CN109970540B - 一种基于对羟基苯醌骨架α-葡萄糖苷酶抑制剂及其制备方法与应用 - Google Patents
一种基于对羟基苯醌骨架α-葡萄糖苷酶抑制剂及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种基于对羟基苯醌骨架α‑葡萄糖苷酶抑制剂及其制备方法与应用;该葡萄糖苷酶抑制剂以天然产物骨架对羟基苯醌为起始原料,经过6步反应合成得到;该化合物能够有效抑制α‑葡萄糖苷酶活性,通过延缓肠道对葡萄糖的吸收以达到控制血糖过高的目的,可用于治疗糖尿病和肥胖病,并具有心血管的保护作用。
Description
技术领域
本发明公开了一种α-葡萄糖苷酶抑制剂,具体的说,是一种半天然来源的基于对羟基苯醌骨架的α-葡萄糖苷酶抑制剂,本发明还涉及该半天然来源的基于对羟基苯醌骨架的α-葡萄糖苷酶抑制剂的制备方法与应用。
背景技术
截至2017年我国约有1.14亿糖尿病患者,患病率高达11.6%,位居世界第一。WHO预测2025年全球的糖尿病患者数量将突破3亿,其中2型糖尿病患者将超过1.3亿,这部分疾病管理的费用将占总医疗开支的40%,这导致了医疗支出和相关社会问题的增加。糖尿病如果不加控制容易出现高血糖症或血糖升高,而这种长期的高血糖症随着时间的推移,人体的许多系统会受到严重损害,特别是神经系统和心脑血管系统。在发达国家,糖尿病已经成为继癌症和心脑血管疾病之后危害人类健康的第三大“杀手”。控制血糖水平一直是缓解疾病、预防高血糖和糖尿病加重的有效途径。众所周知,所有的碳水化合物最终都会在肠道中被酶水解。α-葡萄糖苷酶位于肠道细胞的刷缘表面膜,是碳水化合物消化过程中最重要的酶。该酶可以打断二糖的α-1,4糖苷键,产生单糖,从而被人体吸收。研究表明,大多数2型糖尿病患者在服用α-葡萄糖苷酶抑制药物后,空腹及餐后的血糖、血脂、糖化血红蛋白显著降低,胰岛素敏感性提高,从而达到了预防或治疗糖尿病及肥胖症的用途。我们还知道,一些葡萄糖苷酶抑制剂可能通过干扰糖蛋白和糖脂的正常处理而表现出抗病毒、抗转移和免疫刺激活性。
前用于临床的α-葡萄糖苷酶抑制剂有阿卡波糖、伏格列波糖和米格列醇三种,但他们都存在不同程度的不良反应,包括腹胀、肠鸣、腹痛、腹泻等,其原因主要是由于未被彻底消化的碳水化合物在肠道菌群的作用下进行异常发酵而引起。因此寻找高效低毒植物来源的活性化合物治疗糖尿病具有广阔的前景,国内外的研究者已经从植物中提取出多种能够抑制α-葡萄糖苷酶活性的化合物,提取出的有效成分的类型主要有多酚类、黄酮类及其苷、生物碱类、三萜类及其苷、肽类、脂类、酸类等。
摁贝素(2,5-二羟基3-十一烷基-对苯醌)是天然植物酸藤果的活性成分,具有多种药理活性,包括抗肿瘤、抗炎、镇痛,抗菌,XIAP连锁凋亡抑制蛋白的小分子抑制剂,抗生育,细胞毒活性,脑损伤的保护,抗惊厥,促进伤口愈合,抗抑郁等作用。近年来的研究认为其还有降血糖和胰岛细胞保护的作用。
发明内容
针对上述不足,本发明的第一个目的提供一种基于对羟基苯醌骨架的α-葡萄糖苷酶抑制剂。
本发明的第二个目的提供上述对羟基苯醌骨架的α-葡萄糖苷酶抑制剂的制备。
本发明的第三个目的提供上述对羟基苯醌骨架的α-葡萄糖苷酶抑制剂的应用。
为此,本发明提供的第一个技术方案是这样的:
一种对羟基苯醌骨架的α-葡萄糖苷酶抑制剂,其结构式如式1所示:
本发明提供的第二个技术方案是这样的:
上述的对羟基苯醌骨架的α-葡萄糖苷酶抑制剂的制备方法,包括以下步骤:
