CN113582981A - 一类新颖二芳基庚烷-黄烷酮杂合体及其药物组合物和应用 - Google Patents
一类新颖二芳基庚烷-黄烷酮杂合体及其药物组合物和应用 Download PDFInfo
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- CN113582981A CN113582981A CN202110774946.3A CN202110774946A CN113582981A CN 113582981 A CN113582981 A CN 113582981A CN 202110774946 A CN202110774946 A CN 202110774946A CN 113582981 A CN113582981 A CN 113582981A
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Abstract
本发明提供结构式(I)所示16个新的二芳基庚烷‑黄烷酮杂合体{草豆蔻醇B1–B16(1–16)},及其制备方法和应用,含其为有效量的药物组合物及其应用,及其在制备降血糖药物或保健品中的应用,属于药物技术领域。本发明化合物均具有显著的GPa、PTP1B和α‑葡萄糖苷酶抑制活性。为依据二苯基庚烷‑黄烷酮开发新型多靶点抗糖尿病候选药物的提供了有力参考,并为在食品和制药工业中草豆蔻的应用提供了有价值的科学依据。
Description
技术领域:
本发明属于药物技术领域。具体地,涉及16个新的二芳基庚烷-黄烷酮杂合体,即草豆蔻醇B1–B16(1–16),及其制备方法和应用,以化合物1–16任意成分为有效成分的药物组合物,化合物1–16及其组合物在制备降血糖药物或保健食品中的应用。
背景技术:
2型糖尿病是由胰岛素抵抗和分泌紊乱引起的复杂疾病,根据其多方面的发病机理通常采用多靶点的治疗方法。例如Qtrilmet和Trijardy XR是SGLT-2和DPP-4多靶点的抑制剂,而metformin相比单靶点的抑制剂被认为具有更强的效果。目前临床常用的口服降血糖药物主要为双胍类、α-葡萄糖苷酶抑制剂、胰岛素促泌剂(磺脲类和非磺脲类)、胰岛素增敏剂(噻唑烷二酮类)、DPP-4抑制剂和SGLT-2抑制剂。尽管目前的抗糖尿病药物在控制血糖方面非常有效,但是其临床使用中会产生如急性低血糖、体重增加、胃肠不适、肝毒性等明显的副作用。因此,寻找低毒副作用的多靶点抗糖尿病药物是当前药物研发领域的紧迫任务。
糖原磷酸化酶a(GPa)在催化糖原磷酸水解形成葡萄糖-1-磷酸过程中起关键作用。由于2型糖尿病中肝葡萄糖的产生量异常升高而明显导致高血糖症状,因此GPa被认为是治疗2型糖尿病的有效靶点。蛋白质酪氨酸磷酸酶1B(PTP1B)通过对激活的胰岛素受体及下游底物蛋白的脱磷酸作用来抑制胰岛素的功能,被认为是开发抗糖尿病药物的潜在靶点。然而由于其较差的膜通透性和对T细胞蛋白质酪氨酸磷酸酶(TCPTP)的弱选择性,当前的PTP1B抑制剂的临床应用严重受阻。α-葡萄糖苷酶抑制剂,如阿卡波糖、米格列醇和伏格列波糖,能够有效地抑制高血糖,但其临床中也会产生胃肠道不良症状和体重增加等副作用。因此针对以上三种靶点,寻找低毒高效的抗糖尿病药物具有重要的意义。
草豆蔻(Alpinia katsumadaiHayata)系姜科山姜属植物,主要种植在中国东部及东南亚地区。草豆蔻的干燥种子是著名的香料,并作为传统中药用于治疗呕吐、胃病和一些炎症。我们的前期研究工作发现草豆蔻干燥种子的乙醇提取液对db/db小鼠显示降血糖活性,活性导向分离得到了16个结构新颖且具有GPa、PTP1B及α-葡萄糖苷酶抑制活性的二苯基庚烷-黄烷酮杂合体,草豆蔻醇B1–B16(1–16)。迄今为止,现有技术无草豆蔻醇B1–B16(1–16)的报道,也没有化合物1–16及其药物组合物作为GPa、PTP1B及α-葡萄糖苷酶抑制剂的报道,也没有化合物1–16及其药物组合物在制备降血糖药物或保健食品中的应用的报道。
发明内容:
本发明的目的在于提供一类新的具有药用价值如式(I)所示的草豆蔻醇B1–B16(1–16),化合物1–16的制备方法,化合物1–16及其药物组合物在制备降血糖药物或保健食品中的应用。
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:
结构式(I)所示的草豆蔻醇化合物B1–B16(1–16),
所述的式(I)的化合物草豆蔻醇1–16任一或任意组合在制备降血糖药物或保健食品中的应用。
所述的化合物在制备GPa、PTP1B及α-葡萄糖苷酶抑制剂中的应用。
