CN111889080A - α-葡萄糖苷酶抑制剂及其应用 - Google Patents
α-葡萄糖苷酶抑制剂及其应用 Download PDFInfo
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- CN111889080A CN111889080A CN202010748803.0A CN202010748803A CN111889080A CN 111889080 A CN111889080 A CN 111889080A CN 202010748803 A CN202010748803 A CN 202010748803A CN 111889080 A CN111889080 A CN 111889080A
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- Prior art keywords
- alpha
- glucosidase
- diabetes
- glucosidase inhibitor
- cinnamic acid
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Abstract
本发明公开了α‑葡萄糖苷酶抑制剂及其应用，所述α‑葡萄糖苷酶抑制剂包括具有如下结构式的化合物：
其中，R1独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基或羟基；所述R1位于苯环的邻位、间位或对位。该抑制剂的活性成分为一类肉桂酸‑厚朴酚衍生物，其具有较强的α‑葡萄糖苷酶抑制活性，其抑制活性可达阿卡波糖的25～50倍左右，可用于治疗或辅助治疗II糖尿病，具有良好的潜在医疗保健价值。
Description
技术领域
本发明涉及医药技术领域，具体涉及α-葡萄糖苷酶抑制剂及其应用。
背景技术
糖尿病是一种代谢性、终身性疾病，其并发症严重威胁着人类的健康。糖尿病是由于胰 岛素分泌不足等原因而引起蛋白质、脂肪、水和电解质等一系列的代谢紊乱，其中以高血糖 为主要标志。近年来，糖尿病的患病率较高，目前已成为继肿瘤、心血管疾病之后第三大类 严重危害人类健康的慢性疾病。随着我国经济、社会的迅速发展，膳食结构和生活方式的改 变，以及人口老龄化速度的加快，糖尿病的患病率也呈现快速增加的趋势。在糖尿病患病率 快速上升的同时，我国糖尿病的知晓率、治疗率及控制率明显偏低。因此，糖尿病已成为一 个严重危害我国人群健康的公共卫生问题，对经济社会发展产生越来越严重的影响。
α-葡萄糖苷酶抑制剂已被作为单纯饮食控制不佳II型糖尿病患者的首选降糖药物，以及 I型糖尿病患者在使用胰岛素治疗时的首选辅助药物，临床上常用的α-葡萄糖苷酶抑制剂包 括阿卡波糖，米格列醇和伏格列波糖等。它通过抑制碳水化合物在小肠内的吸收，降低餐后 血糖及胰岛素水平，进而起到控制血糖的作用。近年来，大量临床调查研究表明，α-葡萄糖 苷酶抑制剂能够延缓糖耐量异常患者向II型糖尿病转化的进程，并且在调节糖脂代谢、提高 胰岛素敏感性、保护胰岛细胞功能及改善糖尿病血管并发症等方面具有更广阔的应用前景。
目前，临床上可选择的α-葡萄糖苷酶抑制剂均为化学合成，虽然有一定的降血糖效果， 但其种类少、作用效果有限，因此，研究得到新的高效低毒的α-葡萄糖苷酶抑制剂，为临床 应用提供更多的选择仍具有十分重要的意义。
厚朴酚是植物厚朴中的主要成分，因其结构简单且具有较好的生物活性而被广泛研究。 厚朴酚具有广泛的生物活性，如抗肿瘤、抑菌、抗溃疡、抗过敏、止痛、消炎和防龋等作用。 肉桂酸类化合物是水果、咖啡和葡萄酒中天然存在的芳香脂肪酸，其结构的共同特点是含有 一个丙烯酸基团取代的苯环。目前，有研究表明，肉桂酸及其衍生物常作为消炎消肿等药物 成分。但目前市场未见以上述药物化合制成的具有抑制α-葡萄糖苷酶活性的药物。然而，尚 未有将肉桂酸与厚朴酚的拼合骨架，即肉桂酸-厚朴酚衍生物应用于抑制葡萄糖苷酶中的相关 报道。
发明内容
本发明旨在至少解决现有技术中存在的技术问题之一。为此，本发明提出一类具有肉桂 酸-厚朴酚型活性成分的α-葡萄糖苷酶抑制剂，对α-葡萄糖苷酶具有较高的抑制活性。
本发明还提出了上述α-葡萄糖苷酶的应用。
根据本发明的第一方面实施方式的α-葡萄糖苷酶抑制剂，所述α-葡萄糖苷酶抑制剂包括 具有如下结构式的化合物：
其中，R1独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基或羟基；
所述R1位于苯环的邻位、间位或对位。
根据本发明实施方式的α-葡萄糖苷酶抑制剂，至少具有以下有益效果：
本发明的抑制剂中的活性成分为一类肉桂酸-厚朴酚衍生物，其具有较强的α-葡萄糖苷酶 抑制活性，其抑制活性可达阿卡波糖的25～50倍左右；本发明利用骨架拼接原理将厚朴酚结 构与肉桂酸相连，由于两者的作用位点不同，制备得到的肉桂酸-厚朴酚衍生物能够增强抑制 活性和提高选择性；该抑制剂的活性成分不仅毒性低，而且能够有效抑制α-葡萄糖苷酶的活 性，具有良好的潜在医疗保健价值。
根据本发明的一些实施方式，所述R1独立地选自C1～10烷基、C1～10烷氧基或C1～10卤代 烷基。
根据本发明的一些实施方式，所述R1独立地选自C1～4烷基、C1～4烷氧基或C1～4卤代烷 基。
根据本发明的一些实施方式，所述R1独立地选自氢原子、羟基、卤素、甲基、甲氧基或 三氟甲基。
根据本发明的一些实施方式，以下结构所示的化合物具有最好的α-葡萄糖苷酶抑制效果：
根据本发明的第一方面实施方式的应用，上述α-葡萄糖苷酶抑制剂治疗糖尿病药物的制 备中。
根据本发明实施方式的应用，至少具有以下有益效果：本发明的α-葡萄糖苷酶抑制剂对 α-葡萄糖苷酶表现出显著的抑制活性，可达阿卡波糖的25～50倍左右。
根据本发明的一些实施方式，所述糖尿病为II型糖尿病。
根据本发明的一些实施方式，所述药物的剂型选自片剂、胶囊剂、软胶囊剂、颗粒剂、 丸剂、口服液、干混悬剂、滴丸剂、干浸膏剂、注射剂或输注剂。
根据本发明的一些实施方式，所述药物还包括药学上可接受的载体。
进一步地，所述药学上可接受的载体是指药学领域常规的药物载体，可以为任意合适的 生理学或药学上可接受的药物辅料；优选地，所述药用辅料选自崩解剂、稀释剂、润滑剂、 粘合剂、湿润剂、矫味剂、助悬剂、表面活性剂或防腐剂中的至少一种；更优选地，所述崩 解剂选自玉米淀粉、马铃薯淀粉、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、低取代羟丙基纤维 素、交联羧甲纤维素钠、羧甲基纤维素、羧甲基纤维素钙或藻酸中的至少一种；更优选地， 所述稀释剂选自乳糖、蔗糖、甘露醇、玉米淀粉、马铃薯淀粉、磷酸钙、柠檬酸钙或结晶纤 维素中的至少一种；更优选地，所述润滑剂选自微粉硅胶、硬脂酸镁、硬脂酸钙、硬脂酸、滑石粉或无水硅胶中的至少一种；更优选地，所述粘合剂选自阿拉伯胶、明胶、糊精、羟丙基纤维素、甲基纤维素或聚乙烯吡咯烷酮中的至少一种；更优选地，所述湿润剂选自十二烷基硫酸钠；更优选地，所述矫味剂可以为阿斯巴甜、甜菊甙、蔗糖、麦芽糖醇或柠檬酸中的至少一种；更优选地，所述助悬剂选自阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素钠、羟 甲基纤维素或硬脂酸铝凝胶中的至少一种；更优选地，所述表面活性剂选自卵磷脂、山梨糖醇酐单油酸酯或单硬脂酸甘油酯中的至少一种；更优选地，所述防腐剂选自对羟苯甲酸甲酯 或对羟苯甲酸丙酯中的至少一种。