1)将2,5二羟基-1,4苯醌溶于极性有机溶剂中,缓慢滴加无机酸,室温搅拌8~15个小时,然后抽滤浓缩得到黄色固态的中间产物1;
2)将所得中间产物1溶于水中,加入连二亚硫酸钠,在80~120℃下,反应回流8~15分钟,于-4~4℃下冷却结晶,抽滤得到粉白色晶状中间产物2;
3)将中间产物2溶于有机溶剂中,加入无机碱将反应液的pH调至8~9,室温搅拌15~30分钟,逐滴加入碘甲烷,室温搅拌8~15小时。反应液依次用无机酸溶液调节pH至5~6、用有机溶剂萃取,有机相依次用饱和食盐水、蒸馏水洗涤;收集有机相,将有机相用无水硫酸镁干燥,然后减压浓缩得到粗产品,过柱纯化得到白色晶状中间体A;
4)将中间体A放入圆底烧瓶中,烘箱干燥15~30分钟,加入HMPA,换气2~5次,再加入四氢呋喃作溶剂,在-50℃~-30℃下无水无氧反应5~15分钟,缓慢加入正丁基锂,将温度调至-15℃~-5℃反应40~80分钟,逐滴加入溴代甲联苯,继续反应5~15分钟。置于室温反应10~15小时。减压浓缩得到粗产品,用有机溶剂溶解,用无机酸溶液调节pH至5~6,有机相依次用饱和食盐水、蒸馏水洗涤;收集有机相,将有机相用无水硫酸镁干燥,过滤,然后减压浓缩得到粗产品,过柱纯化得到油状中间体B;
5)将中间体B溶于有机溶剂,用有机水溶液溶解硝酸铈铵,在-10℃~2℃冰盐浴中逐滴加入硝酸铈铵于中间体B中,并搅拌反应10~20分钟。在室温下反应1~2.5小时。减压浓缩得到粗产品,用有机溶剂溶解,依次用饱和食盐水、蒸馏水洗涤;收集有机相,将有机相用无水硫酸镁干燥,过滤,然后减压浓缩得到粗产品,过柱纯化得到固体中间体C或D;
6)将中间体C或D溶于有机醇,加入氢氧化钠,于70℃~90℃下蒸发回流1.5~2.5小时,减压浓缩,溶于有机溶剂,用无机酸调节pH值至5~6,有机相依次用饱和食盐水、蒸馏水洗涤;收集有机相,将有机相用无水硫酸镁干燥,过滤,然后减压浓缩得到粗产品,然后用低极性的有机溶剂冲洗抽滤,得到最终产物E。
其中:
步骤1)所述的化合物2,5二羟基-1,4苯醌、无机酸的摩尔比为1:1~5;
步骤2)所述中间产物1和连二亚硫酸钠的摩尔比是1:1~5;
步骤3)所述中间产物2、无机碱、碘甲烷的摩尔比是1:1~5:1~5;
步骤4)所述中间体A、HMPA、正丁基锂、溴代甲基连苯的摩尔比是1:0.3~0.5:1~1.5:1~1.5;
步骤5)所述中间体B、硝酸铈铵的摩尔比是1:2~4,有机溶剂与水的比例为8/1~7/3;
步骤6)所述中间体C或D或C和D与无机碱的摩尔比是1:40~50;
进一步的,上述的基于对羟基苯醌骨架的α-葡萄糖苷酶抑制剂的制备方法,步骤1)所述的无机酸为浓盐酸、浓硫酸等;
进一步的,上述的基于对羟基苯醌骨架的α-葡萄糖苷酶抑制剂的制备方法,步骤3)、步骤4)、步骤6)所述的有机酸为稀盐酸或饱和氯化铵;
进一步的,上述的基于葡萄糖苷酶抑制剂的制备方法,步骤1)、步骤2)、步骤3)、步骤4)、步骤5)、步骤6)所述的有机溶剂为乙酸乙酯或二氯甲烷;
进一步的,上述的基于对羟基苯醌骨架的α-葡萄糖苷酶抑制剂的制备方法,步骤3)所述的有机碱为氢氧化钠或氢氧化钾。
进一步的,上述的基于葡萄糖苷酶抑制剂的制备方法,步骤1)、步骤2)、步骤3)、步骤4)、步骤5)、步骤6)所述的有机溶剂为乙酸乙酯或二氯甲烷;
上述基于对羟基苯醌骨架的α-葡萄糖苷酶抑制剂作为降血糖药物的应用。
上述基于对羟基苯醌骨架的α-葡萄糖苷酶抑制剂作为保护心脑血管保健品的应用。
上述基于对羟基苯醌骨架的α-葡萄糖苷酶抑制剂作为治疗肥胖病药物的应用。