本发明同时还提供了含有治疗有效量的式(I)化合物草豆蔻醇1–16任意一种或任意组合与药学上可接受的载体或赋型剂组成的药物组合物。
所述的药物组合物在制备降血糖药物或保健食品中的应用。
所述的药物组合物在制备GPa、PTP1B及α-葡萄糖苷酶抑制剂中的应用。
本发明还提供了制备所述的式(I)化合物草豆蔻醇1–16的方法,取草豆蔻的干燥种子(20kg),粉碎,用90%乙醇回流提取两次,每次2h,合并乙醇提液,减压回收乙醇得浸膏。浸膏分散在水中后用乙酸乙酯萃取,随后浓缩的到乙酸乙酯萃取部分。然后将乙酸乙酯萃取部分(Fr.A,1.5kg)过硅胶柱层析,以甲醇-氯仿(0:100、2:98、5:95、10:90、20:80和100:0,v/v)为洗脱剂梯度洗脱得到Fr.A-1~Fr.A-8八个流分。流分Fr.A-6(500g)经MCICHP 20P gel柱层析(甲醇-水,30:70、40:60、50:50、70:30和100:0)得到五个亚流分Fr.A-6-1~Fr.A-6-5。Fr.A-6-2经硅胶柱层析(MeOH-CHCl3,5:95和10:90)得到五个亚流分Fr.A-6-2-1~Fr.A-6-2-5。Fr.A-6-2-4(5.0g)经Sephadex LH-20(氯仿-甲醇,50:50)、硅胶柱层析(MeOH-CHCl3,15:85)和半制备高效液相(MeCN-H2O,35:65,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物6(33mg),7(8mg),8(8mg)和11(11mg)。Fr.A-6-4(105g)经Rp-C18柱层析(甲醇-水,40:60、50:50、60:40、70:30和100:0)得到七个亚流分Fr.A-6-4-1-Fr.A-6-4-7。Fr.A-6-4-3(14g)经Sephadex LH-20(氯仿-甲醇,50:50)、硅胶柱层析(MeOH-CHCl3,6:94;acetone-CHCl3,65:35)和半制备高效液相(MeCN-H2O,35:65,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物9(18mg),10(11mg),12(8mg),13(5mg)和14(18mg)。Fr.A-6-4-6(24g)经Rp-C18柱层析(甲醇-水,40:60、50:50、60:40和70:30)、Sephadex LH-20(氯仿-甲醇,50:50)、硅胶柱层析(MeOH-CHCl3,10:90)和半制备高效液相(MeCN-H2O,40:60,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物1(210mg),2(140mg),15(2mg)和16(2mg)。Fr.A-6-5(24g)经Rp-C18柱层析(甲醇-水,40:60、50:50、60:40和70:30)、Sephadex LH-20(氯仿-甲醇,50:50)、硅胶柱层析(MeOH-CHCl3,5:95,10:90;acetone-CHCl3,40:60)和半制备高效液相(MeCN-H2O,40:60,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物3(13mg),4(7mg)和5(8mg)。
制备含化合物1–16的药物组合物的方法是,以化合物1–16任一或任意组合为原料,加入可药用载体或赋形剂。所述的药用载体或赋形剂是一种或多种固体、半固体和液体稀释剂、填料以及药物制品辅剂。
本发明化合物1–16用作GPa、PTP1B及α-葡萄糖苷酶抑制剂或药物时,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%,优选为0.5~90%的化合物1–16任一或任意组合,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和/或赋形剂。将本发明的药物组合物以单位体重服用量的形式使用。本发明的药物可经注射(静注、肌注)和口服两种形式给药。,
附图说明:
图1为本发明化合物1–16的结构式示意图。
具体实施方式:
为了更好地理解本发明的实质,下面结合附图,用本发明的试验例和实施例来进一步说明本发明16个新的二芳基庚烷-黄烷酮杂合体,即化合物草豆蔻醇B1–B16(1–16)及其制备方法、结构鉴定、药理作用,以及药物组合物的制备方法,但不以此试验例和实施例来限定本发明。
实施例1:
化合物1–16的制备:
取草豆蔻的干燥种子(20kg),粉碎,用90%乙醇回流提取两次,每次2h,合并乙醇提液,减压回收乙醇得浸膏。浸膏分散在水中后用乙酸乙酯萃取,随后浓缩的到乙酸乙酯萃取部分。然后将乙酸乙酯萃取部分(Fr.A,1.5kg)过硅胶柱层析,以甲醇-氯仿(0:100、2:98、5:95、10:90、20:80和100:0,v/v)为洗脱剂梯度洗脱得到Fr.A-1~Fr.A-8八个流分。流分Fr.A-6(500g)经MCI CHP 20P gel柱层析(甲醇-水,30:70、40:60、50:50、70:30和100:0)得到五个亚流分Fr.A-6-1~Fr.A-6-5。Fr.A-6-2经硅胶柱层析(MeOH-CHCl3,5:95和10:90)得到五个亚流分Fr.A-6-2-1~Fr.A-6-2-5。Fr.A-6-2-4(5.0g)经Sephadex LH-20(氯仿-甲醇,50:50)、硅胶柱层析(MeOH-CHCl3,15:85)和半制备高效液相(MeCN-H2O,35:65,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物6(33mg),7(8mg),8(8mg)和11(11mg)。Fr.A-6-4(105g)经Rp-C18柱层析(甲醇-水,40:60、50:50、60:40、70:30和100:0)得到七个亚流分Fr.A-6-4-1-Fr.A-6-4-7。Fr.A-6-4-3(14g)经Sephadex LH-20(氯仿-甲醇,50:50)、硅胶柱层析(MeOH-CHCl3,6:94;acetone-CHCl3,65:35)和半制备高效液相(MeCN-H2O,35:65,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物9(18mg),10(11mg),12(8mg),13(5mg)和14(18mg)。Fr.A-6-4-6(24g)经Rp-C18柱层析(甲醇-水,40:60、50:50、60:40和70:30)、Sephadex LH-20(氯仿-甲醇,50:50)、硅胶柱层析(MeOH-CHCl3,10:90)和半制备高效液相(MeCN-H2O,40:60,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物1(210mg),2(140mg),15(2mg)和16(2mg)。Fr.A-6-5(24g)经Rp-C18柱层析(甲醇-水,40:60、50:50、60:40和70:30)、Sephadex LH-20(氯仿-甲醇,50:50)、硅胶柱层析(MeOH-CHCl3,5:95,10:90;acetone-CHCl3,40:60)和半制备高效液相(MeCN-H2O,40:60,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物3(13mg),4(7mg)和5(8mg)。
化合物1–16的结构数据:
旋光由Jasco model 1020旋光仪(Horiba,Tokyo,Japan)测定;红外光谱(IR)采用KBr压片法,由Bio-Rad FTS-135型红外光谱仪(Hercules,California,USA)测定;紫外光谱由UV-2401PC型紫外光谱仪(Shimadzu,Kyoto,Japan)测定;ECD谱由Applied Photophysics圆二色谱仪(Agilent,Santa Clara,United States)测定;核磁共振谱(1D和2D NMR)用AV800或Avance III-600型超导核磁共振仪(Bruker,Bremerhaven,Germany)测定,以氘代甲醇作为溶剂;高分辨质谱(HRMS)用LCMS-IT-TOF型质谱仪(Shimadzu,Kyoto,Japan)测定;薄层色谱硅胶、柱层析硅胶(200-300目)购自青岛美高及青岛海洋化工集团有限公司,葡聚糖凝胶LH-20(Sephadex LH-20)购自Amersham Bioscience(瑞典)。CHP20P MCI凝胶购自Mitsubishi Chemical Corporation(Tokyo,Japan)。
草豆蔻醇B1(1)
分子式:C35H34O9
分子量:598
性状:淡黄色粉末
HRESIMSm/z:599.2291[M+H]+(calcd.for C35H35O9,599.2276)
UV(MeOH)λmax(logε):224(3.57),286(3.22)nm
IR(KBr)vmax:3442,1651,1617,1600,1542,1449,1260cm–1