根据本发明的一些实施方式，还提供了一种用于辅助治疗糖尿病的药物，所述药物包括 上述α-葡萄糖苷酶抑制剂。
进一步地，所述糖尿病为II型糖尿病。
本文中“C1～10烷基”是指碳原子个数为1至10的烷基，意指包括具有指定碳原子数目 的支链和直链的饱和脂族烃基。例如，C1～10，如在“C1～10烷基”中定义为包括在直链或者支 链结构中具有1、2、3、4、5、6、7、8、9或者10个碳原子的基团。例如，“C1～10烷基”具 体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基、庚基、辛基、 壬基和癸基等。
“C1～4烷基”表示碳原子个数为1至4的烷基，例如包括甲基、乙基、丙基、异丙基、 正丁基、异丁基或叔丁基等。
类似地，“C1～10烷氧基”表示通过氧原子连接的如上文所定义的烷基，如甲氧基、乙氧 基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基等。同理，“C1～10卤代烷基”指 卤素取代如上文所定义的烷基。
术语“卤素”包括F、Cl、Br或I。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显， 或通过本发明的实践了解到。
附图说明
图1为本发明实施例中肉桂酸-厚朴酚衍生物5h在体外对α-葡萄糖苷酶的酶动力学图；
图2为本发明实施例中肉桂酸-厚朴酚衍生物5i在体外对α-葡萄糖苷酶的酶动力学图；
图3为本发明实施例中肉桂酸-厚朴酚衍生物5j在体外对α-葡萄糖苷酶的酶动力学图；
图4为本发明实施例中肉桂酸-厚朴酚衍生物5h在体外对α-葡萄糖苷酶的底物动力学双 倒数图；
图5为本发明实施例中肉桂酸-厚朴酚衍生物5h在体外对α-葡萄糖苷酶的底物动力学斜 率-浓度关系曲线图；
图6为本发明实施例中肉桂酸-厚朴酚衍生物5h在体外对α-葡萄糖苷酶的底物动力学截 矩-浓度关系曲线图；
图7为本发明实施例中肉桂酸-厚朴酚衍生物5i在体外对α-葡萄糖苷酶的底物动力学双 倒数图；
图8为本发明实施例中肉桂酸-厚朴酚衍生物5i在体外对α-葡萄糖苷酶的底物动力学斜 率-浓度关系曲线图；
图9为本发明实施例中肉桂酸-厚朴酚衍生物5i在体外对α-葡萄糖苷酶的底物动力学截 矩-浓度关系曲线图；
图10为本发明实施例中肉桂酸-厚朴酚衍生物5j在体外对α-葡萄糖苷酶的底物动力学双 倒数图；
图11为本发明实施例中肉桂酸-厚朴酚衍生物5j在体外对α-葡萄糖苷酶的底物动力学斜 率-浓度关系曲线图；
图12为本发明实施例中肉桂酸-厚朴酚衍生物5j在体外对α-葡萄糖苷酶的底物动力学截 矩-浓度关系曲线图；
图13为本发明实施例中肉桂酸-厚朴酚衍生物5j与α-葡萄糖苷酶的相互作用的分子对接 图；图中，(a)和(b)为5j与α-葡萄糖苷酶的对接模拟图，(c)显示了5j与活性口袋处的 氨基酸残基的结合相互作用。
具体实施方式
为详细说明本发明的技术内容、所实现目的及效果，以下结合实施方式并配合附图予以 说明。
实施例1：α-葡萄糖苷酶抑制剂及其制备
本发明实施例中的α-葡萄糖苷酶抑制剂均为肉桂酸-厚朴酚衍生物，肉桂酸-厚朴酚衍生 物的结构式为：
其中，R1独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基或羟基；R1位于苯环的邻位、间位或对位。
具体地，在本发明的实施例中，包括如下表1所列出的化合物(分别记做4a～4j和5a～5j)：
表1.肉桂酸-厚朴酚衍生物
在本发明中，“2-”对应苯环的邻位，“3-”对应苯环的间位，“4-”对应苯环的对位。
表1中4a～4j的化合物对应单分子肉桂酸与厚朴酚拼合的如式I所示的化合物，其结构式 为：
5a～5j的化合物对应双分子肉桂酸与厚朴酚拼合的如式II所示的化合物，其结构式为：
上表中的化合物可以通过下述步骤制备得到，由于基团对反应的影响，制备的方法有所 不同：
制备方法一(适用于制备化合物4a～4g和5a～5g)：在1-乙基-3-(3-二甲基氨基丙基) 碳二亚胺盐酸盐(EDCI)和4-二甲基氨基吡啶(DMAP)存在下，用等摩尔的厚朴酚2将取代的肉桂酸1酯化，可得到肉桂酸-厚朴酚衍生物(4a～4g)。而用双摩尔厚朴酚取代肉桂酸可制得肉桂酸-厚朴酚衍生物(5a～5g)。制备方法一的化学反应式如下所示：
上式中试剂和条件为：(a)EDCI，DMAP，DCM，
4h。
制备方法二(由于肉桂酸中羟基的影响，适用于制备化合物4h～j和5h～j)：首先用叔丁 基二甲基氯硅烷(TBSCl)保护羟基肉桂酸3，得到TBSCl保护的肉桂酸x，TBSCl保护的肉 桂酸x与不同摩尔厚朴酚2的酯化反应得到中间体y和z，中间体在HF存在下进行脱保护反 应，最终分别生成肉桂酸-厚朴酚衍生物4h～j和5h～j。制备方法二的化学反应式如下所示：
上式中试剂和条件：(a)TBSCl，咪唑，DMAP，DMF，
(b)EDCI，DMAP， DCM，
4h；(c)HF，THF，室温，1h。
采用以上典型的合成策略以中等至良好的产率生产肉桂酸-厚朴酚衍生物4a-j和5a-j；以 下为化合物的性状、产率、核磁和质谱结果表征：
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl cinnamate(4a,C27H24O3).白色固体；产率 68.2％；mp:79-81℃；1H NMR(500MHz,氯仿-d)δ7.67(d,J＝16.0Hz,1H),7.54-7.45(m, 2H),7.42-7.35(m,3H),7.29(dd,J＝8.2,2.2Hz,1H),7.23(d,J＝2.2Hz,1H),7.20(d,J＝8.2Hz, 1H),7.04(dd,J＝8.3,2.3Hz,1H),6.98(d,J＝2.2Hz,1H),6.89(d,J＝8.2Hz,1H),6.42(d,J＝ 15.9Hz,1H),5.95(dddt,J＝40.4,16.7,10.0,6.7Hz,2H),5.17-5.09(m,2H),5.05-4.94(m,2H), 3.45(d,J＝6.8Hz,2H),3.30(d,J＝6.7Hz,2H).13CNMR(126MHz,氯仿-d))δ29.74,30.18(d), 31.50(d),39.46(d),115.54,116.28,116.56(d),123.05,123.93,128.35,128.96,129.71(d),130.13, 130.71(d),131.91,134.04,136.81,137.79,138.72,146.92(d),151.33,165.78,HRMS:calcd for C27H24O3[M+Na]+419.1617,found 419.1615。