CN115785190A - 化合物Caffarolide A及其药物组合物与其在制药中的应用 - Google Patents
化合物Caffarolide A及其药物组合物与其在制药中的应用 Download PDFInfo
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- CN115785190A CN115785190A CN202211623999.6A CN202211623999A CN115785190A CN 115785190 A CN115785190 A CN 115785190A CN 202211623999 A CN202211623999 A CN 202211623999A CN 115785190 A CN115785190 A CN 115785190A
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Abstract
提供化合物Caffarolide A及其药物组合物与其在制药中的应用，属于医药食品技术领域。本发明化合物Caffarolide A的制备方法原料易得，易于操作，收率高，适于工业化生产。化合物Caffarolide A作为有效成分的药物组合物，为新的降脂药物提供了具有较好药用作用的产品。从细胞活力检测结果看，Caffarolide A在100μM浓度下仍然未显示细胞毒性，表明其具有较宽的活性窗口。Caffarolide A在40μM浓度下，脂滴已经明显消失，残留的很少。化合物Caffarolide A能应用于制备3T3‑L1前脂肪细胞脂质抑制活性剂和降脂药物和治疗肥胖疾病的药物，能用于制备降脂的健康产品。
Description
技术领域
本发明属于食品、医药领域，具体涉及一种咖啡二萜有效成分化合物CaffarolideA的制备方法及其降脂功能的应用。
技术背景
肥胖作为一种代谢疾病已成为危害全球公众健康的主要问题之一。肥胖与高血压、II型糖尿病、冠心病和中风等多种疾病的发生关系密切。人体脂肪组织，尤其是白色脂肪组织(white adipose tissue,WAT)，不单储存能量，更具有重要的内分泌和免疫功能。其中，脂肪细胞参与能量代谢的调节，在肥胖和其它慢性代谢疾病产生中起到重要作用。除脂肪细胞外，脂肪组织还含有前脂肪细胞、内皮细胞、巨噬细胞、T-淋巴细胞和肥大细胞等一系列基质血管相(stromal vascular fraction,SVF)细胞。研究发现，巨噬细胞、T-淋巴细胞和肥大细胞等多种免疫细胞，与肥胖的发生、发展相关，其中巨噬细胞与肥胖的关系研究最为深入。研究发现，这些细胞浸润入白色脂肪组织中，产生一系列细胞因子(如肿瘤坏死因子-α，TNF-α；白介素-6，IL-6)、趋化因子(如单核细胞趋化蛋白-1，MCP-1)等炎性分子，导致脂肪沉积(adipogenesis)和胰岛素抵抗(insulin resistance)等一系列并发症。治疗肥胖的药物主要有西布曲明(Sibutramine)和奥利司他(Orlistat)，但是上述两种药物均具有毒副作用，其中西布曲明可能增加服用者患严重心血管疾病的风险，其制剂和原料药已经停止生产和销售。奥利司他是一种强效的胃肠道脂肪酶抑制剂，它通过与胃、小肠内的脂肪酶作用，能够抑制胃肠道中的脂肪酶活性，阻止食物中的脂肪水解为人体可吸收的游离脂肪酸和单酰基甘油，未分解的脂肪不能被人体吸收直接排出体外，实现从源头阻止脂肪吸收，减少人体的热量摄入，从而达到减肥目的。
新近研究表明，脂肪沉积已被认为是肥胖发展关键步骤，控制这一步骤将能够有效地控制肥胖的进程。脂肪沉积包括脂肪组织中脂肪细胞的增殖和前脂肪细胞分化，其中单个脂肪细胞的体积与其分化程度及甘油三酯积累量密切相关。成熟脂肪细胞内脂肪的过度沉积是肥胖病理生理过程的核心。目前，通过脂肪沉积现象机理研究的实验模型主要包括体外的3T3-L1分化模型和动物体内模型(如小鼠、秀丽线虫等)。在3T3-L1细胞分化和小鼠模型中的研究已发现，脂肪沉积是一个高度精细的调控过程，多种转录因子(如CCAAT增强子结合蛋白α，C/EBPα)；过氧化物酶体增殖物激活受体γ(PPARγ)；固醇调节原件结合蛋白(SREBP)等、脂质代谢蛋白(如脂肪酸合成酶(FAS)、乙酰辅酶A羧化酶(ACC1)、葡萄糖转运子4(GLUT4)和脂蛋白脂酶(LPL)等)和相关信号转导(AMPK，MAPK，Wnt/β-catenin等通路在其中发挥重要的作用。