与现有技术相比,本发明提供的技术方案具有如下技术优点:该产品由天然来源的化合物通过结构改造反应制备,是一种半天然的基于对羟基苯醌骨架的α-葡萄糖苷酶抑制剂,且制备方法简单易行。与现有常用的基于对羟基苯醌骨架的α-葡萄糖苷酶抑制剂阿卡波糖相比,该产品对酪氨酸酶的抑制活性高出200多倍,在医药、保健、食品等领域具有良好的应用前景。
附图说明
图1是中间体A的1H NMR检测谱图;
图2是中间体B的1H NMR检测谱图;
图3是中间体B的13C NMR检测谱图;
图4是中间体C的1H NMR检测谱图;
图5是中间体C的13C NMR检测谱图;
图6是中间体D的1H NMR检测谱图;
图7是中间体D的13C NMR检测谱图;
图8是成品E的1H NMR检测谱图;
图9是成品E的13C NMR检测谱图;
图10是成品E和阳性对照组阿卡波糖对α-葡萄糖苷酶的抑制效应;
图11是成品E对α-葡萄糖苷酶的抑制机制
图12是成品E对α-葡萄糖苷酶的抑制动力学。
具体实施方式
为了使本发明的目的、技术方案和有益技术效果更加清晰,以下结合实施例,对本发明进行进一步详细说明。应当理解的是,本说明书中描述的实施例仅仅是为了解释本发明,并非为了限定本发明,实施例的参数、比例等可因地制宜做出选择而对结果并无实质性影响。
实施例1
1,2,4,5-四甲氧基苯(中间体A)的合成
将2,5二羟基-1,4苯醌(5.0g,36.0mmol)溶于甲醇中,缓慢滴加38%盐酸(6mL,72.0mmol),室温搅拌反应10个小时,然后抽滤浓缩得到黄色固态中间体1;将此中间体溶于100mL水中,加入连二亚硫酸钠(10.0g,57.4mmol),120℃下,反应回流8分钟,于-4℃下冷却结晶,抽滤得到粉白色晶状物中间体2(4.5g,73.5%)。将该中间体溶于DMSO中,加入氢氧化钾(3,71g,66.1mmol)使反应液pH呈碱性,室温搅拌15分钟,逐滴加入碘甲烷(4.2mL,66.1mmol)搅拌8小时。减压浓缩,用乙酸乙酯溶解,用稀盐酸溶液调节pH至5~6,依次用饱和食盐水、蒸馏水洗涤;收集有机相,将有机相用无水硫酸镁干燥,然后减压浓缩得到粗产品,过柱纯化得到白色晶状的中间体A(2.8g 53.4%)
进行1H NMR,结果参阅图1,1H NMR(400MHz,CDCl3)δ6.69(s,2H),3.71(s,12H).
1,2,4,5-四甲氧基-3甲基联苯基-苯(中间体B)的合成
将中间体A(1.0g,5.1mmol)放入圆底烧瓶中,烘箱干燥15分钟,加入HMPA(353uL,2mmol),换气3次,再加入60mL四氢呋喃作溶剂,在-50℃下无水无氧反应5min,缓慢加入正丁基锂(2.44mL,6.12mmol),将温度调至-15℃反应40分钟,逐滴加入4-溴甲基代联苯(2.746g,5.6mmol)反应5分钟。在置于室温反应10小时。减压浓缩得到粗产品,用有乙酸乙酯溶解,用饱和氯化钠溶液调节pH至弱酸性,依次用饱和食盐水、蒸馏水洗涤;收集有机相,将有机相用无水硫酸镁干燥,过滤,然后减压浓缩得到粗产品,过柱纯化得到油状中间体B。(221.5mg,12%)。
进行1H NMR,结果参阅图2,1H NMR(400MHz,CDCl3)δ7.54(d,J=7.6Hz,2H),7.46(d,J=8.1Hz,2H),7.38(t,J=7.6Hz,2H),7.33-7.26(m,3H),6.48(s,1H),4.07(s,2H),3.85(s,6H),3.66(s,6H).