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(p-tolyl)acrylate(4b,C28H26O3).白色固 体；产率51.8％；mp:75-77℃,1H NMR(500MHz,氯仿-d)δ7.65(d,J＝16.0Hz,1H),7.38(d, J＝7.8Hz,2H),7.29(dd,J＝8.3,2.2Hz,1H),7.23(d,J＝2.2Hz,1H),7.19(dd,J＝8.1,1.7Hz, 3H),7.03(dd,J＝8.3,2.3Hz,1H),6.98(d,J＝2.2Hz,1H),6.89(d,J＝8.2Hz,1H),6.37(d,J＝ 16.0Hz,1H),5.95(dddt,J＝39.9,16.7,9.9,6.7Hz,2H),5.17-5.09(m,2H),5.04-4.96(m,2H), 3.45(d,J＝6.8Hz,2H),3.30(d,J＝6.6Hz,2H),2.37(s,3H).13C NMR(126MHz,氯仿-d)δ 166.00,146.97(d),141.32,138.64,137.80,136.83,131.89(d),131.33,130.66,130.18,129.67(d), 128.37,123.99,123.08,116.41(d),115.48(d),39.46(d),21.56,HRMS:calcd for C28H26O3 [M+H]+411.1954,found 411.1953。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(4-methoxyphenyl)acrylate(4c, C28H26O4).白色固体；产率52.8％；mp:87-88℃,1H NMR(500MHz,氯仿-d)δ7.63(d,J＝ 15.9Hz,1H),7.47-7.41(m,2H),7.28(dd,J＝8.2,2.2Hz,1H),7.23(d,J＝2.2Hz,1H),7.19(d,J ＝8.2Hz,1H),7.03(dd,J＝8.3,2.3Hz,1H),6.98(d,J＝2.2Hz,1H),6.89(d,J＝8.4Hz,3H), 6.28(d,J＝16.0Hz,1H),5.95(dddt,J＝37.2,16.7,10.0,6.7Hz,2H),5.18-5.08(m,2H),5.05- 4.95(m,2H),3.84(s,3H),3.44(d,J＝6.8Hz,2H),3.32-3.28(m,2H).13C NMR(126MHz,氯 仿-d)δ166.16,161.77,151.39,147.04,146.63,138.58,137.81,136.85,131.88(d),130.68,130.23, 130.11,129.65(d),126.81,124.07,123.10,116.41(d),115.53,114.39,113.92,55.43,39.46(d), 29.74,HRMS:calcd for C28H26O4[M+H]+427.1903,found 427.1900。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(4-fluorophenyl)acrylate(4d, C27H23FO3).白色固体；产率88.1％；mp:89-90℃,1H NMR(500MHz,氯仿-d)δ7.63(d,J＝ 16.0Hz,1H),7.50-7.44(m,2H),7.29(dd,J＝8.3,2.2Hz,1H),7.23(d,J＝2.2Hz,1H),7.19(d,J ＝8.2Hz,1H),7.10-7.02(m,3H),6.97(d,J＝2.2Hz,1H),6.89(d,J＝8.2Hz,1H),6.33(d,J＝ 16.0Hz,1H),5.94(dddt,J＝40.3,16.7,10.0,6.6Hz,2H),5.19-5.08(m,2H),5.04-4.94(m,2H), 3.45(d,J＝6.8Hz,2H),3.30(dd,J＝6.6,1.8Hz,2H).13CNMR(126MHz,氯仿-d)δ165.66, 151.32,146.90,145.54,138.77,137.79,136.79,131.91(d),130.66,130.28(d),130.10,129.71(d), 39.45(d),HRMS:calcd for C28H23FO3[M+H]+415.1703,found 415.1702。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(4-chlorophenyl)acrylate(4e, C27H23ClO3).白色固体；产率69.9％；mp:78-79℃,1H NMR(500MHz,氯仿-d)δ7.61(d,J＝ 16.0Hz,1H),7.43-7.39(m,2H),7.37-7.33(m,2H),7.29(dd,J＝8.3,2.2Hz,1H),7.23(d,J＝ 2.2Hz,1H),7.19(d,J＝8.2Hz,1H),7.04(dd,J＝8.3,2.3Hz,1H),6.97(d,J＝2.2Hz,1H),6.89 (d,J＝8.3Hz,1H),6.38(d,J＝16.0Hz,1H),5.94(dddt,J＝40.5,16.7,10.0,6.7Hz,2H),5.17- 5.09(m,2H),5.03-4.95(m,2H),3.45(d,J＝6.8Hz,2H),3.32-3.27(m,2H).13C NMR(126 MHz,氯仿-d)δ165.52,151.31,146.88,145.36,138.80,137.78,136.74(d),132.52,131.92, 130.65,130.05,129.73(d),129.49,129.26,123.88,123.00,117.16,116.57,116.24,115.54,39.45 (d),HRMS:calcd for C28H23ClO3[M+H]+431.1408,found 431.1400。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(4-bromophenyl)acrylate(4f, C27H23BrO3).