ECD(c 0.10,MeOH)λmax(Δε):217(+4.38),233(+1.84),2.54(+0.21),291(–2.61),323(+0.80)nm
1H-NMR和13C-NMR(DEPT)数据见表1和2。
草豆蔻醇B2(2)
分子式:C35H34O9
分子量:598
性状:淡黄色粉末
HRESIMS m/z:599.2267[M+H]+(calcd.for C35H35O9,599.2276)
UV(MeOH)λmax(logε):224(3.62),285(3.26)nm
IR(KBr)vmax:3424,1653,1617,1595,1516,1486,1449,1352,1258,1140,1100cm–1
ECD(c 0.10,MeOH)λmax(Δε):228(+5.72),292(-0.50),318(+0.86)nm
1H-NMR和13C-NMR(DEPT)数据见表1和2。
草豆蔻醇B3(3)
分子式:C35H32O8
分子量:580
性状:淡黄色粉末
HRESIMS m/z:581.2172[M+H]+(calcd.for C35H33O8,581.2170)
UV(MeOH)λmax(logε):224(3.07),287(2.77)nm
IR(KBr)vmax:3449,1623,1510,1455,1384,1208,1090cm–1
ECD(c 0.10,MeOH)λmax(Δε):228(+3.66),241(-0.93),290(+2.81),330(-0.21)nm
1H-NMR和13C-NMR(DEPT)数据见表1和2。
草豆蔻醇B4(4)
分子式:C42H38O9
分子量:686
性状:淡黄色粉末
HRESIMS m/z:687.2588[M+H]+(calcd.for C42H39O9,687.2589)
UV(MeOH)λmax(logε):226(3.40),287(2.99)nm
IR(KBr)vmax:3442,1634,1615,1603,1567,1517,1456,1154,1080cm–1
ECD(c 0.10,MeOH)λmax(Δε):225(-1.82),236(+11.05),293(-1.59),331(+1.44)nm
1H-NMR和13C-NMR(DEPT)数据见表1和2。
草豆蔻醇B5(5)
分子式:C42H38O9
分子量:686
性状:淡黄色粉末
HRESIMS m/z:687.2588[M+H]+(calcd.for C42H39O9,687.2589)
UV(MeOH)λmax(logε):227(3.18),284(2.80)nm
IR(KBr)vmax:3442,1637,1603,1517,1455,1384,1246,1105cm–1
ECD(c 0.10,MeOH)λmax(Δε):222(-3.08),236(+5.97),291(+2.52),337(-0.47)nm
1H-NMR和13C-NMR(DEPT)数据见表1和2。
草豆蔻醇B6(6)
分子式:C42H38O9
分子量:686
性状:淡黄色粉末
HRESIMS m/z:687.2588[M+H]+(calcd.for C42H39O9,687.2589)
UV(MeOH)λmax(logε):227(3.18),284(2.80)nm
IR(KBr)vmax:3442,1637,1603,1517,1455,1384,1246,1105cm–1
ECD(c 0.10,MeOH)λmax(Δε):222(-3.08),236(+5.97),291(+2.52),337(-0.47)nm
1H-NMR和13C-NMR(DEPT)数据见表1和3。
草豆蔻醇B7(7)
分子式:C35H34O8
分子量:582
性状:淡黄色粉末
HRESIMS m/z:581.2174[M-H]-(calcd.for C35H33O8,581.2181)
UV(MeOH)λmax(logε):225(3.76),288(3.09)nm
IR(KBr)vmax:3425,1701,1652,1604,1575,1517,1463,1447,1367,1262,1201,1154,1110cm-1
ECD(c 0.10,MeOH)λmax(Δε):219(+6.83),289(-9.37),332(+2.90)nm
1H-NMR和13C-NMR(DEPT)数据见表1和3。
草豆蔻醇B8(8)
分子式:C35H34O8
分子量:582
性状:淡黄色粉末
