CN107793353A - 牛奶树碱类化合物及其应用 - Google Patents
牛奶树碱类化合物及其应用 Download PDFInfo
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- CN107793353A CN107793353A CN201711091643.1A CN201711091643A CN107793353A CN 107793353 A CN107793353 A CN 107793353A CN 201711091643 A CN201711091643 A CN 201711091643A CN 107793353 A CN107793353 A CN 107793353A
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Abstract
本发明涉及合成药物技术领域,尤其涉及牛奶树碱类化合物及其药用盐,以及在治疗和预防肥胖及高脂血症方面的应用。本发明所述的牛奶树碱类化合物能显著抑制3T3‑L1前脂肪细胞分化过程中甘油三酯和总脂肪的积累,抑制效果优于阳性对照化合物小檗碱,且没有明显细胞毒性。此外,这些β‑内酰胺类牛奶树碱衍生物还能调节控制脂肪代谢的转录因子AMPK和ACC的磷酸化,以及SIRT1的表达量,能调节控制脂肪细胞分化的转录因子PPARγ、SREBP‑1c和FABP4的表达量。因此,本发明所述的含牛奶树碱类化合物和/或其药用盐的药物具有良好的抑制脂肪细胞分化、降低脂肪细胞中油滴和甘油三酯的效果,在治疗或预防肥胖及降血脂方面有良好的发展前景。
Description
技术领域
本发明涉及合成药物技术领域,尤其涉及牛奶树碱类化合物及其药用盐,以及在治疗和预防肥胖及高脂血症方面的应用。
背景技术
近年来随着人们生活方式以及饮食结构的改变,全球肥胖和高脂血症人数剧增,成为了威胁人类健康和生活质量的世界性公共卫生问题。肥胖和高脂血症可能导致高血压、脂肪肝以及某些癌症等,肥胖已经是全球第五大致死因素,高脂血症也是危害我国人民健康的十大疾病之一。因此,肥胖和高脂血症对我国国民健康危害极大,对应的药物研发问题是我国社会发展中迫切需要解决的关键科技问题,具有重大的社会效益。
肥胖的发病机制复杂,目前尚无一个很好的药物靶点,减肥药物开发过程中,很多药物都通过作用于神经摄食中枢发挥作用,因为种种副作用无法被广泛应用。因此开发更有效,更安全的减肥药物成为了当今的研究热点和挑战。降血脂药物能够降低血浆甘油三酯或降胆固醇,主要分为他汀类、贝特类、和烟酸类似物,然而这些药物引起的肝、肾损伤以及过敏皮疹副作用严重限制了其广泛、长期应用。
近十几年来的研究表明,脂肪组织不仅是个能量储存器官,还是个极其重要的分泌器官,在机体的能量和代谢调控方面发挥着重要作用。脂肪细胞功能的紊乱,与肥胖及其相关疾病的发生密切相关。脂肪细胞数目的增多或者体积的增大是肥胖的病理基础,因此抑制脂肪细胞分化是当前抗肥胖药物发展的一个重要方向。同时,脂肪细胞模拟了甘油三酯从头合成过程,能够用于评价脂肪细胞利用葡萄糖合成甘油三酯的能力。因此,3T3-L1前脂肪细胞是一种优秀的可用于抗肥胖、以及降血脂药物筛选的模型。
中药是中国劳动人民几千年来与疾病作斗争的实践经验总结,从中药资源宝库中寻找先导化合物是我国药物开发的优势之一。牛奶树碱来源于牛奶树,能治疗感冒发热及各种炎症,进一步开发牛奶树碱类化合物的药用价值具有重要的意义。
发明内容
本发明提供一种牛奶树碱类化合物及其药用盐,该类化合物能显著抑制3T3-L1前脂肪细胞分化,降低3T3-L1前脂肪细胞内油滴、甘油三酯积累。