白色固体；产率61.1％；mp:100-102℃,1H NMR(500MHz,氯仿-d)δ7.59(d, J＝16.0Hz,1H),7.53-7.50(m,2H),7.36-7.32(m,2H),7.29(dd,J＝8.2,2.2Hz,1H),7.23(d,J ＝2.2Hz,1H),7.19(d,J＝8.2Hz,1H),7.04(dd,J＝8.3,2.3Hz,1H),6.97(d,J＝2.2Hz,1H), 6.89(d,J＝8.2Hz,1H),6.39(d,J＝16.0Hz,1H),5.94(dddt,J＝40.5,16.7,9.9,6.7Hz,2H),5.18 -5.09(m,2H),5.07-4.92(m,2H),3.45(d,J＝6.8Hz,2H),3.29(d,J＝6.6Hz,2H).13C NMR (126MHz,氯仿-d)δ165.50,151.30,146.87,145.43,138.81,137.77,136.76,132.95,132.23, 131.92,130.65,130.05,129.81-129.63(m),125.10,123.86,122.99,117.28,116.57,116.24, 115.54,39.45(d),HRMS:calcd for C28H23BrO3[M+Na]+497.0722,found 497.0722。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(4-(trifluoromethyl)phenyl)acrylate(4g, C28H23F3O3).白色固体；产率65.6％；mp:74-76℃,1H NMR(500MHz,氯仿-d)δ7.68(s, 1H),7.64(d,J＝8.4Hz,5H),7.58(d,J＝8.1Hz,4H),7.30(dd,J＝8.2,2.2Hz,2H),7.24(d,J＝ 2.2Hz,2H),7.20(d,J＝8.2Hz,2H),7.04(dd,J＝8.2,2.3Hz,2H),6.97(d,J＝2.3Hz,2H),6.89 (d,J＝8.2Hz,2H),6.48(d,J＝16.0Hz,2H),5.94(dddt,J＝42.5,16.8,10.0,6.7Hz,4H),5.18- 5.09(m,5H),5.04-4.95(m,4H),3.45(d,J＝6.8Hz,4H),3.30(dd,J＝6.7,1.6Hz,4H).13C NMR (126MHz,氯仿-d)δ165.18,151.28,146.80,144.84,138.93,137.76,136.73,131.95,130.64, 129.99,129.77(d),128.44,125.93(d),123.78,122.95,119.20,116.61,116.21,115.55,39.45(d), HRMS:calcd for C28H23F3O3[M+H]+465.1672,found 465.1667。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(2-hydroxyphenyl)acrylate(4h, C27H24O4).淡黄色固体；产率85.5％；mp:107-109℃,1H NMR(500MHz,氯仿-d)δ7.97(d, J＝16.0Hz,1H),7.39(dd,J＝7.8,1.6Hz,1H),7.22(dd,J＝9.4,1.8Hz,2H),7.18(d,J＝8.3Hz, 1H),7.02(dd,J＝8.2,2.3Hz,1H),6.99(d,J＝2.2Hz,1H),6.91-6.86(m,2H),6.77(dd,J＝8.1, 1.1Hz,1H),6.57(d,J＝16.1Hz,1H),5.94(dddt,J＝36.1,16.8,10.0,6.7Hz,2H),5.15-5.09(m, 2H),5.03-4.95(m,2H),4.13(d,J＝7.2Hz,1H),3.43(d,J＝6.7Hz,2H),3.29(dd,J＝6.6,1.6 Hz,2H).13C NMR(126MHz,氯仿-d)δ166.81,155.51,151.24,146.99,142.54,138.64,137.78, 136.84,132.04-131.86(m),130.76,130.28,129.76-129.44(m),124.02,123.06,121.30,120.81, 116.90,116.49,116.33,115.56,60.60,39.60,39.28,HRMS:calcd for C27H24O4[M+H]+413.1747, found 413.1741。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(3-hydroxyphenyl)acrylate(4i, C27H24O4).淡黄色固体；产率87.4％；mp:110-112℃,1H NMR(500MHz,氯仿-d)δ7.58(d, J＝16.0Hz,1H),7.28(d,J＝2.2Hz,1H),7.25-7.21(m,2H),7.19(t,J＝8.4Hz,1H),7.02(td,J ＝5.2,2.4Hz,2H),6.98(d,J＝2.2Hz,1H),6.92-6.87(m,2H),6.84(dd,J＝8.1,2.5Hz,1H), 6.39-6.32(m,1H),5.93(dddt,J＝33.7,16.7,9.9,6.7Hz,2H),5.17-5.08(m,2H),5.03-4.95(m, 2H),3.43(d,J＝6.8Hz,2H),3.29(dd,J＝6.5,1.6Hz,2H).13C NMR(126MHz,氯仿-d)δ 166.01,156.06,151.24,146.80(d),138.79,137.76,136.79,135.48,131.97(d),130.71,130.14, 129.72(d),123.89,122.98,121.11,118.02,116.80,116.55,116.33,115.59,114.63,39.44(d), HRMS:calcd for C27H24O4[M+H]+413.1747,found413.1740。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(4-hydroxyphenyl)acrylate(4j, C27H24O4).Light白色固体；产率58.6％；mp:114-116℃,1H NMR(500MHz,氯仿-d)δ7.60 (d,J＝15.9Hz,1H),7.38-7.32(m,2H),7.22(d,J＝2.2Hz,1H),7.18(d,J＝8.2Hz,1H),7.03 (dd,J＝8.2,2.3Hz,1H),6.98(d,J＝2.2Hz,1H),6.89(d,J＝8.2Hz,1H),6.81-6.76(m,2H), 6.24(d,J＝15.9Hz,1H),5.94(dddt,J＝31.3,16.8,10.0,6.7Hz,2H),5.17-5.07(m,2H),5.04- 4.94(m,2H),3.43(d,J＝6.7Hz,2H),3.29(d,J＝6.4Hz,2H).13CNMR(126MHz,氯仿-d)δ 166.51(d),158.26(d),151.23(d),147.40-146.66(m),138.70(d),137.77,136.80,131.98(d), 130.73(d),130.36,130.18(d),129.71(d),126.70(d),124.01,123.07,116.44(d),115.77(dd), 113.66(d),39.45(d),HRMS:calcd for C27H24O4[M+H]+413.1747,found 413.1739。