咖啡二萜属于对映贝壳杉烷型的二萜，是咖啡中一类主要的次生代谢产物，常见的两个主要成分为咖啡醇，咖啡豆醇。目前咖啡二萜类化合物抗肿瘤活性研究比较深，除了具有抗肿瘤活性外,还具有抗菌,抗病毒等活性。本发明人从云南咖啡中得到120多个咖啡二萜类化合物，包括氧化型二萜、重排型二萜、呋喃型二萜、内酰胺型二萜、内酯型二萜、Δ4,18型二萜、降解型二萜、维拉诺瓦型二萜和阿替生烷型二萜。而十分有趣的是，本研究团队发现的内酯型咖啡二萜化合物在进行3T3-L1前脂肪细胞的增殖、降低脂肪细胞中油酯含量的活性筛选中，发现一些咖啡二萜具有较强的对3T3-L1前脂肪细胞的脂肪抑制作用。
迄今，现有技术中未有咖啡二萜Caffarolide A及其制备方法，及其药物组合物，以及该化合物在降脂功能中的应用的报道。
发明内容
本发明的目的在于提供一种咖啡二萜Caffarolide A及其制备方法，及其药物组合物，以及该化合物在降脂功能中的应用的报道。
为了实现本发明的上述目的，本发明提供了如下的技术方案：
如下结构式所示的化合物Caffarolide A，
所述的化合物Caffarolide A的制备方法，该方法包括下述步骤：将云南咖啡生豆粉碎，用5倍量丙酮热回流提取2次，每次3小时，浓缩得提取物浸膏；使用硅胶柱色谱，石油醚：乙酸乙酯＝5:1对提取物浸膏进行划段分离，通过薄层色谱，显色剂10％硫酸乙醇，监测内酯型咖啡二萜，显色为紫红色富集段，浓缩得到内酯型咖啡二萜富集物；再使用HPLC：ZORBAX,RX-C8,5μm,9.4×250mm,乙腈:水，纯化内酯型咖啡二萜富集物得到CaffarolideA。
所述的化合物Caffarolide A在制备降脂药物中的应用。
所述的化合物Caffarolide A在制备食品中的应用。
所述的化合物Caffarolide A在制备治疗肥胖疾病的药物中的应用。
所述的化合物Caffarolide A在制备3T3-L1前脂肪细胞的脂质抑制剂中的应用。
含有所述的化合物Caffarolide A及可药用载体的药物组合物。
所述的药物组合物在制备降脂药物中的应用，及在制备治疗肥胖疾病的药物中的应用。
所述的药物组合物在制备3T3-L1前脂肪细胞的脂质抑制剂中的应用。
所述的药物组合物的制备方法，该方法包括下述步骤：将云南咖啡生豆粉碎，用5倍量丙酮热回流提取2次，每次3小时，浓缩得提取物浸膏；使用硅胶柱色谱，石油醚：乙酸乙酯＝5:1对提取物浸膏进行划段分离，通过薄层色谱，显色剂10％硫酸乙醇，监测内酯型咖啡二萜，显色为紫红色富集段，浓缩得到内酯型咖啡二萜富集物；再使用HPLC：ZORBAX,RX-C8,5μm,9.4×250mm,乙腈:水，纯化内酯型咖啡二萜富集物得到Caffarolide A，再加入可药用载体。
一种3T3-L1前脂肪细胞的脂质抑制剂，其以化合物Caffarolide A为活性成分。
本发明化合物用作药物时，可以直接使用，或者以药物组合物的形式使用。该药物组合物含有0.1-99％，优选0.5-90％的本发明化合物，其余为药物学上可接受的，对人和动物无毒和惰性的可药用载体。
所述的可药用载体是一种或多种固体、半固体和液体稀释剂、填料以及药物制品辅剂。将本发明的药物组合物以单位体重服用量的形式使用。本发明的药物可经多种形式(液体制剂、固体制剂、注射剂、外用制剂、喷剂、复方制剂)给药。
与现有技术相比，本发明具备如下的优益性：
1.本发明提供了化合物Caffarolide A，填补了现有技术的空白。
2.本发明提供了制备化合物Caffarolide A的方法，该方法原料易得，易于操作，收率高，适于工业化生产。
3.本发明提供了化合物Caffarolide A作为有效成分的药物组合物，为新的降脂药物提供了具有较好药用作用的新的药物。
4.从细胞活力检测结果看，Caffarolide A在100μM浓度下仍然未显示细胞毒性，表明其具有较宽的活性窗口。无毒副作用。从图2看Caffarolide A在40μM浓度下，脂滴已经明显消失，残留的很少。
5.化合物Caffarolide A可作为药物用于3T3-L1前脂肪细胞脂质抑制活性剂和降脂药物，用于治疗肥胖疾病。也能用于制备降脂的健康产品。
附图说明
图1Caffarolide A细胞活力检测结果(μM)；
图2使用油红O颜色观察2.5-40μM下Caffarolide A对3T3-L1细胞中脂滴积累抑制情况；
图3不同给药浓度下3T3-L1细胞中脂滴积累量化结果；
图4为本发明Caffarolide J的制备工艺流程图。
具体实施方式