本发明的另一方面,针对现有的抗肥胖药物安全性和疗效欠佳的问题,提供一种含牛奶树碱类化合物和/或其药用盐的用于治疗或预防肥胖的药物。
本发明的另一方面,针对现有的降血脂药副作用多的问题,提供一种含牛奶树碱类化合物和/或其药用盐的用于降血脂的药物。
为实现上述目的,本发明采用以下技术方案。
一种牛奶树碱类化合物及其药用盐,其结构如式(Ⅰ)所示:
式(Ⅰ);
其中,X为O或NH,R1为CH3或H,R2为H、甲氧基、卤素、苯基烯丙基、N,N-二甲基,或是呋喃环、2-甲基呋喃环、噻吩环、环己烷。
优选的,所述牛奶树碱类化合物及其药用盐的结构式中,X为O 时,R1为CH3;X为NH时,R1为H。
更优选的,所述牛奶树碱类化合物为β-内酰胺类牛奶树碱衍生物,所述β-内酰胺类牛奶树碱衍生物及其药用盐的结构式如下所示:
以上所述牛奶树碱类化合物及其药用盐在制备治疗和/或预防肥胖的药物中的应用。
一种预防或治疗肥胖的药物,包括有效量的作为活性成分的以上所述牛奶树碱类化合物和/或其药用盐,以及含有药学上可接受的载体。
以上所述牛奶树碱类化合物及其药用盐在制备降血脂的药物中的应用,用于治疗和/或预防高脂血症。
一种用于降血脂的药物,包括有效量的作为活性成分的以上所述牛奶树碱类化合物和/或其药用盐,以及含有药学上可接受的载体。
与现有技术相比,本发明的有益效果是:本发明所述的牛奶树碱类化合物能显著抑制3T3-L1前脂肪细胞分化过程中甘油三酯和总脂肪的积累,抑制效果优于阳性对照化合物小檗碱,且没有明显细胞毒性,尤其是β-内酰胺类牛奶树碱衍生物的抑制效果尤为显著。此外,这些β-内酰胺类牛奶树碱衍生物还能调节控制脂肪代谢的转录因子 AMPK和ACC的磷酸化,以及SIRT1的表达量,能调节控制脂肪细胞分化的转录因子PPARγ、SREBP-1c和FABP4的表达量。因此,本发明所述的含牛奶树碱类化合物和/或其药用盐的药物,尤其是含β-内酰胺类牛奶树碱衍生物和/或其药用盐的药物具有良好的抑制脂肪细胞分化、降低脂肪细胞中油滴和甘油三酯生成的效果,在治疗或预防肥胖及降血脂方面有良好的发展前景。
附图说明
图1为化合物20和21抑制总脂肪积累的油红O染色图;
图2为化合物3-23抑制细胞中甘油三酯生成的活性数据;
图3为化合物20和21的细胞毒性数据;
图4为化合物20和21不改变脂肪细胞甘油三酯积累过程中关键转录因子AMPK的mRNA表达的活性数据;
图5为化合物20和21不改变控制脂肪代谢的转录因子ACC的 mRNA表达的活性数据;
图6为化合物20和21上调控制脂肪代谢的转录因子SIRT1的 mRNA表达的活性数据;
图7为化合物20和21增加控制脂肪代谢的关键转录因子AMPK、 ACC的磷酸化,同时增加SIRT1的表达量;
图8为化合物20和21下调控制脂肪细胞分化的转录因子 PPARγ的mRNA表达量的活性数据;
图9为化合物20和21下调控制脂肪细胞分化的转录因子 SREBP-1c的mRNA表达量的活性数据;
图10为化合物20和21下调控制脂肪细胞分化的转录因子 FABP4的mRNA表达量的活性数据;
图11为化合物20和21降低控制脂肪细胞分化的关键转录因子 PPARγ、SREBP-1c、FABP4的蛋白表达量。
图12为化合物20的质谱图;
图13为化合物21的质谱图。
具体实施方式
为了更充分理解本发明的技术内容,下面结合具体实施例对本发明的技术方案作进一步介绍和说明。
本发明所述牛奶树碱类化合物的制备方法,包括如下步骤:以 4-羟基-6-甲基-2-吡喃酮为原料,通过硫酸二甲酯,碳酸钾溶剂为丙酮条件下,使羟基甲基化得4-甲氧基-6-甲基-2-吡喃酮,然后在碱性试剂甲醇镁和相应的醛反应得到β-内酯牛奶树碱类化合物,再将反应物与过量36%氨水,乙醇在120℃于密封管中反应36h,得到β-内酰胺牛奶树碱类化合物。
