CN116375582A - 异甜菊醇衍生物及其应用 - Google Patents
异甜菊醇衍生物及其应用 Download PDFInfo
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- CN116375582A CN116375582A CN202310155679.0A CN202310155679A CN116375582A CN 116375582 A CN116375582 A CN 116375582A CN 202310155679 A CN202310155679 A CN 202310155679A CN 116375582 A CN116375582 A CN 116375582A
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Abstract
本发明公开了异甜菊醇衍生物及其应用，其通式结构如化学式1所示，其中R1为不同碳链长度的卤代烃或溴苄，R2为O、OH或NOH，R3为H或Br，具有PTP1B抑制活性，且抑制PTP1B酶活性的IC50为0.24μM，以异甜菊醇为原料经过化学修饰制备得到。本发明提供一类异甜菊醇衍生物，合成路线设计合理、原料易得，适于工业化应用，对PTP1B有显著的抑制活性和良好的选择性，可作为PTP1B抑制剂或选择性PTP1B抑制剂，在预防或治疗以PTP1B为靶点的Ⅱ型糖尿病或肥胖症等方面均有广泛的应用价值。
Description
技术领域
本发明属于药物化学领域，具体涉及异甜菊醇衍生物及其应用。
背景技术
糖尿病是胰岛素分泌缺陷或胰岛素作用障碍导致的一种以高血糖为特征的代谢性疾病，它已成为当前威胁全球人类健康最重要的非传染性疾病之一。近年来，Ⅱ型糖尿病发病率急速增加，患者需通过口服降糖药物来控制血糖。因此，降糖药物的研发具有重要的现实意义。
蛋白酪氨酸激酶(PTKs)和蛋白酪氨酸磷酸酶(PTPs)是调节酪氨酸磷酸化水平的两大类酶。蛋白质酪氨酸磷酸酶1B(PTP1B)是PTP超家族的成员，在催化蛋白质酪氨酸去磷酸化和调节各种信号转导途径方面发挥重要作用，PTP1B维持适当水平的酪氨酸磷酸化，并调节细胞过程，包括生长、分化、代谢、迁移和存活，从而调节葡萄糖和脂质代谢，它还可以负调节胰岛素代谢途径，这是治疗II型糖尿病和肥胖症的一个有吸引力的方式。由于PTP1B在组织中广泛表达并参与几乎所有的生理反应，PTP1B被认为是各种疾病中的一个有前途的靶点，如肝病、心血管疾病、癌症(尤其是乳腺癌)，尽管近年来已经开发大量PTP1B抑制剂，但尚没有PTP1B抑制剂用于临床应用。
异甜菊醇(Isosteviol)是一种具有贝叶烷骨架的四环二萜类化合物，可以通过天然产物甜菊糖酸水解获得。近年来，异甜菊醇衍生物因其广泛的生物活性而受到广泛关注，包括降血压、抗降血糖、抗炎、抗氧化和潜在的抗肿瘤以及其他的生物活性。以异甜菊醇为先导化合物，通过结构修饰寻找活性分子已成为药物化学的热点。
发明内容
本发明的主要目的在于，提供一类具有PTP1B抑制活性的异甜菊醇衍生物，以异甜菊醇为先导化合物，对其特定的活性位点进行化学修饰，得到高活性的异甜菊醇衍生物。
本发明的另一目的在于，提供所述异甜菊醇衍生物的制备方法。
本发明的再一目的在于，提供所述异甜菊醇衍生物在抑制PTP1B活性方面或者药物制备中的应用。
为实现上述目的，本发明采用的技术方案如下：
本发明第一方面提供一类具有PTP1B抑制活性的异甜菊醇衍生物，其通式结构如化学
式1所示：
化学式1中，R1为不同碳链长度的卤代烃或溴苄，R2为O、OH或NOH，R3为H或Br。
作为优选，所述异甜菊醇衍生物具有PTP1B抑制活性，且抑制PTP1B酶活性的IC50为0.24μM。
本发明第二方面还提供所述异甜菊醇衍生物的制备方法，以异甜菊醇为原料，经过一系列化学修饰制备得到异甜菊醇衍生物，包括以下步骤：
步骤1：异甜菊醇和有机卤化物在碱性条件下发生亲核反应，得到衍生物1-13；
步骤2：在NaHCO3存在的情况下，用NH2OH·HCl处理异甜菊醇和衍生物1-3发生肟化反应，得到相应的肟14-17；
步骤3：异甜菊醇通过1,2-二溴乙烷连接得到中间体4，引入哌嗪环或哌啶环得到衍生物18-19；
步骤4：中间体5通过1,4-二溴丁烷作为连接链，引入哌啶环，得到目标衍生物20；
步骤1-4如合成路线1所示：
步骤5：异甜菊醇通过与对甲苯磺酰肼或对甲苯磺酸一水合物在MeOH中反应转化为相应的甲苯磺酰腙21；用NaBH4还原异甜菊醇的酮羰基，生成衍生物22；该衍生物在吡啶中用乙酸酐进一步酰化，得到衍生物23，如合成路线2所示：
步骤6：溴化衍生物24通过在碱性条件下用过量的溴乙烷和DMSO处理衍生物2得到；在EtOH中用NaBH4立体选择性还原衍生物2的羰基，得到醇衍生物25；用DCC/DMAP和苯甲酸，将衍生物25转化为芳香酯26-27；在NaHCO3存在的条件下，衍生物2与NH2OH·HCl在EtOH中回流反应得到肟16；衍生物16与NaH和CH3I通过醚化反应得到衍生物28，如合成路线3所示：
本发明第三方面还提供所述异甜菊醇衍生物在制备PTP1B抑制剂中的应用。
本发明第四方面还提供所述异甜菊醇衍生物在制备选择性PTP1B抑制剂中的应用。
本发明第五方面还提供所述异甜菊醇衍生物在制备治疗Ⅱ型糖尿病或者肥胖症的药物中的应用。
与现有技术相比，本发明具有如下有益效果：
(1)本发明提供一类异甜菊醇衍生物，合成路线设计合理、原料易得，适于工业化应用。
(2)本发明中异甜菊醇衍生物对PTP1B有显著的抑制活性和良好的选择性，对TCPTP的选择性为7倍，对CDC25B的选择性为14倍，可作为PTP1B抑制剂或选择性PTP1B抑制剂，在预防或治疗以PTP1B为靶点的Ⅱ型糖尿病或肥胖症等方面均有广泛的应用价值。
附图说明
图1是实施例中衍生物10的分子对接结果。
图2是实施例中衍生物13的分子对接结果。
图3是实施例中衍生物24的分子对接结果。
图4是实施例中衍生物27的分子对接结果。
具体实施方式
下面结合具体实施例对本发明进一步描述，但本发明的保护范围并不仅限于此。
实施例1衍生物1的制备
取200mg(0.628mmol)异甜菊醇置于反应瓶中，加3mL丙酮溶解，在搅拌状态下加入117μL(1.88mmol)碘甲烷和347.2mg(2.51mmol)的碳酸钾，室温下搅拌11小时。然后用乙酸乙酯和水提取该混合物，有机层用水洗涤，用无水硫酸钠干燥。在真空中去除溶剂后，用硅胶柱色谱洗脱法(石油醚/乙酸乙酯＝20：1)纯化，得白色粉末。收率：63.0％。1H NMR(400MHz,CDCl3)δ3.61(s,3H),2.60(dd,J＝18.6,3.8Hz,1H),2.15(d,J＝13.5Hz,1H),1.91–1.73(m,3H),1.73–1.65(m,3H),1.65–1.58(m,1H),1.58–1.44(m,3H),1.43–1.30(m,3H),1.26–1.18(m,1H),1.16(s,3H),1.14–1.07(m,2H),1.06–0.96(m,1H),0.95(s,3H),0.92–0.86(m,1H),0.66(s,3H)；13C NMR(100MHz,CDCl3)δ222.7,178.0,57.1,54.8,54.4,51.3,48.8,48.5,43.9,41.6,39.9,39.5,38.0,37.9,37.4,28.9,21.8,20.4,19.9,19.0,13.2；ESI-MS:m/z 333.49[M+H]+。