进行13C NMR,结果参阅图3,13C NMR(101MHz,CDCl3)δ149.82,149.09,141.27,141.21,140.76,138.58,129.10,128.73,127.01,126.96,126.93,97.69,60.88,56.36,29.95.
2,5-二甲氧基-6-甲基联苯基-1,4-苯醌(中间体C)和2-甲氧基-5-羟基-6-甲基联苯基-1,4-苯醌(中间体D)的合成。
将中间体B(200.0mg,0.546mmol)溶于4mL乙腈,用5mL乙腈/水(3/2)溶液溶解硝酸铈铵(748.8mg,1.37mmol),在-10℃冰盐浴中逐滴加入硝酸铈铵于中间体B中,搅拌反应10分钟。在室温下反应1h。减压浓缩得到粗产品,用有机溶剂溶解,依次用饱和食盐水、蒸馏水洗涤;收集有机相,将有机相用无水硫酸镁干燥,过滤,然后减压浓缩得到粗产品,过柱纯化得到固体中间产物C(35.2mg,19.3%)和D(62.1mg,35.5%)。
中间体C进行1H NMR,结果参阅图4,1H NMR(400MHz,CDCl3)δ7.55(d,J=7.5Hz,2H),7.48(d,J=8.1Hz,2H),7.41(t,J=7.6Hz,2H),7.36-7.30(m,3H),5.73(s,1H),4.12(s,3H),3.82(s,2H),3.80(s,3H).
中间体C进行13C NMR,结果参阅图5,13C NMR(101MHz,CDCl3)δ183.78,182.19,158.88,155.92,141.08,139.41,138.14,129.58,128.84,128.53,127.30,127.23,127.14,105.64,61.55,56.57,28.52.
中间体D进行1H NMR,结果参阅图6,1H NMR(400MHz,CDCl3)δ7.55(d,J=7.5Hz,2H),7.48(d,J=8.1Hz,2H),7.43-7.28(m,6H),5.85(s,1H),3.88-3.78(m,5H).
中间体D进行13C NMR,结果参阅图7,13C NMR(101MHz,CDCl3)δ182.87,181.49,161.27,151.76,141.11,139.48,137.98,129.65,128.83,127.32,127.22,127.16,117.93,102.49,56.97,28.22.
6-甲基联苯基-2,5-对羟基-1,4-苯醌(成品E)的合成
将中间体C(20mg,0.060mmol)和D(30mg,0.0937mmol)溶于乙醇,加入3.6mL氢氧化钠(2M,6.91mmol),于70℃下蒸发回流2.5小时,减压浓缩,溶于乙酸乙酯,用饱和氯化钠溶液调节pH值至5~6,有机相依次用饱和食盐水、蒸馏水洗涤;收集有机相,将有机相用无水硫酸镁干燥,过滤,然后减压浓缩得到粗产品,然后用石油醚冲洗抽滤得到最终产品E(20mg,42.3%)。
进行1H NMR,结果参阅图8,1H NMR(500MHz,Acetone-d6)δ7.61(d,J=7.4Hz,2H),7.54(d,J=8.1Hz,2H),7.43(t,J=7.7Hz,2H),7.38(d,J=8.1Hz,2H),7.32(t,J=7.3Hz,1H),5.93(s,1H),3.80(s,2H).