本发明合成牛奶树碱类化合物以4-羟基-6-甲基-2-吡喃酮为原料,原料价廉易得,合成方法简单易操作,产率高,产物稳定。
本发明所述牛奶树碱化合物3-23的具体合成方法如下:
合成4-甲氧基-6-甲基-2-吡喃酮(化合物2):将4-羟基-6-甲基-2- 吡喃酮(11.2mmol),碳酸钾(33.6mmol),丙酮(20mL),硫酸二甲酯(22.4mmol),室温过夜,TLC检测反应,反应完全后,减压除去溶剂,用流动相环己烷:乙酸乙酯(v/v)1:4过硅胶柱,既得化合物2;产率:91%。
合成β-内酯牛奶树碱类化合物(化合物3-14):化合物2(5mmol),相应的醛(5mmol),甲醇镁(5mL),回流,氮气保护过夜,TLC 检测反应,反应完全后,减压除去溶剂,用流动相环己烷:乙酸乙酯 (v/v)1:2过硅胶柱,既得化合物3-14;产率:32-59%。
合成β-内酰胺牛奶树碱类化合物(化合物15-23):化合物3-14 (2mmol)36%氨水过量,乙醇(5mL),120℃,密封管中,36h, TLC检测反应,反应完全后,减压除去溶剂,用流动相环己烷:乙酸乙酯(v/v)4:1过硅胶柱,既得化合物15-23;产率:19-51%。
以上所述牛奶树碱类化合物3-23的合成路线如下:
化合物20和化合物21的质谱如图12、图13所示。以上所述牛奶树碱类化合物3-23的产率及核磁共振氢谱如下。
化合物3,其中,R2为产率56%,核磁共振氢谱如下:δ7.58(d,J=7.1Hz,2H),7.44(s,1H),7.37(d,J=7.6Hz,1H),7.31(s, 2H),6.59(dd,J=16.0,4.1Hz,1H),5.95(s,1H),5.50(s,1H),3.82(s, 3H).
化合物4,其中,R2为产率57%,核磁共振氢谱如下:δ7.79(d,J=16.1Hz,1H),7.49(d,J=7.0Hz,1H),7.30(dd,J=15.5, 8.3Hz,2H),7.11–6.85(m,3H),6.69(t,J=14.5Hz,1H),5.91(s,1H), 5.46(s,1H),3.90(s,3H),3.83(s,3H).
化合物5,其中,R2为产率54%,核磁共振氢谱如下:δ7.46–7.33(m,1H),7.19(dd,J=11.1,8.5Hz,1H),7.03(d,J=7.6 Hz,1H),6.93(d,J=10.9Hz,1H),6.82(dd,J=8.2,2.2Hz,1H),6.49(d, J=15.9Hz,1H),5.87(d,J=1.8Hz,1H),5.42(d,J=1.8Hz,1H),3.76 (s,3H),3.75(s,3H).
化合物6,其中,R2为产率59%,核磁共振氢谱如下:δ7.37(d,J=5.9Hz,1H),7.32(s,2H),,6.82(d,J=8.2Hz,2H),6.37 (d,J=15.9Hz,1H),5.81(s,1H),5.39(s,1H),3.75(s,3H),3.74(s,3H).
化合物7,其中,R2为产率43%,核磁共振氢谱如下:δ7.76(d,J=16.0Hz,1H),7.51(dd,J=6.1,3.4Hz,1H),7.33(dd,J= 5.8,3.5Hz,1H),7.20(d,J=2.7Hz,1H),7.18(d,J=2.9Hz,1H),6.51 (d,J=16.0Hz,1H),5.92(d,J=2.0Hz,1H),5.44(d,J=2.0Hz, 1H)3.78–3.54(m,3H).