实施例2衍生物2的制备
在溶解于DMSO中的异甜菊醇(200mg，0.628mmol)溶液中加入EtBr(236μL，3.14mmol)和KOH(105.7mg，1.88mmol)，室温下搅拌5小时。然后用乙酸乙酯和水提取该混合物，有机层用无水Na2SO4干燥，过滤并在减压下蒸发滤液。通过使用石油醚/乙酸乙酯(20:1)作为洗脱剂对粗提物进行柱色谱，得到白色无定形粉末。收率：73.1％。1H NMR(400MHz,CDCl3)δ4.05(q,J＝7.2Hz,2H),2.59(dd,J＝18.6,3.8Hz,1H),2.13(d,J＝13.5Hz,2H),1.92–1.80(m,2H),1.80–1.75(m,1H),1.73–1.65(m,3H),1.62(dd,J＝6.5,3.7Hz,1H),1.60–1.54(m,1H),1.54–1.49(m,1H),1.48–1.40(m,2H),1.39–1.31(m,2H),1.27(t,J＝7.1Hz,3H),1.23–1.21(m,1H),1.14(s,3H),1.16–1.08(m,2H),0.93(s,3H),0.89–0.81(m,1H),0.67(s,3H)；13C NMR(100MHz,CDCl3)δ223.2,177.5,60.2,57.1,54.7,54.3,48.8,48.5,43.8,41.6,39.9,39.5,38.1,37.9,37.4,29.0,21.8,20.4,19.9,19.0,14.1,13.5；ESI-MS:m/z 347.48[M+H]+。
实施例3衍生物3的制备
在溶解于N,N-二甲基甲酰胺(DMF)中的异甜菊醇(100mg，0.318mmol)溶液中，加入43.5μl溴丙烷(0.477mmol)和65.1mg碳酸钾(0.477mmol)。将混合物在室温下搅拌4小时。然后用乙酸乙酯和水提取混合物。有机层用水洗涤，用无水硫酸钠干燥。真空去除溶剂后，用石油醚和乙酸乙酯(20：1)洗脱硅胶柱层析纯化，得到白色无定形粉末，产率65.1％。1HNMR(400MHz,CDCl3)δ4.05–3.89(m,2H),2.61(dd,J＝18.6,3.8Hz,1H),2.17(d,J＝13.4Hz,1H),1.92–1.83(m,1H),1.83–1.73(m,2H),1.73–1.63(m,4H),1.63–1.56(m,3H),1.55–1.44(m,3H),1.43–1.29(m,2H),1.27–1.19(m,1H),1.17(s,4H),1.15–1.07(m,1H),1.04–0.97(m,1H),0.96(s,4H),0.94(s,1H),0.93–0.83(m,2H),0.69(s,3H)；13CNMR(100MHz,CDCl3)δ222.7,177.5,66.0,57.2,54.8,54.4,48.8,48.5,43.9,41.6,40.0,39.6,38.1,38.0,37.4,29.1,22.0,21.8,20.4,19.9,19.1,13.5,10.9；ESI-MS:m/z 361.48[M+H]+。
实施例4衍生物4的制备
在溶解于N,N-二甲基甲酰胺(DMF)中的异甜菊醇(200mg，0.628mmol)溶液中，加入81μl1，2-二溴乙烷(0.942mmol)和130.2mg碳酸钾(0.942mmol)。将混合物在室温下搅拌5小时。然后用乙酸乙酯和水提取混合物。有机层用水洗涤，用无水硫酸钠干燥。真空去除溶剂后，用石油醚和乙酸乙酯(5：1)洗脱硅胶柱层析纯化，得到白色无定形粉末，产率27.2％。1HNMR(500MHz,CDCl3)δ4.45–4.31(m,2H),3.53(t,J＝5.7Hz,2H),2.60(dd,J＝18.6,3.8Hz,1H),2.20(d,J＝13.4Hz,1H),1.95–1.86(m,1H),1.86–1.77(m,3H),1.77–1.67(m,3H),1.67–1.58(m,1H),1.58–1.50(m,1H),1.47–1.39(m,2H),1.38–1.33(m,1H),1.28–1.23(m,2H),1.23(s,3H),1.20–1.15(m,2H),1.08–0.99(m,1H),0.98(s,3H),0.95–0.84(m,1H),0.74(s,3H)；13C NMR(125MHz,CDCl3)δ222.6,177.1,64.0,57.1,54.7,54.3,48.7,48.4,44.0,41.5,39.8,39.5,38.1,37.9,37.3,29.0,28.9,21.7,20.3,19.9,18.9,13.5；ESI-MS:m/z 425.45[M+H]+。
实施例5衍生物5的制备
在溶解于N,N-二甲基甲酰胺(DMF)中的异甜菊醇(100mg，0.318mmol)溶液中，加入266μl 1，4-二溴丁烷和270mg碳酸钠，将混合物在室温下搅拌36小时。然后用乙酸乙酯和水提取混合物。有机层用水洗涤，用无水硫酸钠干燥。真空去除溶剂后，用石油醚和丙酮(8：1)洗脱硅胶柱层析纯化，得到粉色无定形粉末，产率47.9％。1H NMR(400MHz,CDCl3)δ4.12–3.96(m,2H),3.42(t,J＝6.5Hz,2H),2.60(dd,J＝18.6,3.8Hz,1H),2.17(d,J＝13.4Hz,1H),2.01–1.91(m,1H),1.91–1.81(m,2H),1.80–1.75(m,1H),1.73–1.68(m,3H),1.62(dd,J＝6.5,3.7Hz,1H),1.60–1.52(m,2H),1.51–1.40(m,2H),1.39–1.30(m,2H),1.27–1.21(m,3H),1.17(s,3H),1.24–1.07(m,3H),1.06–0.95(m,1H),0.96(s,3H),0.94–0.82(m,1H),0.68(s,3H)；13C NMR(100MHz,CDCl3)δ222.6,177.4,63.3,57.1,54.8,54.3,48.8,48.5,43.9,41.6,39.9,39.5,38.1,37.4,33.1,29.8,29.6,29.1,27.3,21.8,20.4,19.9,19.0,13.5；ESI-MS:m/z 453.44[M+H]+。
实施例6衍生物6的制备
