAT)、肩胛骨棕色脂肪组织(BAT)的重量明显低于对照组,且腹股沟白色脂肪组织iWAT重量变化最显著(图4C)。这些结果均说明2,2′:5′,2″-三噻吩-5-羧酸能够抑制小鼠体重增长,减少脂肪组织含量,具备显著的降脂减肥、抗肥胖活性,可以用于制备抗肥胖药物、降脂减肥药物。
实施例4、Compound K增加了HFD小鼠适应性产热和能量消耗。
测试方法:HFD小鼠的饲养和药物处理方法同实施例2。利用呼吸代谢系统研究Compound K对HFD小鼠全身能量消耗的影响,具体是在代谢笼中研究基础条件和冷暴露条件下小鼠的代谢活动。
测试结果:由图5可知,在基础条件下,药物组小鼠代谢活动更强(图5A);冷暴露下,药物处理后的小鼠耗氧率(VO2)明显高于对照组小鼠(图5B)。能量消耗(Enegyexpenditure,图5C)的检测结果表明,在寒冷环境下,药物组小鼠能够更好地增加产热保持体温。这些结果均说明2,2′:5′,2″-三噻吩-5-羧酸能够增强小鼠适应性产热和能量消耗,具备显著的降脂减肥、抗肥胖活性,可以用于制备抗肥胖药物、降脂减肥药物。
实施例5、Compound K能够改善肥胖相关症状
测试方法:HFD小鼠的饲养和药物处理方法同实施例2。取出肝脏,对小鼠肝脏形态进行观察;用总胆固醇、甘油三酯比色法测试盒(Elascience)测试小鼠血清胆固醇(TC)和甘油三酯(TG)的含量变化。
测试结果:由图6可知,小鼠喂养高脂饲料12周后小鼠肝脏体积大,颜色偏白,而Compound K处理组的小鼠肝脏体积小,颜色偏红(图6A)。对4周、8周小鼠血清中的总胆固醇(TC)、甘油三酯(TG)进行检测,结果表明药物能够改善小鼠的脂代谢水平(图6B)。这些结果均说明2,2′:5′,2″-三噻吩-5-羧酸能够缓解预防肥胖引发的肝脂肪变性,可以用于制备抗肥胖药物、降脂减肥药物。
综上所述,2,2′:5′,2″-三噻吩-5-羧酸(Compound K)可以有效促进白色脂肪细胞棕色化,提高细胞产热程序关键基因的表达,提升小鼠的呼吸能力,显著降低小鼠体重,减少小鼠脂肪组织含量,增强小鼠适应性产热和能量消耗,从而改善小鼠肥胖。并且2,2′:5′,2″-三噻吩-5-羧酸还能够缓解预防肥胖引发的肝脂肪变性,为临床提供了新的降脂减肥药物,具有较好的临场应用价值和广阔的应用前景。
Claims (8)
1.2,2':5',2”-三噻吩-5-羧酸在制备降脂减肥药物中的应用;
所述2,2':5',2”-三噻吩-5-羧酸的结构式如下所示:
2.如权利要求1所述的应用,其特征在于,所述2,2':5',2”-三噻吩-5-羧酸的合成方法如下:
步骤a:在0℃条件下,将2,2':5',2”-三噻吩溶于二氯甲烷中,再依次加入POCl3和DMF,然后在氩气保护,90℃下加热回流10h;反应体系冷却至室温,将反应混合物倒入冰水中,快速搅拌4h;分液保留有机层,旋干得2,2':5',2”-三噻吩-5-甲醛粗品,石油醚洗涤2,2':5',2”-三噻吩-5-甲醛粗品,得到2,2':5',2”-三噻吩-5-甲醛;
步骤b:在0℃条件下,将2,2':5',2”-三噻吩-5-甲醛溶解于四氢呋喃与叔丁醇的混合溶剂中,加入2-甲基-2-丁烯,搅拌5min;向反应体系中加入NaH2PO4和NaClO2的溶液,恢复室温继续搅拌4h,旋干溶剂,石油醚/乙酸乙酯柱层析纯化后,得到2,2':5',2”-三噻吩-5-羧酸。
3.如权利要求1所述的应用,其特征在于,所述降脂减肥药物促进脂肪细胞产热,抑制体重增长。
4.如权利要求1所述的应用,其特征在于,所述降脂减肥药物促进白色脂肪细胞棕色化。
5.如权利要求1所述的应用,其特征在于,所述降脂减肥药物减少脂肪组织含量,缓解预防肥胖引发的肝脂肪变性。
6.如权利要求1所述的应用,其特征在于,所述降脂减肥药物是以2,2':5',2”-三噻吩-5-羧酸作为活性成分的药物组合物。
7.如权利要求6所述的应用,其特征在于,所述降脂减肥药物还包括药学上可接受的辅料。
8.如权利要求1所述的应用,其特征在于,所述降脂减肥药物的有效剂量为5mg/kg/d~15mg/kg/d。
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