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-phenylacrylate)(5a,C36H30O4).白色固 体；产率47.3％；mp:124-126℃,1H NMR(500MHz,氯仿-d)δ7.66(d,J＝16.0Hz,2H),7.50 (dd,J＝6.6,2.9Hz,4H),7.39(hept,J＝3.7Hz,5H),7.20(dd,J＝4.4,1.9Hz,5H),6.47(d,J＝ 16.0Hz,2H),5.94(ddt,J＝16.8,10.1,6.7Hz,2H),5.08(q,J＝1.8Hz,1H),5.06-5.00(m,3H), 3.39(d,J＝6.7Hz,3H).13C NMR(126MHz,氯仿-d)δ165.46,146.36(d),137.57,137.06, 134.27,131.30,130.59,130.25,128.98(d),128.32,122.54,117.32,116.21,39.60,HRMS:calcd for C36H30O4[M+H]+527.2216,found 527.2211。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(p-tolyl)acrylate)(5b,C38H34O4).白色 固体；产率50.4％；mp:132-134℃,1H NMR(500MHz,氯仿-d)δ7.64(d,J＝16.0Hz,2H), 7.43-7.38(m,4H),7.22-7.15(m,10H),6.41(d,J＝15.9Hz,2H),5.94(ddt,J＝16.8,10.0,6.7 Hz,2H),5.09-5.00(m,4H),3.43-3.36(m,4H),2.38(s,6H).13C NMR(126MHz,氯仿-d)δ 165.66,146.49,141.05,137.47,137.08,131.56,131.29,130.27,129.66,128.96,128.32,122.58, 116.19(d,J＝4.2Hz),39.60,21.56,HRMS:calcdfor C38H34O4[M+H]+555.2529,found 555.2523。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(4-methoxyphenyl)acrylate)(5c, C38H34O6).白色固体；产率40.1％；mp:123-125℃,1H NMR(500MHz,氯仿-d)δ7.61(d,J＝ 15.9Hz,2H),7.49-7.43(m,4H),7.18(d,J＝2.0Hz,5H),6.93-6.87(m,4H),6.33(d,J＝15.9 Hz,2H),5.93(ddt,J＝16.7,9.9,6.7Hz,2H),5.10-4.99(m,4H),3.84(s,5H),3.38(dd,J＝6.7, 1.5Hz,4H).13C NMR(126MHz,氯仿-d)δ165.78,161.59,146.55,145.91,137.38,137.11, 131.28,130.32,130.02,128.91,127.07,122.59,116.14,114.78,114.34,55.43,39.59,HRMS: calcd for C38H34O6[M+H]+587.2428,found 587.2421。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(4-fluorophenyl)acrylate)(5d, C36H28F2O4).白色固体；产率44.2％；mp:121-122℃,1H NMR(500MHz,氯仿-d)δ7.60(d, J＝16.0Hz,2H),7.53-7.44(m,4H),7.23-7.15(m,6H),7.11-7.04(m,4H),6.38(d,J＝16.0Hz, 2H),5.94(ddt,J＝16.8,10.0,6.7Hz,2H),5.08(q,J＝1.7Hz,1H),5.06-5.00(m,3H),3.39(dt,J ＝6.7,1.5Hz,4H).13C NMR(126MHz,氯仿-d)δ165.29,146.42,144.91,137.60,137.03,131.30, 130.52(d),130.20(d),129.00,122.48,117.06(d),116.19,116.03,39.58,HRMS:calcd for C36H28F2O4[M+H]+563.2028,found 563.2021。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(4-chlorophenyl)acrylate)(5e, C36H28Cl2O4).淡黄色固体；产率37.6％；mp:150-154℃,1H NMR(500MHz,氯仿-d)δ7.58 (d,J＝16.0Hz,2H),7.46-7.40(m,4H),7.35(d,J＝8.5Hz,4H),7.24-7.15(m,6H),6.42(d,J＝ 15.9Hz,2H),5.94(ddt,J＝16.8,9.9,6.7Hz,2H),5.08(q,J＝1.7Hz,1H),5.06-5.00(m,3H), 3.39(d,J＝6.7Hz,4H).13C NMR(126MHz,氯仿-d)δ165.17,146.38,144.78,137.66,137.01, 136.52,132.73,131.30,130.20,129.34(d),129.03,122.46,117.87,116.22,39.57,HRMS:calcd for C36H28Cl2O4[M+H]+595.1437,found 595.1429。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(4-bromophenyl)acrylate)(5f, C36H28Br2O4).白色固体；产率53.9％；mp:158-159℃,1H NMR(500MHz,氯仿-d)δ7.56(d, J＝15.9Hz,2H),7.53-7.49(m,4H),7.38-7.33(m,4H),7.23-7.15(m,6H),6.43(d,J＝16.0Hz, 2H),5.93(ddt,J＝16.8,10.0,6.7Hz,2H),5.08(q,J＝1.7Hz,1H),5.06-5.01(m,3H),3.39(d,J ＝6.4Hz,4H).13C NMR(126MHz,氯仿-d)δ165.16,146.37,144.85,137.68,137.00,133.15, 132.20,131.30,130.18,129.65,129.04,124.91,122.45,117.98,116.23,39.57,HRMS:calcd for C36H28Br2O4[M+H]+683.0427,found 683.0419。