在溶解于N,N-二甲基甲酰胺(DMF)中的异甜菊醇(100mg，0.318mmol)溶液中，加入64μl1,5二溴戊烷(0.477mmol)和65.1mg碳酸钾(0.477mmol)。将混合物在室温下搅拌4小时。然后用乙酸乙酯和水提取混合物。有机层用水洗涤，用无水硫酸钠干燥。真空去除溶剂后，用石油醚和丙酮(8：1)洗脱硅胶柱层析纯化，得到白色无定形粉末，产率28.8％。1H NMR(400MHz,CDCl3)δ4.10–3.94(m,2H),3.40(t,J＝6.6Hz,2H),2.60(dd,J＝18.6,3.8Hz,1H),2.16(d,J＝13.4Hz,1H),1.91–1.82(m,3H),1.82–1.74(m,2H),1.74–1.64(m,4H),1.63–1.59(m,2H),1.58–1.52(m,2H),1.52–1.46(m,2H),1.46–1.39(m,2H),1.39–1.30(m,2H),1.25–1.20(m,1H),1.17(s,4H),1.14–1.07(m,1H),1.06–0.95(m,1H),0.95(s,3H),0.92–0.82(m,1H),0.68(s,3H)；13C NMR(100MHz,CDCl3)δ222.6,177.5,63.9,57.1,54.8,54.4,48.8,48.5,43.9,41.6,39.9,39.6,38.1,38.0,37.4,33.6,32.3,29.1,27.8,24.9,21.8,20.4,19.9,19.1,13.5；ESI-MS:m/z 467.43[M+H]+。
实施例7衍生物7的制备
在溶解于N,N-二甲基甲酰胺(DMF)中的异甜菊醇(50mg，0.157mmol)溶液中，加入37.3μl溴苄(0.314mmol)和39.5mg碳酸氢钠(0.471mmol)。将混合物在室温下搅拌4小时。然后用乙酸乙酯和水提取混合物。有机层用水洗涤，用无水硫酸钠干燥。真空去除溶剂后，用石油醚和丙酮(8：1)洗脱硅胶柱层析纯化，得到白色无定形粉末，产率35.9％。1HNMR(500MHz,CDCl3)δ7.45–7.31(m,5H),5.18–5.04(m,2H),2.57(dd,J＝18.7,3.8Hz,1H),2.16(d,J＝13.4Hz,1H),1.93–1.74(m,3H),1.74–1.58(m,4H),1.56–1.53(m,1H),1.51–1.34(m,4H),1.31–1.27(m,1H),1.23(s,3H),1.22–1.12(m,2H),1.11–1.01(m,1H),0.99(s,3H),0.95–0.85(m,2H),0.62(s,3H)；13C NMR(125MHz,CDCl3)δ222.7,177.1,136.0,129.0,128.5,128.4,128.4,128.2,66.1,57.2,54.7,54.3,48.7,48.4,43.9,41.5,39.8,39.4,38.0,37.9,37.3,29.0,21.7,20.3,19.9,19.0,13.3；ESI-MS:m/z 409.46[M+H]+。
实施例8衍生物8的制备
在溶解于N,N-二甲基甲酰胺(DMF)中的异甜菊醇(50mg，0.157mmol)溶液中，加入41μl邻氯溴苄(0.314mmol)和39.5mg碳酸氢钠(0.471mmol)。将混合物在室温下搅拌4小时。然后用乙酸乙酯和水提取混合物。有机层用水洗涤，用无水硫酸钠干燥。真空去除溶剂后，用石油醚和丙酮(10：1)洗脱硅胶柱层析纯化，得到白色无定形粉末，产率64.3％。H NMR(600MHz,CDCl3)δ7.48–7.38(m,3H),7.32–7.29(m,1H),5.25–5.14(m,2H),2.57(dd,J＝18.7,3.8Hz,1H),2.23(d,J＝13.4,1H),1.93–1.80(m,2H),1.80–1.74(m,1H),1.73–1.64(m,3H),1.64–1.57(m,1H),1.55–1.53(m,1H),1.50–1.41(m,3H),1.41–1.33(m,1H),1.31–1.26(m,1H),1.24(s,3H),1.23–1.11(m,3H),1.05(m,1H),0.98(s,3H),0.94–0.84(m,1H),0.60(s,3H)；13C NMR(150MHz,CDCl3)δ222.6,176.9,138.2,130.7,129.0,129.0,128.5,127.0,63.7,57.1,54.6,54.3,48.7,48.4,44.0,41.5,39.8,39.4,38.0,37.9,37.3,29.0,21.7,20.3,19.9,18.9,13.3；ESI-MS:m/z 443.51[M+H]+。
实施例9衍生物9的制备
在溶解于N,N-二甲基甲酰胺(DMF)中的异甜菊醇(50mg，0.157mmol)溶液中，加入79mg邻溴溴苄(0.314mmol)和39.5mg碳酸氢钠(0.471mmol)。将混合物在室温下搅拌7小时。然后用乙酸乙酯和水提取混合物。有机层用水洗涤，用无水硫酸钠干燥。真空去除溶剂后，用石油醚和丙酮(10：1)洗脱硅胶柱层析纯化，得到白色无定形粉末，产率68.5％。1H NMR(500MHz,CDCl3)δ7.62–7.56(m,1H),7.48–7.42(m,1H),7.34–7.27(m,1H),7.24–7.17(m,1H),5.23–5.11(m,2H),2.56(dd,J＝18.7,3.8Hz,1H),2.23(d,J＝13.5,1H),1.92–1.73(m,4H),1.72–1.64(m,2H),1.63–1.57(m,2H),1.57–1.51(m,1H),1.50–1.42(m,2H),1.41–1.31(m,2H),1.24(s,3H),1.21–1.10(m,3H),1.09–0.99(m,1H)0.97(s,3H),0.93–0.86(m,1H),0.60(s,3H)；13C NMR(125MHz,CDCl3)δ222.6,176.9,135.3,132.9,130.8,129.9,127.5,124.1,65.8,57.1,54.6,54.3,48.7,48.4,44.0,41.5,39.8,39.4,38.0,37.9,37.3,29.0,21.7,20.3,19.9,18.9,13.3；ESI-MS:m/z 487.42[M+H]+。
实施例10衍生物10的制备