下面结合附图，用本发明的实施例来进一步说明本发明的实质性内容，但并不以此来限定本发明。
实施例1
1.化合物Caffarolide A的制备：
将云南咖啡DR155生豆10kg粉碎，用5倍量丙酮热回流提取2次，每次3小时。浓缩得提取物浸膏(得率8％-15.0％)；使用硅胶柱色谱(石油醚：乙酸乙酯＝5:1)对提取物浸膏进行划段分离，通过薄层色谱(显色剂10％硫酸乙醇)监测内酯型咖啡二萜(显色为紫红色)富集段，浓缩得到内酯型咖啡二萜富集物CCD(得率0.1‰-0.3‰)；再使用HPLC(ZORBAX,RX-C8,5μm,9.4×250mm,乙腈:水)纯化内酯型咖啡二萜富集物得到Caffarolide A(得率0.05‰-0.01‰)；2.制备工艺流程
根据实验总结，目标活性分子Caffarolide A的制备工艺流程归纳如图4所示。3.目标活性分子Caffarolide A的结构表征
1)化合物Caffarolide A的化学结构
2)化合物Caffarolide A的结构表征
Caffarolide A,C36H58O6；白色无定形粉末,[α]-246.9°(c＝0.1,CHCl3)；UV(CHCl3)λmax(logε):239(1.59),201(1.04),193(1.05)nm；IR(KBr)vmax:3511,3422,3088,3922,1767,1719,1654,1453,1293,1161,943,875cm-1。
1H NMR(CDCl3,600MHz),1.46-2.08(overlapped,H-1—H-3),2.26(1H,m,H-5),1.46-2.08(overlapped,H-6—H-7,H-9,H-11—H-12),2.07(1H,m,H-13),1.46-2.08(overlapped,H-14—H-15),4.23(1H,d,J＝11.4Hz,H-17a),4.26(1H,d,J＝11.4Hz,H-17b),5.61(1H,s,H-18),2.36(2H,t,J＝6.7Hz,H-2′),1.23-1.36(overlapped,H-3′－H-15′),0.88(3H,t,J＝7.0Hz,H-16)；13C NMR(CDCl3,150MHz)δC:35.4(C-1),34.2(C-2),104.2(C-3),172.0(C-4),46.9(C-5),21.7(C-6),39.4(C-7),44.5(C-8),53.2(C-9),43.5(C-10),19.1(C-11),27.2(C-12),45.8(C-13),37.4(C-14),52.8(C-15),79.9(C-16),68.1(C-17),112.8(C-18),170.8,(C-19),14.3(C-20),174.0(C-1′),34.2(C-2′),25.3(C-3′),29.1-29.7(C-4′—C-13′),31.9(C-14′),22.6(C-15′),14.1(C-16′)。
4.3T3-L1前脂肪细胞脂质抑制活性实验
4.1实验方法
4.1.1细胞分化
3T3-L1前脂肪细胞(购于美国ATCC公司)，培养于DMEM培养基中，包含10％的小牛血清和1％青霉素/链霉素(P/S)，37℃，5％ CO2。第一天，将生长状态良好的3T3-L1前脂肪细胞培养液替换成分化诱导液(Differentiation induction medium，DIM))，诱导液由DMEM培养基配置而成，含有1μg/mL胰岛素，0.5mM 3-异丁基-1-甲基黄嘌呤(IBMX)，1μM地塞米松。第三天，将分化诱导液吸出，加入后分化培养基[DMEM+10％胎牛血清(FBS)+1μg/mL胰岛素]保持一天，在第4天的时候将后分化培养基替换成正常的DMEM(含10％胎牛血清)，保持两天后细胞分化完成。待测样品用DMSO溶解，使用时稀释1000倍，不给药组加入含0.1％DMSO的DMEM培养基。
4.1.2细胞存活率实验
采用MTS实验测定化合物对于3T3-L1前脂肪细胞生存率的影响，选择生长状态良好的3T3-L1细胞，加入96孔板，每孔细胞为1×104个，采用二倍稀释法将化合物稀释成不同浓度，加入含药培养基后保持48小时，然后加入20％的MTS溶液，在37℃条件的孵箱中培养1小时，最后使用酶标仪(PerkinElmerEnVision multilabel reader)492nm测定吸光度，细胞存活率(％)＝OD给药组/OD空白组×100％。
4.1.3脂质含量分析