进行13C NMR,结果参阅图9,13C NMR(101MHz,Chloroform-d)δ206.26,141.69,139.73,139.53,130.07,129.67,127.98,127.69,127.59,116.82,104.20,28.47。
实施例2
1,2,4,5-四甲氧基苯(中间体A)的合成
将2,5二羟基-1,4苯醌(5.0g,36.0mmol)溶于甲醇中,缓慢滴加38%盐酸溶液(6mL,72.0mmol),室温搅拌反应12个小时,然后抽滤浓缩得到黄色固态中间体1;将此中间体溶于100mL水中,加入连二亚硫酸钠(10.0g,57.4mmol),100℃下,反应回流10分钟,于0℃下冷却结晶,抽滤得到粉白色晶状物中间体2(5g,81.6%)。将该中间体溶于DMSO中,加入氢氧化钾(3,71g,66.1mmol)使反应液pH呈碱性,室温搅拌10分钟,逐滴加入碘甲烷(4.2mL,66.1mmol)搅拌12小时。减压浓缩,用乙酸乙酯溶解,用7%盐酸溶液调节pH至5~6,依次用饱和食盐水、蒸馏水洗涤;收集有机相,将有机相用无水硫酸镁干燥,然后减压浓缩得到粗产品,过柱纯化得到白色晶状的中间体A(3.6g,61.8%)
进行1H NMR,结果参阅图1,1H NMR(400MHz,CDCl3)δ6.69(s,2H),3.71(s,12H).
1,2,4,5-四甲氧基-3甲基联苯基-苯(中间体B)的合成
将中间体A(1.0g,5.1mmol)放入圆底烧瓶中,烘箱干燥15分钟,加入HMPA(353uL,2mmol),换气3次,再加入60mL四氢呋喃作溶剂,在-40℃下无水无氧反应5min,缓慢加入正丁基锂(2.44mL,6.12mmol),将温度调至-10℃反应60分钟,逐滴加入4-溴甲基代联苯(2.746g,5.6mmol)反应10分钟。在置于室温反应12小时。减压浓缩得到粗产品,用有乙酸乙酯溶解,用7%盐酸溶液调节pH至5~6,依次用饱和食盐水、蒸馏水洗涤;收集有机相,将有机相用无水硫酸镁干燥,过滤,然后减压浓缩得到粗产品,过柱纯化得到油状中间体B。(276.86mg,15%)。
进行1H NMR,结果参阅图2,1H NMR(400MHz,CDCl3)δ7.54(d,J=7.6Hz,2H),7.46(d,J=8.1Hz,2H),7.38(t,J=7.6Hz,2H),7.33-7.26(m,3H),6.48(s,1H),4.07(s,2H),3.85(s,6H),3.66(s,6H).
进行13C NMR,结果参阅图3,13C NMR(101MHz,CDCl3)δ149.82,149.09,141.27,141.21,140.76,138.58,129.10,128.73,127.01,126.96,126.93,97.69,60.88,56.36,29.95.
2,5-二甲氧基-6-甲基联苯基-1,4-苯醌(中间体C)和2-甲氧基-5-羟基-6-甲基联苯基-1,4-苯醌(中间体D)的合成
将中间体B(200.0mg,0.546mmol)溶于3mL乙腈,用5mL乙腈/水(2/1)溶液溶解硝酸铈铵(748.8mg,1.37mmol),在-7℃冰盐浴中逐滴加入硝酸铈铵于中间体B中,搅拌反应15分钟。在室温下反应2h。减压浓缩得到粗产品,用有机溶剂溶解,依次用饱和食盐水、蒸馏水洗涤;收集有机相,将有机相用无水硫酸镁干燥,过滤,然后减压浓缩得到粗产品,过柱纯化得到固体中间产物C(40mg,21.9%)和D(56.9mg,32.5%)。
中间体C进行1H NMR,结果参阅图4,1H NMR(400MHz,CDCl3)δ7.55(d,J=7.5Hz,2H),7.48(d,J=8.1Hz,2H),7.41(t,J=7.6Hz,2H),7.36-7.30(m,3H),5.73(s,1H),4.12(s,3H),3.82(s,2H),3.80(s,3H).
中间体C进行13C NMR,结果参阅图5,13C NMR(101MHz,CDCl3)δ183.78,182.19,158.88,155.92,141.08,139.41,138.14,129.58,128.84,128.53,127.30,127.23,127.14,105.64,61.55,56.57,28.52.
中间体D进行1H NMR,结果参阅图6,1H NMR(400MHz,CDCl3)δ7.55(d,J=7.5Hz,2H),7.48(d,J=8.1Hz,2H),7.43-7.28(m,6H),5.85(s,1H),3.88-3.78(m,5H).