在溶解于N,N-二甲基甲酰胺(DMF)中的异甜菊醇(50mg，0.157mmol)溶液中，加入92.7mg邻碘溴苄(0.314mmol)和39.5mg碳酸氢钠(0.471mmol)。将混合物在室温下搅拌6小时。然后用乙酸乙酯和水提取混合物。有机层用水洗涤，用无水硫酸钠干燥。真空去除溶剂后，用石油醚和乙酸乙酯(30：1)洗脱硅胶柱层析纯化，得到白色无定形粉末，产率52.1％。1H NMR(500MHz,CDCl3)δ7.86(dd,J＝7.8,1.2Hz,1H),7.41(dd,J＝7.6,1.8Hz,1H),7.36–7.32(m,1H),7.05–6.99(m,1H),5.20–5.04(m,2H),2.56(dd,J＝18.6,3.8Hz,1H),2.23(d,J＝13.4,1H),1.93–1.79(m,2H),1.79–1.71(m,2H),1.71–1.63(m,2H),1.63–1.56(m,1H),1.54–1.51(m,1H),1.48–1.39(m,2H),1.39–1.30(m,1H),1.30–1.25(m,1H),1.24(s,3H),1.21–1.09(m,3H),1.08–0.99(m,1H),0.97(s,3H),0.93–0.84(m,2H),0.61(s,3H)；13C NMR(125MHz,CDCl3)δ222.6,176.9,139.5,138.4,130.3,129.9,128.3,99.2,69.9,57.1,54.6,54.2,48.7,48.4,44.0,41.4,39.7,39.4,38.0,37.9,37.3,29.0,21.8,20.3,19.8,18.9,13.3；ESI-MS:m/z 535.46[M+H]+。
实施例11衍生物11的制备
在溶解于N,N-二甲基甲酰胺(DMF)中的异甜菊醇(50mg，0.157mmol)溶液中，加入61.5mg 3-氰基苄基溴(0.314mmol)和39.5mg碳酸氢钠(0.471mmol)。将混合物在室温下搅拌5小时。然后用乙酸乙酯和水提取混合物。有机层用水洗涤，用无水硫酸钠干燥。真空去除溶剂后，用石油醚和丙酮(20：1)洗脱硅胶柱层析纯化，得到白色无定形粉末，产率68.2％。1H NMR(400MHz,CDCl3)δ7.64–7.54(m,3H),7.49–7.42(m,1H),5.15–4.99(m,2H),2.51(dd,J＝18.6,3.8Hz,1H),2.17(d,J＝13.4,1H),1.91–1.83(m,1H),1.80–1.71(m,2H),1.70–1.61(m,2H),1.62–1.51(m,2H),1.51–1.45(m,1H),1.44–1.29(m,3H),1.22(s,1H),1.19(s,3H),1.16–1.13(m,3H),1.12–1.08(m,1H),1.08–0.98(m,1H),0.94(s,3H),0.89–0.78(m,1H),0.57(s,3H)；13C NMR(100MHz,CDCl3)δ222.5,176.9,137.7,132.6,131.9,131.7,129.5,118.6,112.8,64.8,57.1,54.7,54.3,48.8,48.4,44.0,41.5,39.7,39.5,38.1,38.0,37.3,29.0,21.8,20.4,19.9,19.0,13.4；ESI-MS:m/z 434.51[M+H]+。
实施例12衍生物12的制备
在溶解于N,N-二甲基甲酰胺(DMF)中的异甜菊醇(50mg，0.157mmol)溶液中，加入58.1mg对甲基溴苄(0.314mmol)和39.5mg碳酸氢钠(0.471mmol)。将混合物在室温下搅拌8小时。然后用乙酸乙酯和水提取混合物。有机层用水洗涤，用无水硫酸钠干燥。真空去除溶剂后，用石油醚和乙酸乙酯(20：1)洗脱硅胶柱层析纯化，得到白色无定形粉末，产率64.6％。1H NMR(600MHz,CDCl3)δ7.53–7.48(m,2H),7.25–7.22(m,2H),5.08–4.97(m,2H),2.58(dd,J＝18.6,3.8Hz,1H),2.17(d,J＝13.4,1H),1.91–1.86(m,1H),1.82–1.74(m,2H),1.74–1.65(m,4H),1.64–1.58(m,2H),1.57–1.53(m,1H),1.50–1.41(m,3H),1.41–1.34(m,2H),1.30–1.25(m,1H),1.21(s,3H),1.19–1.14(m,3H),1.08–1.01(m,1H),0.98(s,3H),0.94–0.87(m,1H),0.64(s,3H)；13C NMR(150MHz,CDCl3)δ222.7,177.1,137.9,133.0,129.2,128.5,66.1,57.2,54.7,54.3,48.7,48.4,43.9,41.5,39.8,39.4,38.0,37.9,37.3,29.6,29.5,29.0,21.7,21.2,20.3,19.9,19.0,13.4；ESI-MS:m/z 423.52[M+H]+。
实施例13衍生物13的制备
在溶解于N,N-二甲基甲酰胺(DMF)中的异甜菊醇(50mg，0.157mmol)溶液中，加入78.5mg对溴溴苄(0.314mmol)和39.5mg碳酸氢钠(0.471mmol)。将混合物在室温下搅拌5小时。然后用乙酸乙酯和水提取混合物。有机层用水洗涤，用无水硫酸钠干燥。真空去除溶剂后，用石油醚和丙酮(20：1)洗脱硅胶柱层析纯化，得到白色无定形粉末，产率78.4％。1HNMR(600MHz,CDCl3)δ7.57–7.45(m,2H),7.26–7.22(m,2H),5.11–4.93(m,2H),2.58(dd,J＝18.6,3.8Hz,1H),2.23(d,J＝13.4,1H),1.91–1.86(m,1H),1.82–1.75(m,2H),1.74–1.65(m,3H),1.64–1.58(m,1H),1.58–1.52(m,1H),1.51–1.41(m,2H),1.41–1.33(m,1H),1.27(s,1H),1.21(s,3H),1.20–1.12(m,3H),1.08–1.01(m,1H),0.98(s,3H),0.94–0.87(m,1H),0.64(s,3H)；13C NMR(150MHz,CDCl3)δ222.5,176.9,135.0,131.8,131.7,130.0,122.2,65.3,57.1,54.7,54.3,48.7,48.4,43.9,41.4,39.7,39.4,38.0,37.9,37.3,29.7,28.9,21.7,20.3,19.9,18.9,13.4；ESI-MS:m/z 487.42[M+H]+。
实施例14衍生物14的制备
在200mg(0.628mmol)异甜菊醇的EtOH(2mL)溶液中加入盐酸羟胺(70mg，0.942mmol)和碳酸氢钠(80.1mg，0.942mmol)。60℃搅拌5h，在真空下浓缩混合物，用二氯甲烷和水提取残余物。用饱和氯化钠洗涤有机层，用无水硫酸钠干燥，真空浓缩，粗品在二氧化硅(石油醚/丙酮＝8：1)上用柱层析纯化，得到白色粉末。产率72.8％。1H NMR(400MHz,CDCl3)δ2.97(dd,J＝18.8,3.1Hz,1H),2.15(d,J＝13.2Hz,1H),2.03–1.94(m,1H),1.90–1.69(m,2H),1.68–1.53(m,3H),1.50–1.37(m,4H),1.34–1.27(m,3H),1.24(s,2H),1.22(s,3H),1.08(s,3H),1.03–0.93(m,2H),0.94–0.85(m,1H),0.83(s,3H)；13C NMR(100MHz,CDCl3)δ170.7,57.2,56.3,54.9,44.0,43.7,40.9,40.0,39.5,38.3,37.1,31.6,30.2,29.8,29.1,22.2,21.6,20.5,19.0,13.5；ESI-MS:m/z 333.49[M+H]+。