3T3-L1细胞内的脂质含量通过油红O染色表示。给药完成后，吸出培养基，加入PBS磷酸盐缓冲液清洗两次，然后加入甲醛溶液固定，室温下保持1小时后，洗去固定液，使用油红O染色15min，使用60％异丙醇溶液洗去染色液，再用蒸馏水清洗，使用荧光倒置显微镜Nikon TS100(Tokyo,Japan)照相，最后使用100％异丙醇溶液萃取染料，在492nm酶标仪下进行定量。
4.2实验结果
表1Caffarolide A细胞活力检测原始数据(μM)
表2不同Caffarolide A浓度下3T3-L1细胞中脂滴积累量化结果原始数据
结果分析：从细胞活力检测结果看，Caffarolide A在100μM浓度下仍然未显示细胞毒性，表明其具有较宽的活性窗口。无毒副作用。从图2看Caffarolide A在40μM浓度下，脂滴已经明显消失，残留的脂滴很少。
制剂实施例1-7：
在以下制剂实施例中，选择常规试剂，并按照现有常规方法进行制剂制备，本应用例仅体现本发明所述化合物Caffarolide A能够制备成不同的制剂，对具体试剂和操作不作具体限定：
1.将化合物Caffarolide A，用DMSO溶解后，按常规方法加注射用水，精滤，灌封灭菌制成注射液，所述注射液的浓度为0.5-5mg/mL。
2.将化合物Caffarolide A，用DMSO溶解后，将其溶于无菌注射用水中，搅拌使其溶解，用无菌抽滤漏斗过滤，再无菌精滤，分装于安瓿中，低温冷冻干燥后无菌熔封，得粉针剂。
3.将化合物Caffarolide A，按其与赋形剂质量比为9:1的比例加入赋形剂，制成粉剂。
4.将化合物Caffarolide A，按其与赋形剂质量比为5:1的比例加入赋形剂，制粒压片。
5.将化合物Caffarolide A，按常规口服液制备方法制成口服液。
6.将化合物Caffarolide A，按其与赋形剂质量比为5:1的比例加入赋形剂，制成胶囊。
7.将化合物Caffarolide A，按其与赋形剂质量比为5:1的比例加入赋形剂，制成颗粒剂。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.如下结构式所示的化合物Caffarolide A，
2.权利要求1所述的化合物Caffarolide A的制备方法，其特征在于该方法包括下述步骤：将云南咖啡生豆粉碎，用5倍量丙酮热回流提取2次，每次3小时，浓缩得提取物浸膏；使用硅胶柱色谱，石油醚：乙酸乙酯＝5:1对提取物浸膏进行划段分离，通过薄层色谱，显色剂10％硫酸乙醇，监测内酯型咖啡二萜，显色为紫红色富集段，浓缩得到内酯型咖啡二萜富集物；再使用HPLC：ZORBAX,RX-C8,5μm,9.4×250mm,乙腈:水，纯化内酯型咖啡二萜富集物得到CaffarolideA。
3.权利要求1所述的化合物Caffarolide A在制备降脂药物和/或食品中的应用。
4.权利要求1所述的化合物Caffarolide A在制备治疗肥胖疾病的药物中的应用。
5.权利要求1所述的化合物Caffarolide A在制备3T3-L1前脂肪细胞的脂质抑制剂中的应用。
6.含有权利要求1所述的化合物Caffarolide A及可药用载体的药物组合物。
7.权利要求6所述的药物组合物在制备治疗肥胖疾病的药物中、在制备降脂药物和/或食品中的应用。
8.权利要求6所述的药物组合物在制备3T3-L1前脂肪细胞的脂质抑制剂中的应用。
9.权利要求6所述的药物组合物的制备方法，其特征在于该方法包括下述步骤：将云南咖啡生豆粉碎，用5倍量丙酮热回流提取2次，每次3小时，浓缩得提取物浸膏；使用硅胶柱色谱，石油醚：乙酸乙酯＝5:1对提取物浸膏进行划段分离，通过薄层色谱，显色剂10％硫酸乙醇，监测内酯型咖啡二萜，显色为紫红色富集段，浓缩得到内酯型咖啡二萜富集物；再使用HPLC：ZORBAX,RX-C8,5μm,9.4×250mm,乙腈:水，纯化内酯型咖啡二萜富集物得到Caffarolide A，再加入可药用载体。
10.一种3T3-L1前脂肪细胞的脂质抑制剂，其以化合物Caffarolide A为活性成分。
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| KR20160092071A (ko) * | 2015-01-19 | 2016-08-04 | 연세대학교 산학협력단 | 카월을 포함하는 비만 예방 또는 치료용 조성물 |
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