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(4-(trifluoromethyl)phenyl)acrylate) (5g,C38H28F6O4).白色固体；产率39.3％；mp:125-127℃,1H NMR(500MHz,氯仿-d)δ7.64 (d,J＝8.1Hz,5H),7.60(t,J＝8.6Hz,5H),7.24-7.17(m,6H),6.54(s,1H),6.51(s,1H),5.94 (ddt,J＝16.8,10.0,6.7Hz,2H),5.09(q,J＝1.7Hz,1H),5.07-5.01(m,3H),3.40(dd,J＝6.8,1.6 Hz,4H).13C NMR(126MHz,氯仿-d)δ164.84,146.31,144.33,137.84,137.56,136.97,131.32, 130.15,129.11,128.40,125.92(q),122.41,119.86,116.27,39.57,HRMS:calcd for C38H28F6O4 [M+K]+701.1523,found701.1516。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(4-(trifluoromethyl)phenyl)acrylate) (5h,C36H30O6).白色固体；产率38.5％；mp:168-170℃,1H NMR(500MHz,DMSO-d6)δ 10.34(s,2H),7.90(d,J＝16.1Hz,2H),7.58(dd,J＝7.9,1.7Hz,2H),7.26(ddd,J＝8.6,7.2,1.7 Hz,2H),7.22(dd,J＝8.3,2.1Hz,2H),7.18(d,J＝8.2Hz,2H),7.13(d,J＝2.1Hz,1H),6.92(dd, J＝8.2,1.1Hz,2H),6.84(td,J＝7.6,1.2Hz,2H),6.62(d,J＝16.1Hz,2H),5.91(ddt,J＝16.9, 10.0,6.8Hz,1H),5.05(dq,J＝17.0,1.7Hz,2H),4.97(dt,J＝10.0,1.6Hz,1H),3.36(d,J＝7.3 Hz,4H).13C NMR(126MHz,DMSO-d6)δ165.92,157.55,146.59,142.33,137.69(d),132.64, 131.21,130.22,129.52(d),123.58,120.94,119.93,116.58(t),HRMS:calcd for C36H30O6[M+H]+ 559.2115,found559.2108。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(3-hydroxyphenyl)acrylate)(5i, C36H30O6).淡黄色固体；产率47.5％；mp:181-182℃,1H NMR(500MHz,DMSO-d6)δ9.70 (s,2H),7.57(d,J＝16.0Hz,2H),7.27-7.18(m,6H),7.17-7.10(m,4H),7.03(t,J＝2.1Hz,2H), 6.86(dd,J＝8.3,2.4Hz,2H),6.52(d,J＝16.0Hz,2H),5.92(ddt,J＝16.8,10.0,6.8Hz,2H),5.05 (dq,J＝17.0,1.7Hz,2H),4.98(dq,J＝10.0,1.4Hz,2H),3.37(s,4H).13C NMR(126MHz, DMSO-d6)δ165.29,158.22,146.67(d),137.78,135.47,131.23,130.52,130.16,129.49,123.48, 119.94,118.54,117.24,116.58,115.26,HRMS:calcd for C36H30O6[M+H]+559.2115, found559.2109。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(4-hydroxyphenyl)acrylate)(5j, C36H30O6).白色固体；产率35.8％；mp:175-176℃,1H NMR(500MHz,DMSO-d6)δ10.11(s, 2H),7.61-7.51(m,6H),7.21(dd,J＝8.4,2.1Hz,2H),7.17(d,J＝8.2Hz,2H),7.12(d,J＝2.2 Hz,2H),6.83-6.78(m,4H),6.39(d,J＝15.9Hz,2H),5.90(ddt,J＝16.8,10.0,6.8Hz,2H),5.04 (dq,J＝17.0,1.7Hz,2H),4.96(dq,J＝9.8,1.4Hz,2H),3.36(s,4H).13C NMR(126MHz, DMSO-d6)δ165.75,160.70,146.76(d),137.67(d),131.14(d),130.27,129.39,125.36,123.57, 116.44(d),113.50,HRMS:calcd forC36H30O6[M+H]+559.2115,found 559.2109。
实施例2：化合物的α-葡萄糖苷酶抑制活性测试
一、微孔板法验证α-葡萄糖苷酶体外抑制活性：
1.1原理：α-葡萄糖苷酶催化水解4-硝基苯-α-D-吡喃葡萄糖苷(PNPG)，产生硝基苯酚 (PNP，黄色物质，在405nm有最大吸收)，α-葡萄糖苷酶抑制剂可抑制α-葡萄糖苷酶与底 物结合从而降低PNP的释放量，以一定时间内反应体系中PNP的含量变化来计算提取物的 酶抑制活性。
(1)100mM pH6.8的磷酸缓冲液(PBS)的配制：分别取17.907g的磷酸氢二钠和6.804g 的磷酸二氢钾混合溶解，然后加去离子水定容至1L，用pH计测定pH值。
(2)肉桂酸-厚朴酚系列衍生物溶液的配制：称取一定量的系列肉桂酸-厚朴酚衍生物加 到二甲基亚砜(DMSO)溶液当中进行溶解，制得浓度为10mM的母液，然后根据所需浓度 用100mM pH6.8的磷酸缓冲液进行稀释，实验当中DMSO的终浓度不超过5％。
(3)pNPG溶液的配制：准确称取0.006025g pNPG溶解于20mL的pH6.8的PBS中充 分溶解，即得1mM的pNPG母液。
α-葡萄糖苷酶溶液的配制：将酶活力为100U的酶加适量100mM的PBS配成工作浓度分 别为0.075U/mL、0.1U/mL、0.125U/mL、0.15U/mL并分装冷冻。
阿卡波糖溶液的配制：准确称取阿卡波糖0.06456g，置于10mL容量瓶中，
然后用100mM pH6.8的PBS溶液定容至刻度，即得到10mM的母液。