实施例15衍生物15的制备
将衍生物1(50mg，0.15mmol)和NH2OH·HCl(15.6mg，0.225mmol)在C2H5OH中的混合物在NaHCO3存在下回流搅拌6小时，然后在真空下浓缩反应混合物，并用二氯甲烷和水萃取。最后，用饱和氯化钠水溶液洗涤有机层，用无水硫酸钠干燥并在真空下浓缩。通过使用石油醚/乙酸乙酯(8:1)作为洗脱剂对粗物质进行柱色谱，并得到白色无定形粉末形式的纯衍生物15。收率89.4％。1H NMR(400MHz,CDCl3)δ3.61(s,3H),2.60(dd,J＝18.6,3.8Hz,1H),2.17(d,J＝13.5Hz,1H),1.91–1.83(m,1H),1.83–1.73(m,2H),1.72–1.63(m,4H),1.62–1.53(m,2H),1.53–1.44(m,2H),1.44–1.29(m,2H),1.26–1.19(m,1H),1.16(s,3H),1.15–1.07(m,2H),1.06–0.96(m,1H),0.95(s,3H),0.93–0.83(m,1H),0.66(s,3H)；13C NMR(100MHz,CDCl3)δ178.1,170.3,57.2,56.3,54.9,51.3,43.9,41.0,40.7,40.0,39.5,38.1,38.0,36.9,29.8,28.8,22.2,21.8,20.5,19.0,13.2；ESI-MS:m/z348.48[M+H]+。
实施例16衍生物16的制备
将衍生物2(50mg，0.15mmol)和NH2OH·HCl(15.0mg，0.216mmol)在C2H5OH中的混合物在NaHCO3存在下回流搅拌22小时，然后在真空下浓缩反应混合物，并用二氯甲烷和水萃取。最后，用饱和氯化钠水溶液洗涤有机层，用无水硫酸钠干燥并在真空下浓缩。通过使用石油醚/乙酸乙酯(5:1)作为洗脱剂对粗物质进行柱色谱，并得到白色无定形粉末形式的纯衍生物16。收率49.3％。1H NMR(500MHz,CDCl3)δ4.19–4.02(m,2H),2.97(dd,J＝18.6,3.2Hz,1H),2.18(d,J＝12.9Hz,1H),2.00(d,J＝18.6Hz,1H),1.91–1.79(m,2H),1.78–1.69(m,2H),1.69–1.58(m,3H),1.51–1.39(m,4H),1.28(t,J＝7.2Hz,4H),1.25–1.20(m,1H),1.19(s,3H),1.11(s,3H),1.09–0.96(m,3H),0.93–0.85(m,1H),0.78(s,3H)；13C NMR(125MHz,CDCl3)δ177.5,170.3,60.0,57.1,56.3,54.9,43.8,43.7,40.9,40.6,40.0,39.5,38.1,38.0,36.7,28.9,22.2,21.7,20.4,18.9,14.2,13.4；ESI-MS:m/z362.48[M+H]+。
实施例17衍生物17的制备
将衍生物3(50mg，0.14mmol)和NH2OH·HCl(15.0mg，0.21mmol)在C2H5OH中的混合物在NaHCO3存在下回流搅拌4小时，然后在真空下浓缩反应混合物，并用二氯甲烷和水萃取。最后，用饱和氯化钠水溶液洗涤有机层，用无水硫酸钠干燥并在真空下浓缩。通过使用石油醚/丙酮(8:1)作为洗脱剂对粗物质进行柱色谱，并得到白色无定形粉末形式的纯衍生物17。收率75.7％。1H NMR(500MHz,CDCl3)δ4.01–3.87(m,2H),2.95(dd,J＝18.6,3.2Hz,1H),2.18(d,J＝12.9Hz,1H),1.99(d,J＝18.7Hz,1H),1.91–1.80(m,2H),1.76–1.69(m,2H),1.69–1.65(m,2H),1.64–1.56(m,2H),1.49–1.42(m,2H),1.41–1.36(m,2H),1.33–1.21(m,3H),1.18(s,3H),1.10(s,4H),1.07(s,1H),1.03–0.99(m,1H),0.96(t,J＝7.4Hz,3H),0.92–0.84(m,1H),0.77(s,3H)；13C NMR(125MHz,CDCl3)δ177.6,170.1,65.8,57.1,56.3,54.9,53.4,43.8,43.7,40.9,40.6,40.0,39.4,38.0,36.7,28.9,22.1,21.9,21.7,20.4,18.9,13.3,10.7；ESI-MS:m/z 376.54[M+H]+。
实施例18衍生物18的制备
向溶于N,N-二甲基甲酰胺(DMF)的衍生物4(43.0mg，0.10mmol)溶液中加入28.0mg(0.20mmol)K2CO3和0.50mmol哌啶。将混合物在室温下搅拌过夜。然后用乙酸乙酯和水萃取混合物。用水洗涤有机层并用无水硫酸钠干燥。在真空中除去溶剂后，使用硅胶柱对残余物进行色谱分离，洗脱剂体系为石油醚：乙酸乙酯＝1：1，得到纯的目标衍生物为棕色无定形粉末，产率76.8％。1H NMR(500MHz,CDCl3)δ4.24–4.10(m,2H),2.68–2.56(m,3H),2.44(s,4H),2.18(d,J＝13.6Hz,1H),2.08–1.97(m,2H),1.91–1.77(m,2H),1.76–1.62(m,2H),1.61–1.52(m,5H),1.47–1.37(m,4H),1.36–1.27(m,1H),1.25(s,4H),1.19(s,3H),1.16–1.07(m,1H),0.98(s,3H),0.97–0.93(m,1H),0.93–0.80(m,2H),0.72(s,3H)；13C NMR(125MHz,CDCl3)δ222.6,177.2,130.9,128.9,61.7,57.1,54.8,54.7,54.3,48.7,48.5,43.8,41.6,39.9,39.5,38.0,37.9,37.3,29.7,29.0,25.9,24.2,21.7,20.3,19.9,18.9,13.4；ESI-MS:m/z 430.58[M+H]+。
实施例19衍生物19的制备