HRESIMS m/z:583.2328[M+H]+(calcd.for C35H35O8,583.2326)
UV(MeOH)λmax(logε):225(3.73),286(3.39)nm
IR(KBr)vmax:3407,1653,1605,1574,1517,1462,1446,1366,1227,1200,1153,1110cm–1
ECD(c 0.08,MeOH)λmax(Δε):223(+2.01),288(+2.51),335(-2.87)nm
1H-NMR和13C-NMR(DEPT)数据见表1和3。
草豆蔻醇B9(9)
分子式:C35H34O8
分子量:582
性状:淡黄色粉末
HRESIMS m/z:583.2328[M+H]+(calcd.for C35H35O8,583.2326)
UV(MeOH)λmax(logε):226(3.70),286(3.31)nm
IR(KBr)vmax:3423,1653,1604,1575,1517,1481,1463,1446,1200,1153,1110cm–1
ECD(c 0.08,MeOH)λmax(Δε):219(+8.20),289(-4.86),336(+1.96)nm
1H-NMR和13C-NMR(DEPT)数据见表1和3。
草豆蔻醇B10(10)
分子式:C35H34O8
分子量:582
性状:淡黄色粉末
HRESIMS m/z:583.2317[M+H]+(calcd.for C35H35O8,583.2326)
UV(MeOH)λmax(logε):224(3.69),286(3.26)nm
IR(KBr)vmax:3426,1651,1605,1575,1517,1481,1463,1447,1364,1225,1201,1154,1108cm-1
ECD(c 0.08,MeOH)λmax(Δε):227(+2.07),291(+2.59),334(-1.49)nm
1H-NMR和13C-NMR(DEPT)数据见表1和3。
草豆蔻醇B11(11)
分子式:C28H26O7
分子量:474
性状:淡黄色粉末
HRESIMS m/z:475.1743[M+H]+(calcd.for C28H27O7,475.1751)
UV(MeOH)λmax(logε):224(3.12),284(2.84)nm
IR(KBr)vmax:3443,1622,1594,1517,1467,1384,1261,1091cm–1
ECD(c 0.10,MeOH)λmax(Δε):227(+5.48),239(-2.34),287(+4.26),330(-0.57)nm
1H-NMR和13C-NMR(DEPT)数据见表1和4。
草豆蔻醇B12(12)
分子式:C36H36O8
分子量:596
性状:淡黄色粉末
HRESIMS m/z:597.2491[M+H]+(calcd.for C36H37O8,597.2483)
UV(MeOH)λmax(logε):225(3.34),287(3.98)nm
IR(KBr)vmax:3442,1632,1613,1596,1515,1447,1384,1284,1174,1096cm–1
ECD(c 0.16,MeOH)λmax(Δε):220(+3.67),232(-4.56),288(+6.50),335(-2.02)nm
1H-NMR和13C-NMR(DEPT)数据见表1和4。
草豆蔻醇B13(13)
分子式:C36H36O8
分子量:596
性状:淡黄色粉末
HRESIMS m/z:595.2333[M-H]-(calcd.for C36H35O8,595.2337)
UV(MeOH)λmax(logε):225(3.26),288(2.93)nm
IR(KBr)vmax:3424,1650,1596,1514,1463,1447,1413,1354,1247,1176,1148,1093cm–1
ECD(c 0.09,MeOH)λmax(Δε):219(-11.21),241(-2.12),292(+3.75),335(-1.91)nm
1H-NMR和13C-NMR(DEPT)数据见表1和4。
草豆蔻醇B14(14)
分子式:C37H36O9
分子量:624
性状:淡黄色粉末
HRESIMS m/z:623.2278[M-H]-(calcd.for C37H35O9,623.2287)
UV(MeOH)λmax(logε):223(3.70),283(3.27)nm
IR(KBr)vmax:3424,1703,1650,1597,1514,1446,1414,1361,1266,1247,1173,1095cm–1