化合物8,其中,R2为产率47%,核磁共振氢谱如下:δ7.37(d,J=8.9Hz,1H),7.34(s,2H),7.27(d,J=8.4Hz,2H),6.47 (d,J=16.0Hz,1H),5.87(d,J=1.8Hz,1H),5.42(d,J=1.8Hz,1H), 3.82–3.63(m,3H).
化合物9,其中,R2为产率32%,核磁共振氢谱如下:δ7.37(d,J=2.9Hz,1H),7.31(s,2H),,6.62(d,J=4.4Hz,2H),6.31 (dd,J=15.8,4.2Hz,1H),5.77(s,1H),5.36(s,1H),3.75(d,J=4.4Hz, 3H),3.15–2.79(m,6H).
化合物10,其中,R2为产率57%,核磁共振氢谱如下:δ6.57(dd,J=15.7,7.0Hz,1H),5.82(d,J=15.7Hz,1H),5.70(d,J= 2.0Hz,1H),5.35(d,J=2.0Hz,1H),3.74(s,3H),2.04(dd,J=10.9,7.0 Hz,1H),1.67(d,J=10.8Hz,4H),1.59(d,J=12.7Hz,1H),1.22(m, 3H),1.07(m,3H).
化合物11,其中,R2为产率43%,核磁共振氢谱如下:δ7.38(d,J=7.2Hz,2H),7.27(d,J=7.7Hz,3H),7.25–7.15(m, 3H),6.86–6.71(m,2H),6.08(d,J=15.1Hz,1H),5.80(s,1H),5.40(s, 1H),3.74(d,J=2.7Hz,3H).
化合物12,其中,R2为产率43%,核磁共振氢谱如下:δ7.11(d,J=15.6Hz,1H),6.33(dd,J=9.2,6.2Hz,2H),5.99(d,J =2.7Hz,1H),5.80(s,1H),5.38(d,J=1.9Hz,1H),3.73(d,J=10.1Hz, 3H),2.27(s,3H).
化合物13,其中,R2为产率41%,核磁共振氢谱如下:δ7.39(s,1H),7.21(t,J=4.7Hz,1H),7.17(d,J=4.8Hz,1H),6.50(d, J=15.7Hz,2H),6.40(d,J=3.1Hz,1H),5.86(s,1H),5.41(d,J=2.9 Hz,1H),3.76(s,3H).
化合物14,其中,R2为产率37%,核磁共振氢谱如下:δ7.54(d,J=15.6Hz,1H),7.24(d,J=4.9Hz,1H),7.11(d,J=3.0Hz, 1H),6.96(t,J=3.8Hz,1H),6.30(d,J=15.6Hz,1H),5.83(s,1H),5.40 (s,1H),3.74(s,3H).
化合物15,其中,R2为产率28%,核磁共振氢谱如下:δ7.57(d,J=7.1Hz,2H),7.42(s,1H),7.38(dd,J=9.6,4.8Hz,3H), 7.33(dd,J=5.2,1.8Hz,1H),6.79(d,J=16.0Hz,1H),6.09(d,J=1.9 Hz,1H),5.14(d,J=1.9Hz,1H).
化合物16,其中,R2为产率27%,核磁共振氢谱如下:δ7.57(d,J=7.3Hz,2H),7.31(t,J=7.4Hz,1H),7.01(d,J=8.3Hz, 1H),6.96(m,1H),6.86(d,J=16.6Hz,1H),6.10(s,1H),5.48(s, 1H),3.90(s,3H).
化合物17,其中,R2为产率23%,核磁共振氢谱如下:δ7.33(s,1H),7.30(d,J=7.3Hz,1H),7.21(d,J=6.7Hz,2H), 6.91(d,J=7.4Hz,1H),6.86(d,J=16.0Hz,1H),6.28(s,1H),6.08(s, 1H),5.08(s,1H),3.84(s,3H).