中间体D进行13C NMR,结果参阅图7,13C NMR(101MHz,CDCl3)δ182.87,181.49,161.27,151.76,141.11,139.48,137.98,129.65,128.83,127.32,127.22,127.16,117.93,102.49,56.97,28.22.
6-甲基联苯基-2,5-对羟基-1,4-苯醌(成品E)的合成
将中间体D(50.0mg,0.1561mmol)溶于乙醇,加入3.5mL氢氧化钠(2M,7.0245mmol),于80℃下蒸发回流2小时,减压浓缩,溶于乙酸乙酯,用7%盐酸溶液调节pH值至5~6,有机相依次用饱和食盐水、蒸馏水洗涤;收集有机相,将有机相用无水硫酸镁干燥,过滤,然后减压浓缩得到粗产品,然后用石油醚冲洗抽滤得到最终产品E(19.6mg,42.3%)。
进行1H NMR,结果参阅图8,1H NMR(500MHz,Acetone-d6)δ7.61(d,J=7.4Hz,2H),7.54(d,J=8.1Hz,2H),7.43(t,J=7.7Hz,2H),7.38(d,J=8.1Hz,2H),7.32(t,J=7.3Hz,1H),5.93(s,1H),3.80(s,2H).
进行13C NMR,结果参阅图9,13C NMR(101MHz,Chloroform-d)δ206.26,141.69,139.73,139.53,130.07,129.67,127.98,127.69,127.59,116.82,104.20,28.47。
实施例3
1,2,4,5-四甲氧基苯(中间体A)的合成
将2,5二羟基-1,4苯醌(5.0g,36.0mmol)溶于甲醇中,缓慢滴加38%盐酸(6mL,72.0mmol),室温搅拌反应15个小时,然后抽滤浓缩得到黄色固态中间体1;将此中间体溶于120mL水中,加入连二亚硫酸钠(10.0g,57.4mmol),80℃下,反应回流15分钟,于4℃下冷却结晶,抽滤得到粉白色晶状物中间体2(4.0g,65.3%)。将该中间体溶于DMSO中,加入氢氧化钾(3,3g,58.73mmol)使反应液pH呈碱性,室温搅拌15分钟,逐滴加入碘甲烷(4.5mL,58.73mmol)搅拌15小时。减压浓缩,用乙酸乙酯溶解,用7%盐酸溶液溶液调节pH至5~6,依次用饱和食盐水、蒸馏水洗涤;收集有机相,将有机相用无水硫酸镁干燥,然后减压浓缩得到粗产品,过柱纯化得到白色晶状的中间体A(2.45g 52.7%)。
进行1H NMR,结果参阅图1,1H NMR(400MHz,CDCl3)δ6.69(s,2H),3.71(s,12H).
1,2,4,5-四甲氧基-3甲基联苯基-苯(中间体B)的合成
将中间体A(1.0g,5.1mmol)放入圆底烧瓶中,烘箱干燥15分钟,加入HMPA(353uL,2mmol),换气5次,再加入60mL四氢呋喃作溶剂,在-30℃下无水无氧反应5min,缓慢加入正丁基锂(2.44mL,6.12mmol),将温度调至-5℃反应80分钟,逐滴加入4-溴甲基代联苯(2.746g,5.6mmol)反应15分钟。在置于室温反应15小时。减压浓缩得到粗产品,用有乙酸乙酯溶解,用7%盐酸溶液调节pH至5~6,依次用饱和食盐水、蒸馏水洗涤;收集有机相,将有机相用无水硫酸镁干燥,过滤,然后减压浓缩得到粗产品,过柱纯化得到油状中间体B。(182.0mg,9.7%)。
进行1H NMR,结果参阅图2,1H NMR(400MHz,CDCl3)δ7.54(d,J=7.6Hz,2H),7.46(d,J=8.1Hz,2H),7.38(t,J=7.6Hz,2H),7.33-7.26(m,3H),6.48(s,1H),4.07(s,2H),3.85(s,6H),3.66(s,6H).
进行13C NMR,结果参阅图3,13C NMR(101MHz,CDCl3)δ149.82,149.09,141.27,141.21,140.76,138.58,129.10,128.73,127.01,126.96,126.93,97.69,60.88,56.36,29.95.
