CN112479849A - 一种化合物及其应用 - Google Patents
一种化合物及其应用 Download PDFInfo
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- CN112479849A CN112479849A CN202011481138.XA CN202011481138A CN112479849A CN 112479849 A CN112479849 A CN 112479849A CN 202011481138 A CN202011481138 A CN 202011481138A CN 112479849 A CN112479849 A CN 112479849A
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Abstract
本发明属于化合物药物应用技术领域。本发明公开了一种化合物及其在制备对蛋白质酪氨酸磷酸酶1B抑制活性制剂中、治疗II型糖尿病药物中、降血糖药物中、降血脂药物、减肥药物、治疗脂肪肝疾病药物中的应用。
Description
技术领域
本发明属于化合物药物应用技术领域。
背景技术
微生物在药物和食品开发中发挥了十分重要的作用，如青霉素、链霉素、他汀类的药物等等，为人类的健康事业做出了巨大的贡献。
本发明属医药食品技术领域，具体涉及一种以冠突散囊菌在不同培养基中发酵，通过提取分离制备化合物。该化合物及其类似物、衍生物、前药、代谢物及其活性盐(代表性的酸加成盐包括但不限于乙酸盐、己二酸盐、海藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐(异硫代硫酸盐，isothionate)、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐和十一烷酸盐。同样，碱性含氮基团可用以下物质季铵化：低级烷基卤化物如甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物；硫酸二烷基酯如硫酸二甲酯、二乙酯、二丁酯和二戊酯；长链卤化物如癸基、十二烷基、十四烷基和十八烷基的氯化物、溴化物和碘化物；芳基烷基卤化物如苄基溴和苯乙基溴及其他。因此得到可溶于或分散于水或油的产品。可用来形成药学可接受的酸加成盐的酸实例包括无机酸如盐酸、氢溴酸、硫酸和磷酸，以及有机酸如草酸、马来酸、琥珀酸和柠檬酸)，及其在制备调节血脂改善血液循环、缓解脂肪肝，以及减肥的药物、保健食品和功能食品等产品中的应用。
发明内容
本发明的目的是提供一种化合物，其结构式如下；
本发明提供的化合物在制备对蛋白质酪氨酸磷酸酶1B抑制活性制剂中、治疗II型糖尿病药物中、降血糖药物中、降血脂药物、减肥药物、治疗脂肪肝疾病药物中的应用。
附图说明
图1是化合物的反相高效液相色谱图。
图2是化合物血糖实验结果图。
图3是化合物脂肪肝实验结果图。
图4是化合物胆固醇、甘油三酯、低密度脂蛋白和体重实验结果图。
具体实施方式
实施例1
1.真菌的分离
冠突散囊菌根据文献(杨瑞娟，王桥美，彭文书，季爱兵，张文杰，严亮，8种市售“金花”茶中微生物的分离鉴定，热带农业科学，2019，39(10)，81-88)的方法分离自泾渭茯茶(咸阳泾渭茯茶有限公司)。
2.真菌的发酵培养
将经活化的冠突散囊菌制成孢子悬浮液，再接种到灭菌的茶叶培养基上，在25-32℃静置发酵培养10-30天。
2.活性化合物的制备
发酵后的产物利用，甲醇、乙醇、乙酸乙酯、丙酮、二氯甲烷、乙醚、超临界萃取等方法(但不限于以上方法)进行提取，获得提取物。
提取物溶解到二氯甲烷和甲醇的混合溶剂中，以重量比为发酵粗提物:柱层析硅胶(100-200目)＝1:1.5拌样品，进行减压柱层析分离。
柱层析用正己烷、二氯甲烷不同配比的有机溶剂体系洗脱，体积比分别为100％正己烷、1:99(正己烷:二氯甲烷，获得样品A)、2:98(正己烷:二氯甲烷，获得样品B)、3:97(正己烷:二氯甲烷，获得样品C)、4:96(正己烷:二氯甲烷，获得样品D)、5:95(正己烷:二氯甲烷，获得样品E)、6:94(正己烷:二氯甲烷，获得样品F)、8:92(正己烷:二氯甲烷，获得样品G)、10:90(正己烷:二氯甲烷，获得样品H)进行洗脱，得到极性从小到大的8个馏分。
样品B利用凝胶Sephadex LH-20柱色谱进行分离，洗脱剂为正己烷:二氯己烷(体积比为2:1)，每10ml收集1个馏分，根据高效液相色谱分析结果进行合并后，得到5个馏分。
其中馏分2利用反相高效液相色谱进行纯化，色谱柱为Agilent反相C18色谱柱，流动相为40％乙腈的水溶液-100％乙腈(时间为20分钟)，得到所述目标化合物(如图1)。
3.化合物的结构鉴定