化合物18,其中,R2为产率31%,核磁共振氢谱如下:δ7.58(d,J=7.9Hz,2H),7.29(d,J=15.9Hz,1H),6.96(d,J=7.7Hz,2H),6.69(d,J=15.9Hz,1H),6.24(s,2H),6.02(s,1H),5.05(s, 1H),3.83(s,3H).
化合物19,其中,R2为产率19%,核磁共振氢谱如下:δ7.84(s,1H),7.70(d,J=5.9Hz,1H),7.48(d,J=2.9Hz,1H),7.37(d, J=2.6Hz,2H),6.91(d,J=7.7Hz,1H),6.33(s,2H),6.16(s,1H),5.11 (d,J=5.4Hz,1H).
化合物20,其中,R2为产率51%,核磁共振氢谱如下:δ6.60(dd,J=15.7,7.0Hz,1H),5.83(d,J=15.7Hz,1H),5.61(s,1H), 5.11(s,1H),4.94(s,2H),2.08(d,J=7.3Hz,1H),1.71(d,J=10.2Hz, 4H),1.23(t,J=16.8Hz,3H),1.11(t,3H).
化合物21,其中,R2为产率34%,核磁共振氢谱如下:δ6.78(d,J=15.7Hz,1H),6.30(d,J=2.7Hz,1H),6.18(d,J=15.7 Hz,1H),5.99(s,2H),5.88(s,1H),5.76(s,1H),4.77(s,1H),2.61(s, 3H).
化合物22,其中,R2为产率36%,核磁共振氢谱如下:δ7.62(s,1H),7.12(d,J=15.8Hz,1H),6.72(t,J=11.6Hz,1H),6.56 (d,J=15.7Hz,2H),6.28(s,2H),6.07(d,J=1.2Hz,1H),5.06(d,J= 1.7Hz,1H).
化合物23,其中,R2为产率32%,核磁共振氢谱如下:δ7.52(d,J=15.7Hz,1H),7.44(d,J=5.0Hz,1H),7.27(d,J=3.2Hz, 1H),7.06(dd,J=5.0,3.7Hz,1H),6.53(d,J=15.7Hz,1H),6.04(d,J= 1.7Hz,1H),5.11(d,J=1.9Hz,1H).
实施例1
本实施例提供一种预防或治疗肥胖的药物,含有药学上可接受的载体,以及有效量的作为活性成分的上述化合物20和/或其药用盐。
实施例2
本实施例提供一种预防或治疗肥胖的药物,含有药学上可接受的载体,以及有效量的作为活性成分的上述化合物21和/或其药用盐。
实施例3
本实施例提供一种预防或治疗肥胖的药物,含有药学上可接受的载体,以及有效量的作为活性成分的上述化合物20与化合物21和/ 或它们的药用盐。
实施例4
本实施例提供一种用于降血脂的药物,含有药学上可接受的载体,以及有效量的作为活性成分的上述化合物20和/或其药用盐。
实施例5
本实施例提供一种用于降血脂的药物,含有药学上可接受的载体,以及有效量的作为活性成分的上述化合物21和/或其药用盐。
实施例6
本实施例提供一种用于降血脂的药物,含有药学上可接受的载体,以及有效量的作为活性成分的上述化合物20与化合物21和/或它们的药用盐。
分析实施例1-6所述药物中的有效成分化合物20和化合物21的生理活性。化合物20和化合物21的药效相关实验如试验1-4所示。
试验1:化合物20和化合物21抑制甘油三酯积累、总脂肪积累的活性测定。
(1)细胞培养
3T3-L1(小鼠胚胎成纤维细胞,前脂肪细胞)采用完全培养基 (DMEM培养基中添加10%胎牛血清、100U/mL青霉素、100μg/mL 链霉素)在37℃、体积分数5%CO2的培养箱中培养。
(2)药物干预