ECD(c 0.08,MeOH)λmax(Δε):219(-3.47),232(+3.03),243(-2.51),288(-5.32),340(+1.94)nm
1H-NMR和13C-NMR(DEPT)数据见表1和4。
草豆蔻醇B15(15)
分子式:C35H34O7
分子量:566
性状:淡黄色粉末
HRESIMS m/z:567.2369[M+H]+(calcd.for C35H35O7,567.2377)
UV(MeOH)λmax(logε):227(3.45),282(3.08)nm
IR(KBr)vmax:3422,1649,1597,1512,1497,1448,1413,1352,1275,1246,1218,1174,1148,1093cm–1
ECD(c 0.10,MeOH)λmax(Δε):220(+8.22),240(+1.50),291(-3.86),337(+1.71)nm
1H-NMR和13C-NMR(DEPT)数据见表1和4。
草豆蔻醇B16(16)
分子式:C35H34O7
分子量:566
性状:淡黄色粉末
HRESIMS m/z:567.2369[M+H]+(calcd.for C35H35O7,567.2377)
UV(MeOH)λmax(logε):227(3.12),286(2.71)nm
IR(KBr)vmax:3411,1651,1596,1512,1448,1414,1352,1278,1247,1218,1174,1148,1093cm–1
ECD(c 0.10,MeOH)λmax(Δε):219(-5.89),232(+0.98),291(+2.06),336(-0.82)nm
1H-NMR和13C-NMR(DEPT)数据见表1和4。
实施例2:
GPa、PTP1B、TCPTP和α-葡萄糖苷酶抑制活性。
1材料和方法
1.1材料
α-葡萄糖苷酶和GPa购自Sigma Aldrich(St.Louis,MO,USA);磷酸盐缓冲液(≥99%,美仑生物,大连);对硝基苯基-α-D-吡喃葡萄糖(≥99%,源叶生物,上海);阿卡波糖(≥98%,拜耳医药,北京);PTP1B(蛋白酪氨酸磷酸酶)和TCPTP(T-细胞酪氨酸磷酸酶)购自Sino Biological(Wayne,PA,USA);苏拉明钠购自ACROS(New Jersey USA);Hepes购自北京夏丝生物科技有限公司(北京);糖原购自美伦生物科技有限公司(大连);α-D-葡萄糖1-磷酸二钠盐(St.Louis,MO,U.S.A.);钼酸铵购自上海九鼎化学有限公司(上海);孔雀石绿购自中国北京八菱威科技有限公司(北京)。
1.2仪器
Flex Station 3台式多功能酶标仪(Bio-RAD 680,美国);分析天平(AG135,Metler Toledo,中国);恒温箱(DHP-9082,上海)。
1.3实验过程
PTP1B抑制活性是根据本课题组先前的研究进行的。简言之,工作缓冲液(workingbuffer,WB)是由3-(N-吗啉代)丙磺酸(MOPS,722.02mg)、二硫苏糖醇(DTT,30mg)、EDTA(25.7mg)、牛血清蛋白(BSA,200mg)和NaCl(12.1g)溶于100mL超纯水配制而成。溶解在1mL超纯水中p-硝基苯基磷酸盐(p-NPP,31mg)作为底物。将70μLWB、10μL PTP1B酶(5mg/L)和10μL溶解在DMSO中的待测样品依次添加到96孔板中,在37℃下孵育15min后,通过加入10μL100mM p-NPP引发反应,之后孵育30min。在反应混合物中加入100μL 0.1M Na2CO3溶液终止反应,用酶标仪在405nm处测定吸光值,记录结果。阴性对照用DMSO代替待测溶液,阳性为苏拉明钠,其他方法相同。PTP1B抑制率计算公式为抑制率(%)=(△酶-△样/△酶-△阴)×100%。利用Graphpad prism 5软件对实验结果进行分析。TCPTP测量方法、所用的材料以及测量方法与PTP1B一致。
α-葡萄糖苷酶抑制活性测试采用文献报道的方法进行了轻微改良。阿卡波糖作为阳性对照,硝基苯基-α-葡萄糖(PNPG)作为底物。将20μL溶解在磷酸盐缓冲液(PB,pH=7)中的0.2U/mLα-葡萄糖苷酶和30μL溶解在MeOH-PB(50:50)中的待测样品依次加入到96孔板中。实验的空白用相同的方法,只是将PB代替α-葡萄糖苷酶。混合液在37℃恒温箱中孵育5分钟后,将底物20μL5.0 mM PNPG依次加到96孔板引发反应,反应混合物在37℃恒温箱中孵育15分钟后,通过加入40μL 0.1M Na2CO3终止反应。用酶标仪在405nm处测定吸光值,记录结果。阴性对照用PB代替待测溶液,其他方法相同。α-葡萄糖苷酶抑制率计算公式为:抑制率(%)=(△酶-△样/△酶-△阴)×100%。利用Graphpad prism 5软件对实验结果进行分析。