1.2实验步骤
(1)肉桂酸-厚朴酚衍生物4a～4j和5a～5j的α-葡萄糖苷酶抑制活性测定，具体步骤为： 将10μLα-葡萄糖苷酶(终浓度为0.1U/mL)和10μL测试化合物添加到130μL PBS(0.1M磷 酸盐，pH6.8)中，并将混合物在37℃下孵育10分钟。然后将PNPG(终浓度为0.25mM) 添加到该混合物中，并使用Microplate reader测定其在405nm处的吸光度变化。所有实验均 进行了四次测定。还分别测定了母体化合物肉桂酸和厚朴酚的α-葡萄糖苷酶抑制作用，以及阳性样品阿卡波糖的α-葡萄糖苷酶抑制作用。每种化合物的IC50值可从抑制率对化合物浓度 的曲线得出。
(2)待测化合物的α-葡萄糖苷酶抑制活性根据如下公式计算：
抑制率抑制率(％)＝[((A1-A0)/A0]×100％，
其中A1和A0分别代表测试化合物和空白的吸光度变化，数据处理：使用MS Excel分析 处理数据，并用Origin 9.1计算得到半数抑制浓度(IC50)，IC50代表在所述实验条件下，α- 葡萄糖苷酶的活性被抑制50％时所需待测化合物的浓度。
1.3结果分析
本发明实施例应用体外酶学实验对合成得到的化合物进行α-葡萄糖苷酶抑制活性评价， 结果表明，大多数衍生物均表现出优异的α-葡萄糖苷酶抑制活性，IC50的范围值为5.11±1.46 至85.52±1.83μM。其中的阳性对照药阿卡波糖IC50为259.90±1.06μM。筛选出三个具有较好 的α-葡萄糖苷酶抑制活性的衍生物(5h、5i、5j)，它们的抑制率分别是9.99±1.68μM、 8.87±1.27μM、5.11±1.46μM，表明这些小分子化合物在与α-葡萄糖苷酶相互作用时表现出较 强的结合亲和力。
由此可以推知，此类肉桂酸-厚朴酚型结构的化合物具有较好的α-葡萄糖苷酶抑制活性， 且其毒性低、安全性高。
化合物与α-葡萄糖苷酶的体外抑制活性评价结果如下表2所示：
表2.化合物的α-葡萄糖苷酶体外抑制活性结果
二、体外酶动力学实验：
采用体外酶动力学实验对合成得到的活性化合物进行α-葡萄糖苷酶抑制活性动力学评 价。
2.1试剂与标准溶液的配制
(1)100mM pH6.8的磷酸缓冲液(PBS)的配制：分别取17.907g的磷酸氢二钠和6.804g 的磷酸二氢钾混合溶解，然后加去离子水定容至1L，用pH计测定pH值。
(2)系列肉桂酸-厚朴酚衍生物溶液的配制：称取一定量的系列肉桂酸-厚朴酚衍生物加 到二甲基亚砜(DMSO)溶液当中进行溶解，制得浓度为10mM的母液，然后根据所需浓度 用100mM pH6.8的磷酸缓冲液进行稀释，实验当中DMSO的终浓度不超过5％。
(3)pNPG溶液的配制：准确称取0.006025g pNPG溶解于20mL的pH6.8 PBS中充分溶解，即得1mM的pNPG母液。
α-葡萄糖苷酶溶液的配制：将酶活力为100U的酶加适量100mM PBS配成工作浓度分别 为0.075U/mL、0.1U/mL、0.125U/mL、0.15U/mL并分装冷冻。
阿卡波糖溶液的配制：准确称取阿卡波糖0.06456g，置于10mL容量瓶中，
然后用100mM pH6.8 PBS溶液定容至刻度，即得到10mM的母液。
2.2实验步骤
(1)根据先前的报告分析了动力学机理。选择了具有最强抑制活性的衍生物5h，5i和 5j作为测试化合物。在5h，5i或5j存在的情况下，在405nm处测量了混合物α-葡萄糖苷酶(终浓度0.075、0.1、0.125和0.15U/mL)和PNPG(终浓度0.25mM)的吸光度变化。然后 通过酶促反应速率与α-葡萄糖苷酶浓度的关系图确定抑制的类型。
(2)数据处理：使用MS Excel，Origin9.1分析处理数据，酶反应体系的反应速率为△ OD/min。
2.3结果分析
通常根据抑制剂的类型，酶抑制剂可分为可逆抑制剂和不可逆抑制剂。不可逆抑制：在 相同的抑制剂浓度下，酶浓度增加曲线的斜率不变，不同抑制剂浓度曲线相互平行。相反， 可逆抑制剂被定义为多条曲线相交于原点。为了获得酶抑制剂与酶结合的原理，有必要研究 酶抑制剂与酶的相互作用。选择有着最低IC50的化合物5h (
)，5i(
)和5j(
)进行抑制动力学的研究，酶反应速率(V)vsα-葡萄糖苷酶生成一系列曲线。以5h为例分析，在不同浓度的5h存在下，改变酶 的浓度，通过绘制不同浓度下剩余酶活性相对于酶的直线。图1～3分别为绘制出的5h、5i和 5j的在体外对α-葡萄糖苷酶的酶动力学图，如图1至图3所示，所有的直线都有良好的线性 关系，都经过原点。此外，图1中随着5h浓度的增加，直线的斜率逐渐减小。显然，5h的 存在并没有改变酶的数量，而是降低了酶的活性。上面的结果清楚地表明，香豆素衍生物的 抑制机制α-葡萄糖苷酶是可逆的。从图1～3可以看出，5i和5j属于类似于5h的可逆抑制。
三、体外底物动力学实验：
采用体外底物动力学实验对合成得到的活性化合物进行α-葡萄糖苷酶抑制活性动力学评 价。
3.1试剂与标准溶液的配制
(1)100mM pH6.8的磷酸缓冲液(PBS)的配制：分别取17.907g的磷酸氢二钠和6.804g 的磷酸二氢钾混合溶解，然后加去离子水定容至1L，用pH计测定pH值。
(2)系列肉桂酸-厚朴酚衍生物溶液的配制：称取一定量的系列肉桂酸-厚朴酚衍生物加 到二甲基亚砜(DMSO)溶液当中进行溶解，制得浓度为10mM的母液，然后根据所需浓度 用100mM pH6.8的磷酸缓冲液进行稀释，实验当中DMSO的终浓度不超过5％。
(3)pNPG溶液的配制：准确称取0.006025g pNPG溶解于20mL的pH6.8 PBS中充分溶解，即得1mM的pNPG母液。
α-葡萄糖苷酶溶液的配制：将酶活力为100U的酶加适量100mM PBS配成工作浓度分别 为0.075U/mL、0.1U/mL、0.125U/mL、0.15U/mL并分装冷冻。
阿卡波糖溶液的配制：准确称取阿卡波糖0.06456g，置于10mL容量瓶中，
然后用100mM pH6.8 PBS溶液定容至刻度，即得到10mM的母液。
3.2实验步骤
(1)对于5h，5i和5j的抑制模式，在405nm下测量了α-葡萄糖苷酶(终浓度0.1U/mL)和PNPG(终浓度0.25、0.5、0.75、1mM)混合物的吸光度变化。5h，5i或5j。然后通过酶 反应速率对PNPG浓度的Lineweaver-Burk图获得抑制模式。常数KI通过斜率与化合物浓度 的关系图计算得出，常数KIS通过截距与化合物浓度的关系图计算得出。
(2)数据处理：使用MS Excel，Origin 9.1分析处理数据，酶反应体系的反应速率为△ OD/min。
3.3结果分析