待测化合物(小檗碱、化合物20、化合物21)以DMSO配成10 mM母液,测试时稀释成不同浓度工作液(1μM和10μM)。为校正母液溶剂DMSO影响,空白对照添加0.1%DMSO。
3T3-L1接种于48孔板中培养至完全接触(第0天),将培养基换成分化培养基I或加入指定浓度待测化合物的分化培养基I培养3 天(第3天)。分化培养基I配方:完全培养基中添加2μg/mL胰岛素, 100ng/mL地塞米松,0.5mM 3-异丁基-1-甲基黄嘌呤和10ng/mL生物素。
分化培养基和待测化合物作用第3天,将培养基更换成分化培养基II或加入指定浓度待测化合物的分化培养基II继续培养3天(第6 天)。分化培养基II配方:完全培养基中添加2μg/mL胰岛素。
第6天,收获细胞进行甘油三酯或油红O染色分析。
(3)甘油三酯测试
收获处理后的3T3-L1细胞,冰PBS(0.2M NaCl,10mM Na2HPO4,3mMKCl,2mM KH2PO4,pH 7.4)洗涤两次,超声破碎细胞,使用甘油三酯试剂盒和多功能酶标仪检测546nm处吸光度,从而计算细胞破碎液中甘油三酯含量。结果以空白对照细胞甘油三酯含量百分比的形式表示。
(4)油红O染色
3T3-L1细胞以10%(V/V)福尔马林溶液室温固定1小时,以新制备的油红O工作溶液60℃染色30分钟,蒸馏水洗两次,则总脂肪被油红O染成红色,以装有CCD数码相机的倒置显微镜观察并拍照。拍摄过程中放大倍数、光强度不变。
(5)结果处理
根据甘油三酯试剂盒和多功能酶标仪检测546nm处吸光度,减去空白对照组的本底吸光度值,比上阴性对照组细胞吸光度值,结果以阴性对照组细胞甘油三酯含量百分比的形式表示。所有数据均表示为平均值±标准方差。
测试结果如图1和图2所示。由图2可知,化合物20和化合物 21均能不同程度降低3T3-L1细胞内甘油三酯积累。由图1可知,降甘油三酯效果最好的化合物20和化合物21明显降低3T3-L1细胞内总脂肪滴含量。
试验2:化合物20和化合物21的细胞毒性测定。
(1)细胞培养
HEK293T(人胚胎肾上皮细胞系)采用完全培养基(DMEM培养基中添加10%胎牛血清、100U/mL青霉素、100μg/mL链霉素)在 37℃、体积分数5%CO2的培养箱中培养。
(2)药物干预
待测化合物以DMSO配成10mM母液,测试时稀释成不同浓度工作液。为校正母液溶剂DMSO影响,空白对照添加与相应化合物等浓度的DMSO。
HEK293T细胞以每孔5千个细胞的密度接种于96孔板中过夜待细胞贴壁。加入指定浓度梯度的待测化合物,作用24小时。
(3)MTT检测
化合物作用24小时后,每孔加入10μL浓度为5mg/mL的MTT 溶液,继续培养4小时。去掉上清,每孔加入100μL DMSO,置摇床上低速震荡10-15分钟。
(4)结果处理
在多功能酶标仪上检测570nm处吸光度,减去空白对照组的本底吸光度值,比上阴性对照组细胞吸光度值,结果以阴性对照组细胞甘油三酯含量百分比的形式表示。所有数据均表示为平均值±标准方差。
测试结果如图3所示。由图3可知,化合物20在13μM时能引起半数细胞凋亡。而化合物21无细胞毒性,在50μM时都未见明显细胞毒性。
试验3:化合物20和化合物21上调AMPK通路上关键转录因子的mRNA、下调PPARγ通路上关键转录因子的mRNA表达量的活性测定。
(1)细胞培养
3T3-L1(小鼠胚胎成纤维细胞,前脂肪细胞)采用完全培养基 (DMEM培养基中添加10%胎牛血清、100U/mL青霉素、100μg/mL 链霉素)在37℃、体积分数5%CO2的培养箱中培养。
(2)药物干预
待测化合物以DMSO配成10mM母液,测试时稀释成不同浓度工作液。为校正母液溶剂DMSO影响,空白对照添加0.1%DMSO。