向溶于N,N-二甲基甲酰胺(DMF)的衍生物4(43.0mg，0.10mmol)溶液中加入28.0mg(0.20mmol)K2CO3和0.50mmol哌嗪。将混合物在室温下搅拌过夜。然后用乙酸乙酯和水萃取混合物。用水洗涤有机层并用无水硫酸钠干燥。在真空中除去溶剂后，使用硅胶柱对残余物进行色谱分离，洗脱剂体系为二氯甲烷：甲醇＝3：1，得到纯的目标衍生物为棕色无定形粉末，产率49.2％。1H NMR(500MHz,CDCl3)δ4.25–4.05(m,2H),3.30–3.17(m,3H),2.83(s,4H),2.69(s,2H),2.60(dd,J＝18.5,3.7Hz,1H),2.15(d,J＝13.4Hz,1H),1.91–1.75(m,2H),1.74–1.64(m,3H),1.66–1.54(m,2H),1.52–1.39(m,3H),1.39–1.28(m,2H),1.24(s,3H),1.19(s,4H),1.17–1.02(m,2H),0.98(s,3H),0.94–0.80(m,2H),0.70(s,3H)；13C NMR(125MHz,CDCl3)δ222.5,177.1,60.6,57.0,56.2,54.7,54.2,49.6,48.7,48.5,43.9,43.7,41.4,39.8,39.5,38.0,37.9,37.3,29.7,29.1,22.7,21.7,20.3,19.8,18.9,13.5；ESI-MS:m/z 431.58[M+H]+。
实施例20衍生物20的制备
向溶于N,N-二甲基甲酰胺(DMF)的衍生物5(45.0mg，0.10mmol)溶液中加入28.0mg(0.20mmol)K2CO3和0.50mmol哌啶。将混合物在室温下搅拌24小时。然后用乙酸乙酯和水萃取混合物。用水洗涤有机层并用无水硫酸钠干燥。在真空中除去溶剂后，通过使用石油醚/丙酮(1∶1)作为洗脱剂对粗物质进行柱色谱，并得到无色粘性液体的纯衍生物20。产率98％。1H NMR(500MHz,CDCl3)δ4.14–3.96(m,2H),2.63(dd,J＝18.3,4.0Hz,1H),2.50–2.23(m,7H),2.18(d,J＝13.6Hz,1H),1.94–1.75(m,2H),1.75–1.67(m,2H),1.67–1.49(m,7H),1.49–1.38(m,4H),1.37–1.33(m,1H),1.32–1.23(m,4H),1.19(s,3H),
1.13–1.02(m,2H),0.98(s,3H),0.92–0.85(m,1H),0.71(s,3H)；13C NMR(125MHz,CDCl3)δ222.5,177.4,64.2,59.0,57.1,54.7,54.5,54.3,50.5,48.7,48.5,43.8,41.5,39.8,
39.5,38.0,37.9,37.3,29.7,29.0,26.7,25.8,24.4,23.5,21.7,20.3,19.8,19.0,13.4；
ESI-MS:m/z 458.60[M+H]+。
实施例21衍生物21的制备
将异甜菊醇(64mg，0.2mmol)、对甲苯磺酰肼(56mg，0.3mmol)，对甲苯磺酸一水合物(3.8mg，0.02mmol)和无水甲醇(2mL)在回流下搅拌12小时；用冷水稀释反应混合物并用乙酸乙酯(3×30mL)萃取。然后分别用饱和NaCl洗涤有机层，并用无水Na2SO4干燥，过滤并在减压下蒸发滤液。通过使用石油醚/丙酮(2∶1)作为洗脱剂对粗物质进行柱色谱，得到白色无定形粉末形式的纯衍生物21。产率66.9％。1H NMR(500MHz,CDCl3)δ7.81(d,J＝8.2Hz,2H),7.30(d,J＝8.2Hz,2H),2.64(dd,J＝17.6,3.0Hz,1H),2.43(s,3H),2.27–2.13(m,1H),1.93–1.80(m,2H),1.79–1.66(m,3H),1.61–1.50(m,3H),1.50–1.40(m,2H),1.39–1.32(m,2H),1.32–1.25(m,3H),1.24(s,3H),1.22–1.15(m,1H),1.13–1.03(m,2H),1.00(s,3H),0.99–0.82(m,1H),0.79(s,3H)；13C NMR(125MHz,CDCl3)δ183.2,143.8,135.4,129.4,129.3,128.0,127.9,56.9,55.8,54.7,53.4,44.9,43.6,41.1,40.9,39.7,39.1,38.1,37.7,29.2,22.0,21.5,21.4,20.2,19.9,18.9,13.5；ESI-MS:m/z 487.55[M+H]+。
实施例22衍生物22的制备
将NaBH4(47.6mg，1.256mmol)加入到原料异甜菊醇(200mg，0.628mmol)的乙醇溶液中，室温放置3小时。搅拌完成后，在真空中除去溶剂。残渣用饱和NaCl水溶液稀释，用乙酸乙酯萃取。联合有机层在无水硫酸钠上干燥，过滤并集中。用柱层析法在二氧化硅(二氯甲烷/甲醇＝20：1，v/v)上纯化残渣，得到产物为白色固体。产率82.4％；1H NMR(400MHz,CDCl3)δ3.61(s,3H),2.21–2.10(m,1H),1.90–1.72(m,3H),1.71–1.58(m,3H),1.57–1.44(m,3H),1.43–1.29(m,3H),1.29–1.19(m,2H),1.16(s,3H),1.13–1.01(m,2H),0.95(s,3H),0.93–0.79(m,1H),0.65(s,3H)；13C NMR(100MHz,CDCl3)δ185.1,84.0,61.0,59.9,59.2,47.5,46.3,46.0,45.9,45.7,43.9,42.1,42.0,37.7,33.0,28.7,25.7,24.2,22.9,17.1；ESI-MS:m/z 338.55[M+H2O]。
实施例23衍生物23的制备
将化合物22(100mg，0.313mmol)和乙酸酐(88μL，0.939mmol)在吡啶中的混合物在室温下搅拌8小时，然后在减压下浓缩。加入饱和NaCl水溶液并用CH2Cl2萃取。用无水硫酸钠干燥有机层，过滤并浓缩。残余物通过硅胶柱色谱(石油醚/丙酮＝5:1)纯化，得到白色固体的化合物23。产率58.6％。1H NMR(400MHz,CD4O)δ4.69(t,J＝7.6Hz,1H),3.30–3.27(m,1H),2.16(d,J＝13.6Hz,1H),2.02(s,3H),1.89–1.76(m,3H),1.77–1.67(m,2H),1.67–1.55(m,3H),1.55–1.45(m,1H),1.41–1.29(m,3H),1.29–1.19(m,2H),1.15(s,3H),1.10–0.99(m,3H),0.99–0.90(m,1H),0.88(s,3H),0.79(s,3H)；13C NMR(100MHz,CD4O)δ180.4,172.0,81.9,56.9,55.7,54.6,43.3,42.2,41.4,41.3,40.5,39.9,38.0,37.8,34.4,28.4,24.2,21.6,20.0,19.9,18.8,12.7；ESI-MS:m/z 381.54[M+H2O]。
实施例24衍生物24的制备