2,5-二甲氧基-6-甲基联苯基-1,4-苯醌(中间体C)和2-甲氧基-5-羟基-6-甲基联苯基-1,4-苯醌(中间体D)的合成
将中间体B(180.0mg,0.4917mmol)溶于3.5mL乙腈,用5mL乙腈/水(2/1)溶液溶解硝酸铈铵(673.88mg,1.23mmol),在2℃冰盐浴中逐滴加入硝酸铈铵于中间体B中,搅拌反应10分钟。在室温下反应2.5h。减压浓缩得到粗产品,用有机溶剂溶解,依次用饱和食盐水、蒸馏水洗涤;收集有机相,将有机相用无水硫酸镁干燥,过滤,然后减压浓缩得到粗产品,过柱纯化得到固体中间产物C(21.87mg,12%)和D(66.47mg,38%)。
中间体C进行1H NMR,结果参阅图4,1H NMR(400MHz,CDCl3)δ7.55(d,J=7.5Hz,2H),7.48(d,J=8.1Hz,2H),7.41(t,J=7.6Hz,2H),7.36-7.30(m,3H),5.73(s,1H),4.12(s,3H),3.82(s,2H),3.80(s,3H).
中间体C进行13C NMR,结果参阅图5,13C NMR(101MHz,CDCl3)δ183.78,182.19,158.88,155.92,141.08,139.41,138.14,129.58,128.84,128.53,127.30,127.23,127.14,105.64,61.55,56.57,28.52.
中间体D进行1H NMR,结果参阅图6,1H NMR(400MHz,CDCl3)δ7.55(d,J=7.5Hz,2H),7.48(d,J=8.1Hz,2H),7.43-7.28(m,6H),5.85(s,1H),3.88-3.78(m,5H).
中间体D进行13C NMR,结果参阅图7,13C NMR(101MHz,CDCl3)δ182.87,181.49,161.27,151.76,141.11,139.48,137.98,129.65,128.83,127.32,127.22,127.16,117.93,102.49,56.97,28.22.
6-甲基联苯基-2,5-对羟基-1,4-苯醌(成品E)的合成
将中间体C(20mg,0.060mmol)和D(60mg,0.1874mmol)溶于乙醇,加入5.57mL氢氧化钠(2M,11.133mmol),于90℃下蒸发回流1.5小时,减压浓缩,溶于乙酸乙酯,用7%盐酸溶液调节pH值至5~6,有机相依次用饱和食盐水、蒸馏水洗涤;收集有机相,将有机相用无水硫酸镁干燥,过滤,然后减压浓缩得到粗产品,然后用石油醚冲洗抽滤得到最终产品E(16.17mg,34.2%)。
进行1H NMR,结果参阅图8,1H NMR(500MHz,Acetone-d6)δ7.61(d,J=7.4Hz,2H),7.54(d,J=8.1Hz,2H),7.43(t,J=7.7Hz,2H),7.38(d,J=8.1Hz,2H),7.32(t,J=7.3Hz,1H),5.93(s,1H),3.80(s,2H).
进行13C NMR,结果参阅图9,13C NMR(101MHz,Chloroform-d)δ206.26,141.69,139.73,139.53,130.07,129.67,127.98,127.69,127.59,116.82,104.20,28.47.