3T3-L1接种于48孔板中培养至完全接触(第0天),将培养基换成分化培养基I或加入指定浓度待测化合物的分化培养基I培养72 小时(第3天)。收获细胞进行荧光定量PCR扩增。
(3)荧光定量PCR
使用RNAiso Plus提取3T3-L1细胞的总RNA,通过Oligo dT18 将1μg总RNA逆转录为cDNA,通过定量PCR技术,使用Toyobo 公司ThunderBird SYBR qPCR Mix试剂按照说明书对引物进行PCR 扩增。每组样品3个复孔,以保证实验数据的有效性。使用β-actin 为内参,检测目的基因相对于内参基因的表达变化来定量。采用2-ΔΔCt方法分析数据(即实验组目的基因相对于对照组的表达量的变化倍数)。
所用引物为:
β-actin,sense 5’-TGGAATCCTGTGGCATCCATGAAA-3’and antisense 5’-TAAAACGCAGCTCAGTAACAGTCC-3’;AMPK, sense 5’-AAGCCGACCCAATGACATCA-3’and antisense 5’-CTTCCTTCGTACACGCAAAT-3’;ACC,sense 5’-AGGATTTGCTGTTTCTCAGAGCTT-3’and antisense5’-CAGGATCTACCCAGGCCACAT-3’;SIRT1,sense 5’-TTGTGAAGCTGTTCGTGGAG-3’andantisense 5’-GCGTGGAGGTTTTTCAGTA-3’;PPARγ,sense 5’-TGCTGTTATGGGTGAAACTCTG-3’antisense 5’-GAAATCAACTGTGGTAAAGGGC-3’;sREBP-1c,sense 5’-CAGCTCAGAGCCGTGGTGA-3’and antisense 5’-TGTGTGCACTTCGTAGGGTC-3’;FABP4,sense 5’-GTCACCATCCGGTCAGAGAGTAC-3’and antisense5’-TCGTCTGCGGTGATTTCATC-3’.
(4)结果处理
检测目的基因相对于内参基因的表达变化来定量。采用2-ΔΔCt方法分析数据(即实验组目的基因相对于对照组的表达量的变化倍数)。
测试结果如图4-6和图8-10所示,10μM浓度下的化合物20和化合物21不影响AMPK和ACC的mRNA表达量。化合物20和化合物21能显著增加SIRT1的mRNA表达量。(化合物20和化合物21处理过的细胞SIRT1的mRNA表达量是阴性对照组的4.28和4.07 倍)。同时化合物20和化合物21能显著下调PPARγ、sREBP-1c和 FABP4的mRNA表达量(化合物20和化合物21处理过的细胞 PPARγ的mRNA表达量是阴性对照组的0.53和0.64,化合物20和化合物21处理过的细胞sREBP-1c的mRNA表达量是阴性对照组的 0.24和0.30,化合物20和化合物21处理过的细胞FABP4的mRNA 表达量是阴性对照组的0.67和0.64)。
试验4:化合物20和化合物21上调AMPK通路上关键转录因子的蛋白磷酸化、表达量、下调PPARγ通路上关键转录因子的蛋白表达量的活性测定。
(1)细胞培养
3T3-L1(小鼠胚胎成纤维细胞,前脂肪细胞)采用完全培养基 (DMEM培养基中添加10%胎牛血清、100U/mL青霉素、100μg/mL 链霉素)在37℃、体积分数5%CO2的培养箱中培养。
(2)药物干预
待测化合物以DMSO配成10mM母液,测试时稀释成不同浓度工作液。为校正母液溶剂DMSO影响,空白对照添加0.1%DMSO。
3T3-L1接种于48孔板中培养至完全接触(第0天),将培养基换成分化培养基I或加入指定浓度待测化合物的分化培养基I培养72 小时(第3天)。收获细胞进行蛋白免疫印迹实验。
(3)蛋白免疫印迹(Western Blotting)