在室温下，向DMSO(2mL)溶液中加入衍生物2(50mg，0.144mmol)、KOH(16.2mg，0.288mmol)和EtBr(357μL)。将反应升温至80℃并搅拌6小时。用冷水稀释反应混合物并用CH2Cl2(3×30mL)萃取。然后分别用饱和NaHCO3洗涤。有机层用无水Na2SO4干燥，过滤并在减压下蒸发滤液。通过使用石油醚/乙酸乙酯(10:1)作为洗脱剂对粗物质进行柱色谱，并得到白色无定形粉末形式的衍生物24。产率35.3％。1H NMR(500MHz,CDCl3)δ4.50(d,J＝2.7Hz,1H),4.11(q,J＝7.1Hz,2H),2.27–2.15(m,2H),1.97–1.89(m,1H),1.88–1.77(m,2H),1.77–1.71(m,1H),1.71–1.59(m,3H),1.53–1.38(m,3H),1.35–1.27(m,2H),1.26(t,J＝7.1Hz,3H),1.19(s,3H),1.18–1.11(m,1H),1.09(s,3H),1.05–0.83(m,3H),0.75(s,3H)；13C NMR(125MHz,CDCl3)δ216.0,177.2,60.2,57.2,56.2,56.0,50.0,48.4,43.7,43.0,39.4,38.8,38.4,37.9,37.8,28.9,20.8,20.7,20.0,18.9,14.1,13.6；ESI-MS:m/z 425.45[M+H]+。
实施例25衍生物25的制备
在0℃下将NaBH4(43.7mg，1.154mmol)加入化合物2(200mg，0.577mmol)的EtOH溶液中搅拌9小时。反应完成后，真空除去溶剂。残余物用饱和NaCl水溶液稀释并用乙酸乙酯萃取。合并的有机层用无水硫酸钠干燥，过滤并浓缩。残余物通过硅胶柱色谱(石油醚/乙酸乙酯＝5:1)纯化，得到白色固体的化合物25。收率87.9％。1H NMR(500MHz,CDCl3)δ4.04(q,J＝7.2,2H),3.85(d,J＝4.5Hz,1H),2.16(d,J＝13.6Hz,1H),1.85–1.76(m,2H),1.76–1.68(m,2H),1.65–1.54(m,3H),1.53–1.43(m,2H),1.42–1.35(m,1H),1.34–1.26(m,2H),1.24(t,J＝7.2Hz,4H),1.22–1.17(m,1H),1.16(s,3H),1.06–1.03(m,1H),1.02–0.99(m,2H),0.99–0.92(m,1H),0.90(s,3H),0.88–0.81(m,1H),0.74(s,3H)；13C NMR(125MHz,CDCl3)δ177.6,80.6,59.9,57.2,55.8,55.3,43.7,42.8,42.1,42.0,41.8,40.0,38.1,38.0,33.7,29.0,24.9,21.8,20.5,19.0,14.1,13.4；ESI-MS:m/z 349.55[M+H]+。
实施例26衍生物26的制备
在室温下，将DMAP、DCC和苯甲酸(0.2mmol)加入溶解于干燥二恶烷中的衍生物25(52mg，0.15mmol)的溶液中。将反应升温至60℃并搅拌2小时。然后用乙酸乙酯和水萃取混合物。用水洗涤有机层并用无水硫酸钠干燥。在真空中除去溶剂后，使用硅胶柱对残余物进行色谱分离，洗脱剂体系为石油醚/乙酸乙酯，5:1，得到白色无定形粉末，产率80.7％。1HNMR(500MHz,CDCl3)δ7.72–7.60(m,3H),4.14–4.03(m,2H),3.85(dd,J＝10.8,4.7Hz,1H),3.55–3.44(m,1H),2.16(d,J＝13.6Hz,1H),2.06–1.94(m,2H),1.76–1.65(m,1H),1.65–1.54(m,3H),1.54–1.45(m,2H),1.45–1.31(m,2H),1.31–1.26(m,2H),1.26–1.22(m,4H),1.22–1.16(m,1H),1.15(s,3H),1.08–0.92(m,4H),0.89(s,3H),0.87–0.81(m,2H),0.74(s,3H)；13C NMR(125MHz,CDCl3)δ177.6,169.7,153.8,127.0,125.6,80.6,60.0,57.2,55.8,55.2,43.7,42.8,42.1,41.8,40.0,38.1,33.7,32.2,30.7,29.0,26.1,25.3,24.9,24.4,21.8,20.5,19.0,14.1,13.4；ESI-MS:m/z 419.45[M-Cl]-。
实施例27衍生物27的制备
在室温下，将DMAP、DCC和对羟基苯甲酸(0.2mmol)加入溶解于干燥二恶烷中的衍生物25(52mg，0.15mmol)的溶液中。将反应升温至60℃并搅拌2小时。然后用乙酸乙酯和水萃取混合物。用水洗涤有机层并用无水硫酸钠干燥。在真空中除去溶剂后，使用硅胶柱对残余物进行色谱分离，洗脱剂体系为二氯甲烷/丙酮，10:1，得到白色无定形粉末，产率80.9％。1H NMR(500MHz,CDCl3)δ7.70–7.63(m,3H),4.13–4.04(m,2H),3.85(dd,J＝10.8,4.7Hz,1H),2.16(d,J＝13.6Hz,1H),1.73–1.69(m,2H),1.60–1.54(m,3H),1.54–1.46(m,2H),1.43–1.35(m,2H),1.32–1.27(m,2H),1.27–1.22(m,4H),1.22–1.16(m,1H),1.15(s,3H),1.05–0.99(m,3H),0.99–0.93(m,1H),0.90(s,3H),0.88–0.82(m,3H),0.74(s,3H)；13CNMR(125MHz,CDCl3)δ178.0,132.5,131.8,128.5,122.7,121.8,115.5,80.1,60.0,57.1,55.8,55.2,49.0,43.7,42.4,41.9,41.7,39.9,38.0,33.6,28.9,26.0,25.2,24.6,21.7,20.3,18.8,13.9,13.2；ESI-MS:m/z 487.49[M+H2O]。
实施例28衍生物28的制备