为了更好的说明本发明的效果,下面给出实施例中制备的α-葡萄糖苷酶抑制活性评价方法。
实验例1
将6-甲基联苯基-2,5-对羟基-1,4-苯醌(成品E)溶于DMSO中配成不同浓度的溶液;配制浓度为0.1mol/LpH=6.8的PBS缓冲溶液;用0.1mol/L,pH=6.8的磷酸盐缓冲溶液(PBS)配制0.7U/mL的α-葡萄糖苷酶溶液和1mmol/L的α-对硝基苯酚葡萄糖苷(PNPG)溶液;然后采用96孔板,每孔先加入35μL的pH=6.8的磷酸盐缓冲溶液,再加入10μL 0.7U/mL的α-葡萄糖苷酶溶液,再加入5μL不同浓度的样品溶液(溶于DMSO),空白对照组加等量的DMSO,混匀后,每孔重复4次,然后将板快速转移至多功能酶标仪中37℃育孵10min,其中环形摇震1min。将育孵完成的96孔板取出,用移液枪(排枪)每孔加入50μL的1mmol/Lα-对硝基苯酚葡萄糖苷溶液引发反应,然后将板快速转移至多功能酶标仪中37℃育孵反应30min,其中环形摇震3min。最后,将96孔板取出,每孔加入50μL的1mol/L的Na2CO3溶液终止反应,然后将板快速转移至多功能酶标仪中环形摇震30s,在405nm波长下,测定每孔的OD值。再通过公式:抑制率=(A0-A1)/A0×100%其中,A0为空白对照组,A1为样品组。计算抑制效果,通过抑制剂浓度和抑制效果的关系进行曲线拟合,从曲线计算得到每个样品对α-葡萄糖苷酶的半抑制浓度IC50值。
6-甲基联苯基-2,5-对羟基-1,4-苯醌(成品E)对α-葡萄糖苷酶的抑制曲线,如图10所示,使用GraphPad Prism计算出IC50值为11.15μM。在同样的测试条件下,阳性对照组阿卡波糖的IC50值为2392μM。因此,实验结果表明6-甲基联苯基-2,5-对羟基-1,4-苯醌(成品E)对α-葡萄糖苷酶具有很强的抑制作用。
实验例2
6-甲基联苯基-2,5-对羟基-1,4-苯醌(成品E)对α-葡萄糖苷酶的抑制机理
以α-对硝基苯酚葡萄糖苷(PNPG)为底物研究6-甲基联苯基-2,5-对羟基-1,4-苯醌(成品E)对α-葡萄糖苷酶的抑制机理,沿用实验例1的α-葡萄糖苷酶抑制活性评价反应体系,固定底物浓度为1mM,加入不同浓度的抑制剂,改变α-葡萄糖苷酶的浓度,测得的酶量的变化对反应进程的影响如图11所示,得到一组过原点的直线。随着抑制剂浓度的增加,线的斜率减小,说明了该抑制剂对α-葡萄糖苷酶的抑制是可逆的。在抑制剂存在的情况下,α-葡萄糖苷酶的活力降低,是因为抑制剂抑制了酶的活力,降低了酶的催化效率,而不是因为有效酶量的减少。
实验例3
6-甲基联苯基-2,5-对羟基-1,4-苯醌(成品E)对酪氨酸酶的抑制动力学
以PNPG为底物研究6-甲基联苯基-2,5-对羟基-1,4-苯醌(成品E)对α-葡萄糖苷酶的抑制类型,沿用上述α-葡萄糖苷酶抑制活性评价的反应体系,固定α-葡萄糖苷酶的浓度为0.7U/mL,改变底物的浓度,测定加入不同浓度的抑制剂对α-葡萄糖苷酶催化底物的影响。如图12A所示,采用Lineweaver-Burk双倒数作图法,以底物浓度的倒数1/[S]对反应速度的倒数1/V作图,可以得到一组斜率不同但相交于X轴的直线。随着抑制剂浓度的增大,酶的米氏常数(Km)值不变而最大反应速度(Vmax)值减小,说明该抑制剂是非竞争型抑制剂。换句话说,该抑制剂既可以与游离酶结合,也可以与酶-底物的复合物相结合。且Ki=Kis。如图12B所示,以Lineweaver-Burk双倒数图中的纵轴截距对抑制剂浓度的作图得到一条直线Y=0.05665+0.04385x,根据非竞争型的公式可以求出Ki=Kis=1.2919μM。
根据上述实验例的分析结果,可以推测上述的基于对羟基苯醌骨架的α-葡萄糖苷酶抑制剂可以用来制备降血糖药物、心脑血管疾病保护剂以及减肥药物。
需要说明的是,本发明所采用的原料,除特殊说明外,均通过常规手段制备或者通过商业渠道购买。
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Effective date of registration: 20230612 Address after: 309-1, Building 5, No. 333, Nanshan Road, Jianghai District, Jiangmen, Guangdong Province, 529000 Patentee after: Qiaoou (Jiangmen) New Material Technology Co.,Ltd. Address before: 529000 School of chemistry and environmental engineering, Wuyi University, No. 22, Dongcheng village, Jiangmen City, Guangdong Province Patentee before: WUYI University Patentee before: INTERNATIONAL HEALTHCARE INNOVATION INSTITUTE (JIANGMEN) |