使用RIPA裂解液(含有蛋白酶抑制剂、磷酸酶抑制剂)提取3T3-L1细胞的总蛋白,加入上样缓冲液后于100℃热干浴煮沸10分钟使蛋白充分变性。使用Thermo公司的BCA蛋白定量试剂盒定量后,使用SDS-PAGE进行分离(90V,30分钟浓缩,120V,60分钟分离),200mA,90分钟将分离胶蛋白转移到PVDF膜上,将PVDF 膜置于对应的抗体稀释液(1:1000稀释)中4℃缓慢震摇过夜,使用 TBST缓冲液快摇漂洗3次,每次10分钟,室温慢摇孵育对应二抗1 小时,使用TBST缓冲液快摇漂洗3次,每次10分钟。
(4)结果处理
使用普通ECL发光液孵育PVDF膜2分钟,于天能化学发光成像仪中进行发光显影,使用quantity one软件对显影条带进行光密度定量分析。
测试结果如图7和图11所示,10μM浓度下的化合物20和化合物21能显著增加3T3-L1细胞内AMPK和ACC的磷酸化,但不影响 AMPK和ACC总蛋白的表达量。化合物20和化合物21能显著增加 SIRT1的蛋白表达量。(化合物20和化合物21处理过的细胞AMPK α的磷酸化是阴性对照组的3.45和3.10倍,化合物20和化合物21 处理过的细胞ACC的磷酸化是阴性对照组的2.98和4.12倍,化合物 20和化合物21处理过的细胞SIRT1的蛋白表达量是阴性对照组的 1.52和1.54倍)。同时化合物20和化合物21能显著下调PPARγ、 sREBP-1c和FABP4的蛋白表达量(化合物21处理过的细胞PPARγ的蛋白表达量是阴性对照组的0.69,化合物20和化合物21处理过的细胞sREBP-1c的蛋白表达量是阴性对照组的0.88和0.17,化合物20和化合物21处理过的细胞FABP4的蛋白表达量是阴性对照组的 0.45和0.44)。
由以上药效试验1-4的实验结果可知,化合物20和化合物21具有良好的抑制脂肪细胞分化、降低脂肪细胞中油滴和甘油三酯的效果,在治疗和预防肥胖、以及降血脂方面有良好的发展前景。因此,实施例1-6所述的药物具有减少3T3-L1前脂肪细胞分化过程中油滴积累及甘油三酯积累的效果,即实施例1-3的药物具有良好的抑制脂肪细胞分化、降低脂肪细胞中油滴和甘油三酯的效果,具有治疗和预防肥胖的效果;实施例4-6的药物具有良好的抑制脂肪细胞中油滴和甘油三酯合成的效果,具有降血脂的效果。
以上所述仅以实施例来进一步说明本发明的技术内容,以便于读者更容易理解,但不代表本发明的实施方式仅限于此,任何依本发明所做的技术延伸或再创造,均受本发明的保护。
Claims (7)
1.一种牛奶树碱类化合物及其药用盐,其特征在于,其结构如式(Ⅰ)所示:
其中,X为O或NH,R1为CH3或H,R2为H、甲氧基、卤素、苯基烯丙基、N,N-二甲基,或是呋喃环、2-甲基呋喃环、噻吩环、环己烷。
2.权利要求1所述牛奶树碱类化合物及其药用盐,其特征在于,X为O时,R1为CH3;X为NH时,R1为H。
3.权利要求2所述牛奶树碱类化合物及其药用盐,其特征在于,所述牛奶树碱类化合物为β-内酰胺类牛奶树碱衍生物,其结构式如下所示:
4.一种如权利要求1所述牛奶树碱类化合物及其药用盐在制备治疗和/或预防肥胖的药物中的应用。
5.一种预防或治疗肥胖的药物,其特征在于,包括有效量的作为活性成分的权利要求1中所述牛奶树碱类化合物和/或其药用盐,以及含有药学上可接受的载体。
6.一种如权利要求1所述牛奶树碱类化合物及其药用盐在制备降血脂的药物中的应用。
7.一种用于降血脂的药物,其特征在于,包括有效量的作为活性成分的权利要求1中所述牛奶树碱类化合物和/或其药用盐,以及含有药学上可接受的载体。
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