向化合物16(50mg，0.138mmol)在DMF(1mL)中的冷却溶液中小心地加入NaH(60％在油中，19.9mg，0.828mmol)。将混合物在0℃下搅拌1小时，然后将碘甲烷溶液滴加到混合物中。将混合物加热至40℃并搅拌7小时。将反应混合物冷却并在0℃用饱和NH4Cl水溶液猝灭。然后，在真空下浓缩混合物以除去大部分DMF，并将残余物溶解在二氯甲烷中。过滤后，滤液用饱和NaCl水溶液洗涤，用Na2SO4干燥并在真空下浓缩。残余物通过硅胶柱色谱(石油醚/乙酸乙酯＝20:1)纯化，得到无色粘性液体的化合物28。收率57.9％。1H NMR(500MHz,CDCl3)δ4.17–4.02(m,2H),3.83(s,3H),2.87(dd,J＝18.6,3.3Hz,1H),2.19–2.10(m,3H),1.91(d,J＝18.6Hz,1H),1.87–1.82(m,1H),1.82–1.77(m,2H),1.74–1.66(m,2H),1.66–1.54(m,2H),1.46–1.37(m,4H),1.27(t,J＝7.0Hz,4H),1.25–1.20(m,1H),1.17(s,3H),1.09(s,2H),1.09–1.04(m,1H),1.03–0.95(m,1H),0.91–0.84(m,1H),0.76(s,3H)；13C NMR(125MHz,CDCl3)δ177.6,169.6,61.3,60.0,57.1,56.4,54.9,50.7,43.7,43.6,40.9,40.6,40.0,39.6,38.0,37.3,28.9,22.2,21.7,20.4,18.9,14.1,13.4；ESI-MS:m/z 376.50[M+H]+。
实施例29PTP1B和其他PTPs抑制活性评价
用Elisa法测试所有异甜菊醇衍生物对PTP1B的抑制活性。首先在10μM的浓度下测试了衍生物的抑制率，根据抑制率的结果，进一步在1μM至100μM的五种浓度下测试了最有效的衍生物的IC50值。齐墩果酸被用作PTP1B抑制活性的阳性药物。
将所有衍生物溶解在100μL DMSO中，再加900μL蒸馏水使其配置成1000umol/L的样品原液。将样品原液再依次稀释至100μM、25μM、10μM、5μM和1μM，并在4℃储存备用。测试孔中DMSO的浓度(10％)对PTP1B抑制活性没有明显影响。
首先，将15μL样品和15μL稀释后的标准品充分混合，并在37℃下孵育10分钟，以制备反应溶液。取25μL反应液小心地加入含有PTP1B固相抗体的96孔酶标板中，于37℃恒温孵育30分钟。孵育结束后，将酶标板内液体弃去并拍干，用稀释好的洗涤液洗涤5次，拍干。其次，每孔加入25μL HRP酶标试剂引发酶反应，于37℃恒温孵育30分钟。将孔板内孵育后液体弃去用稀释好的洗涤液洗涤，拍干，重复5次。然后，每孔加入25μL显色试剂A和25μL的显色试剂B以完成显色反应。最后，通过每孔加入25μL终止液终止反应，在15分钟内用酶标仪记录450nm处的吸光度。
表1：异甜菊醇及其衍生物1-28的化学结构和PTP1B抑制活性测试结果
表2：活性衍生物对PTP1B和相关PTPs的抑制活性
表1和表2列出化合物1-28的活性测试结果。大多数衍生物在10umol/L浓度下显示出良好的PTP1B抑制活性，对PTP1B酶的抑制率在50％以上。衍生物10、13、24、27在体外对PTP1B表现出显著的抑制活性。同时，也显示出对其他PTPs，特别是CDC25B的有效抑制活性。其中，活性最好的衍生物24的IC50值为0.24μM。它表现出显著提高的PTP1B抑制活性(10倍)和选择性(7倍于TCPTP和14倍于CDC25B)。
通过对目标化合物PTP1B的抑制活性分析，将构效关系总结如下：
(1)当羰基变成肟时，其抑制活性略有降低，但肟衍生物的抑制效力随着C-16位碳链的延长而增加，羟基的酰化可以提高其抑制活性。
(2)在C-15位引入溴原子有助于抑制活性。
(3)C-19位异甜菊醇的乙基化有利于PTP1B的抑制活性；在羧基引入烷基可以提高抑制活性；苯环邻位碘有利于PTP1B抑制活性的增强；苯环对位Br有利于抑制活性；在C-19位将哌嗪或哌啶引入异甜菊醇有助于增强抑制活性。
实施例30目标化合物对PTP1B酶的分子对接研究
对接计算使用AutoDock 4.2进行，AutoGrid用于生成网格图作为辅助程序。从PDB(ID:1NNY，
)下载人PTP1B的X射线结构。通过添加氢并从蛋白质结构中去除水分子和配体，将制备的蛋白质转化为分子对接的受体。用于分子对接的配体的化学结构首先由ChemDraw Ultra 14.0绘制，并由ChemDraw3D转换。然后，加入氢原子，生成pH值为7.3–7.5的质子化状态。所有可能的配体灵活性选项都被打开，而早期终止被关闭。所有可能形式的抑制剂分子都被对接到蛋白质中，已手动检查生成的模式。最后，选择了具有高得分和合理绑定的可接受模式，并用Pymol 1.7呈现。其对接结果如表3所示。
表3：活性衍生物的分子对接结果
观察化合物与酶的活性表面之间的相互作用情况可以发现，衍生物10中C-16位羰基与LYS-116形成氢键。其中羧基的氧原子作为氢键供体，与PTP1B中ALA-217的侧链形成一个氢键。根据对接模型，13和24显示出非常相似的结合模式。C-16位的羰基分别与PTP1B催化位点中的残基ARG-221和LYS-116形成氢键。衍生物27也显示出对PTP1B的良好抑制活性，这可能是由于与GLY-183、TRP-179、GLN-266、ARG-221的结合。预测的结合模式可以解释衍生物的良好抑制活性。
本发明成功合成28个异甜菊醇衍生物，所有的衍生物结构均通过13C NMR和1H NMR和ESI-MS质谱确证。对所合成的目标衍生物进行了PTP1B酶抑制活性的测试。大多数化合物均显示出良好的PTP1B抑制活性，其中衍生物24表现出最强的PTP1B活性，IC50值为0.24μM。它提供了显著提高的PTP1B抑制活性(10倍)和选择性(7倍于TCPTP和14倍于CDC25B)。分子对接预测了其与PTP1B酶的具体结合模式，并解释了高抑制活性的原因。本发明中合成的异甜菊衍生物为新的高效PTP1B抑制剂提供有利的指导，以供未来研究使用。
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，在不脱离本发明方法的前提下，还可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。
Claims (9)
1.异甜菊醇衍生物，其通式结构如化学式1所示：
化学式1中，R1为不同碳链长度的卤代烃或溴苄，R2为O、OH或NOH，R3为H或Br。
2.根据权利要求1所述的异甜菊醇衍生物，其特征在于，化学式1所示的异甜菊醇衍生物选自如下1-28所示的化合物：
3.根据权利要求1或2所述的异甜菊醇衍生物，其特征在于，所述异甜菊醇衍生物具有PTP1 B抑制活性。
4.根据权利要求3所述的异甜菊醇衍生物，其特征在于，所述异甜菊醇衍生物抑制PTP1B酶活性的IC50为0.24μM。
5.根据权利要求1至4任一项所述的异甜菊醇衍生物，其特征在于，所述异甜菊醇衍生物以异甜菊醇为原料，经过化学修饰制备得到。
6.权利要求1至5任一项所述异甜菊醇衍生物在制备PTP1 B抑制剂中的应用。
7.权利要求1至5任一项所述异甜菊醇衍生物在制备选择性PTP1 B抑制剂中的应用。
8.权利要求1至5任一项所述异甜菊醇衍生物在制备治疗Ⅱ型糖尿病或者肥胖症的药物中的应用。
9.根据权利要求8所述的应用，其特征在于，所述药物为以PTP1 B为靶点的靶向药物。
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