据报道，抑制剂的抑制类型可根据双倒数作图法的得到的Lineweaver-Burk直线来判断。 象限内直线相交为混合抑制，平行或不相交为反竞争抑制，Y轴上直线相交为竞争抑制，X 轴上直线相交为非竞争抑制。分别在存在5h，5i或5j的条件下，使用酶反应速率与PNPG浓 度的Lineweaver-Burk双倒数图进一步研究了5h，5i和5j的抑制动力学行为。图4、7和10 分别为5h、5i和5j在体外对α-葡萄糖苷酶的底物动力学双倒数图，从图4、7和10可以看 出，这些图在第二象限中给出了具有不同斜率的直线相交的曲线，这表明5h，5i和5j的抑制 动力学行为是混合类型。也就是说5h，5i和5j可以与游离酶以及酶-底物复合物结合以抑制α- 葡萄糖苷酶的催化活性。同时，通过图5、8和11的底物动力学斜率-浓度关系曲线图，计算 了抑制剂与游离酶(KI)，以及通过图6、9和12的底物动力学截矩-浓度关系曲线图计算得 到化合物5h，5i和5j和酶-底物复合物(KIS)结合的平衡常数，并如表2所示。KI值高于 KIS值，表明5h，5i和5j与游离酶的亲和力低于与酶-底物复合物的亲和力。同时，根据图4～12可以得知，化合物5h、5i、5j抑制常数KI分别为15.78、4.08、23.48。
四、分子对接模拟：
采用分子对接(Molecular docking)的方法分析活性化合物5h、5i、5j与α-葡萄糖苷酶 的相互作用规律。
使用Sybyl 2.1.1(USA)和Pymol软件进行了分子对接研究，以了解α-葡萄糖苷酶酶和 衍生物5j之间的结合相互作用，并具有最佳抑制活性。图13中(a)和(b)给出了α-葡萄糖苷酶酶和衍生物5j之间的对接模拟图，揭示了5j很好地插入了与活性位点残基相互作用的 酶的活性口袋中。图13中(c)显示了5j与活性口袋处的氨基酸残基的结合相互作用。一种 羟基肉桂酸的氢原子与氨基酸Asp215形成两个氢键相互作用。其他羟基肉桂酸的氢原子与氨 基酸Lys156形成氢键相互作用，氧原子与氨基酸Ser241形成氢键相互作用。此外，在一种 羟基肉桂酸的苯环与该蛋白质的Tyr158残基之间发现了π-π堆积相互作用。
本说明书的实施例，合成了一系列的肉桂酸-厚朴酚衍生物4a～j和5a～j，并确定了它们对 α-葡萄糖苷酶的活性。结果表明，大多数合成的衍生物对α-葡萄糖苷酶表现出显著的抑制活 性。特别是化合物5h、5i和5j表现出最强的α-葡萄糖苷酶抑制作用，IC50值分别为 9.99±1.68μM、8.87±1.27μM、5.11±1.46μM，是阿卡波糖的25～50倍左右。
以上所述仅为本发明的实施例，并非因此限制本发明的专利范围，凡是利用本发明说明 书及附图内容所作的等同变换，或直接或间接运用在相关的技术领域，均同理包括在本发明 的专利保护范围内。
Claims (10)
1.α-葡萄糖苷酶抑制剂，其特征在于，所述α-葡萄糖苷酶抑制剂包括具有如下结构式的化合物：
其中，R1独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基或羟基；
所述R1位于苯环的邻位、间位或对位。
2.根据权利要求1所述的α-葡萄糖苷酶抑制剂，其特征在于，所述R1独立地选自C1～10烷基、C1～10烷氧基或C1～10卤代烷基。
3.根据权利要求2所述的α-葡萄糖苷酶抑制剂，其特征在于，所述R1独立地选自C1～4烷基、C1～4烷氧基或C1～4卤代烷基。
4.根据权利要求1所述的α-葡萄糖苷酶抑制剂，其特征在于，所述R1独立地选自氢原子、羟基、卤素、甲基、甲氧基或三氟甲基。
5.权利要求1至4任一项所述的α-葡萄糖苷酶抑制剂在制备治疗糖尿病药物中的应用。
6.根据权利要求5所述的应用，其特征在于，所述糖尿病为II型糖尿病。
7.根据权利要求5所述的应用，其特征在于，所述药物的剂型选自片剂、胶囊剂、软胶囊剂、颗粒剂、丸剂、口服液、干混悬剂、滴丸剂、干浸膏剂、注射剂或输注剂。
8.根据权利要求5所述的应用，其特征在于，所述药物还包括药学上可接受的载体。
9.一种用于辅助治疗糖尿病的药物，其特征在于，所述药物包括如权利要求1至4任一项所述的α-葡萄糖苷酶抑制剂。
10.根据权利要求9所述的药物，其特征在于，所述糖尿病为II型糖尿病。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010202536A (ja) * | 2009-02-27 | 2010-09-16 | Erina Co Inc | 脂肪細胞分化促進剤、その促進剤を含有する糖尿病治療剤、その促進剤を含有する脂肪細胞分化促進用機能性食品及び健康食品 |
| US20160374944A1 (en) * | 2011-05-19 | 2016-12-29 | Rakesh Srivastava | Compositions and methods for treating and preventing cancer by targeting and inhibiting cancer stem cells |
| CN108997121A (zh) * | 2018-07-10 | 2018-12-14 | 中国科学院昆明植物研究所 | 厚朴酚衍生物在制备治疗中枢神经系统疾病药物中的应用 |
-
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- 2020-07-30 CN CN202010748803.0A patent/CN111889080B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010202536A (ja) * | 2009-02-27 | 2010-09-16 | Erina Co Inc | 脂肪細胞分化促進剤、その促進剤を含有する糖尿病治療剤、その促進剤を含有する脂肪細胞分化促進用機能性食品及び健康食品 |
| US20160374944A1 (en) * | 2011-05-19 | 2016-12-29 | Rakesh Srivastava | Compositions and methods for treating and preventing cancer by targeting and inhibiting cancer stem cells |
| CN108997121A (zh) * | 2018-07-10 | 2018-12-14 | 中国科学院昆明植物研究所 | 厚朴酚衍生物在制备治疗中枢神经系统疾病药物中的应用 |
Non-Patent Citations (2)
| Title |
|---|
| SIRICHAI ADISAKWATTANA ET AL.: "Structure–activity relationships of trans-cinnamic acid derivatives on a-glucosidase inhibition", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 朱庆亚: "α-葡萄糖苷酶抑制剂的筛选及其对糖尿病大鼠糖吸收抑制作用的研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
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