采用HPLC对制得的目标化合物进行纯度鉴定，纯度大于98％的样品利用质谱和核磁共振技术进行结构鉴定，核磁共振用Bruker AVANCE DRX-500核磁共振仪测定；质谱利用安捷伦6520Q-TOF质谱仪测定。
该目标化合物的核磁共振氢谱数据δH(Pyridine-d5)：12.46(s)，10.94(s)，7.38(s)，5.42，(tm,J＝7.5Hz)，3.50(d,J＝7.5)，3.25(t,J＝8.0Hz)，1.77(m)，1.64(s)，1.60(s)，1.45(m)，1.29(m)，1.19(m)，1.21(m)，0.83(t,J＝7.0Hz)；
该目标化合物的核磁共振碳谱数据δC(Pyridine-d5)：197.4，155.2，148.7，133.6，130.4，128.4，126.6，122.8，118.8，33.0，32.4，30.4，29.8，27.8，26.1，24.7，23.2，18.0，14.6；
该目标化合物的高分辨ESI质谱[M+H]+m/z 305.2116，C19H29O3 +计算值305.2111)。
确定该目标化合物的分子结构式如下：
4.化合物对蛋白质酪氨酸磷酸酶1B的抑制活性：
蛋白质酪氨酸磷酸酶1B(Protein tyrosine phosphatase，PTP1B)是一个筛选治疗II型糖尿病的重要靶点。
(a)重组PTP1B蛋白(Recombinant mouse PTP1B proteinab42574(ab42574))购自Abcam公司。
(b)筛选采用透明Beckman96孔板，反应体系80μL，温度37℃，在此基础上对底物浓度、酶浓度、反应时间等进行了优化。
最终确定酶反应体系组成如下：10mmol/L Tris盐酸，pH 7.6，10mmol/L PNPP，2％DMSO，50μg/mL PTP1B。
反应体系混匀后在37℃放置30min。加入1M的NaOH终止反应，在酶标仪上测定405nm波长下的吸收值(A)，测定结果减去本底值后计算酶活性。
计算IC50为9.13μM。
5.化合物在ob/ob小鼠上的降糖效果
实验分组：根据血糖值和体重对ob/ob小鼠平均分组：(1)以喂养正常饲料的C57小鼠作为空白对照组；(2)模型对照组(ob/ob)；(3)二甲双胍100mg/kg；(4)给药组(化合物5.0mg/kg)每组10只，连续给药5周。
空白、模型、给药组以及阳性对照组血糖水平(图2)。
表1.化合物对ob/ob糖尿病小鼠血糖的的影响(禁食血糖)
6.化合物对可以缓解C57小鼠高脂肪饲喂模型的血脂指标并降低体重
(1)实验材料
①实验动物：C57小鼠，体重20-25g，雄性，由北京华阜康生物科技股份有限公司提供。
②高脂饲料：北京华阜康生物科技股份有限公司。
③受试品：化合物每日给药剂量5mg/kg体重；
④阳性对照药物：辛伐他汀，10mg/kg体重，杭州默沙东制药有限公司。
(2)试验方法：
取C57小鼠40只，体重20-25g，雄性。随机分为2组，其中空白对照组10只，其余30只建立高脂模型。空白对照组喂食普通饲料，其余30只均喂食高脂饲料(配方：78.6％基础饲料，10％猪油，10％蛋黄粉，1％胆固醇，0.4％胆盐)，自由饮水。8周后，所有动物禁食12h后，眼底静脉丛采血，测定血清内TC、TG含量，确认造模情况。
随后将成模动物随机分组，每组8只，饲养情况同前。(1)以喂养正常饲料的C57小鼠作为空白对照组；(2)一直饲喂高脂饲料作为模型高脂对照；(3)辛伐他汀10mg/kg；(4)给药组(化合物5.0mg/kg)。
每日一次灌胃给药，共给药8周。
空白对照组和模型高脂对照组均给予相同体积的蒸馏水。
给药8周于末次给药后禁食12h眼底静脉丛采血，按血清胆固醇、甘油三酯试剂盒说明书的测试方法，利用半自动生化分析仪进行分析。
分析仪检测血清中两个指标含量，并称量体重。
并对小鼠进行解剖，取肝脏切片，显微镜下观察脂肪肝发生状况。
给药组可显著看到脂肪颗粒减少(图3)。
结果显示给药组血液中胆固醇、甘油三酯水平、低密度脂蛋白水平，以及体重相对于对照组明显降低(图4)。
表2.化合物对C57小鼠血液中血脂相关指标的影响
实验过程中，实时观察C57小鼠行为、活动，并记录体重及死亡情况，给药八周后处死并收集血样及肝脏样本。实验十六周内，受试动物无一死亡，摄食、饮水、粪便均正常。
表3.化合物对C57小鼠体重的影响
Claims (7)
1.一种如下结构式的化合物：
2.权利要求1所述化合物在制备对蛋白质酪氨酸磷酸酶1B抑制活性制剂中应用。
3.权利要求1所述化合物在制备治疗II型糖尿病药物中的应用。
4.权利要求1所述化合物在制备降血糖药物中的应用。
5.权利要求1所述化合物在制备降血脂药物中的应用。
6.权利要求1所述化合物在制备减肥药物中的应用。
7.权利要求1所述化合物在治疗脂肪肝疾病药物中的应用。
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