GPa抑制活性根据文献报道的方法进行测试。前期准备:将1.19gHepes溶于100mL纯净水中配置成50mM的缓冲液(pH 7.2);随后称取370mgKCl、25mg MgCl2·6H2O、50mg糖原和7.5mg 1-磷酸葡萄糖二钠盐溶于50mL Hepes缓冲液中配置成溶液I。900mg钼酸铵和34.2mg孔雀石绿加入90mL 1M盐酸,充分混匀,超声至完全溶解,配置成溶液II。首先将10μL用DMSO溶解的样品和50μL用Hepes缓冲液稀释的3U/mLGPa酶依次加入96孔板中,实验的空白用相同的方法,只是将Hepes代替GPa酶。在25℃的恒温箱中孵育15min。随后,通过加入40μL溶液I引发反应,孵育30min后,在反应混合液中加入150μL溶液II,在25℃恒温箱中孵育20min。用酶标仪在620nm处测定吸光值,记录结果。阴性对照用DMSO代替待测溶液,阳性为CP-91149,其他方法相同。GPa抑制率计算公式为抑制率(%)=(△酶-△样/△酶-△阴)×100%。利用Graphpad prism 5软件对实验结果进行分析。
2.结果:
所有化合物均测试了其GPa酶抑制活性,在200μM浓度下除2外的所有化合物均表现明显的抑制活性(>60%)。如表5所示,化合物4和5的抑制活性最为显著,IC50值分别为13.2和11.3μM;化合物6-10和12-16也具有一定的GPa酶抑制活性,IC50值在41.5-95.4μM之间;化合物1、3和11的IC50值大于100μM,表现微弱的活性。
在200μM浓度下所有化合物均具有明显的α-葡萄糖苷酶抑制活性,抑制率在70%以上;其中(见表5),化合物4和5的抑制活性最为显著,IC50值分别为7.1和12.4μM,是阳性对照阿卡波糖的(IC50,209.1μM)的25-29倍;化合物3和5-16的α-葡萄糖苷酶抑制活性也较显著,IC50值在17.5-63.8μM之间;化合物1和2具有相对较弱的抑制活性,IC50值分别为108.4和157.3μM。
PTP1B和TCPTP酶抑制活性测试结果显示在200μM浓度下,大多数化合物均对PTP1B酶表现明显的抑制活性,而对TCPTP酶的抑制活性较弱,说明这些化合物具有一定的选择性。如表5所示,化合物4-6和14的PTP1B酶抑制活性最为显著,IC50值分别为42.8、40.7、52.8和61.0μM;化合物1、2、8、13和15的PTP1B酶抑制活性较弱,IC50值在116.6-196.7μM之间。
表5化合物1-16对GPa,α-Glucosidase,PTP1B和TCPTP的抑制活性.
3、结论:
本发明以生物活性为导向,从草豆蔻的干燥种子中分离得到16个新的二苯基庚烷-黄烷酮杂合体,草豆蔻醇B1–B16(1–16)。大多数化合物均具有显著的GPa、PTP1B和α-葡萄糖苷酶抑制活性。其中,化合物4-10和12-16具有显著的GPa酶抑制活性,IC50值在11.3-95.4μM之间;化合物4和5具有显著的α-葡萄糖苷酶抑制活性,IC50值为7.1和12.4μM;化合物4-6和14具有显著的PTP1B/TCPTP酶选择性抑制活性,IC50值分别是42.8、40.7、52.8和61.0μM;值得注意的是,化合物4和5对上述三种酶均具有明显的抑制活性。这项研究为依据二苯基庚烷-黄烷酮开发新型多靶点抗糖尿病候选药物的提供了有力参考,并为在食品和制药工业中草豆蔻的应用提供了有价值的线索。
制剂实施例:
1.取化合物1–16任其一或任意组合,用少量的DMSO溶解后,按常规加注射用水,精滤,灌封灭菌制成注射液。
2.取化合物1–16任其一或任意组合,用少量的DMSO溶解后,将其溶于无菌注射用水中,搅拌使溶解,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.取化合物1–16任其一或任意组合,按其与赋形剂重量比为9:1的比例加入赋形剂,制成粉剂。
4.取化合物1–16任其一或任意组合,按其与赋形剂重量比为5:1的比例加入赋形剂,制粒压片。
5.取化合物1–16任其一或任意组合,按常规口服液制法制成口服液。
6.取化合物1–16任其一或任意组合,按其与赋形剂重量比为5:1的比例加入赋形剂,制成胶囊。
7.取化合物1–16任其一或任意组合,按其与赋形剂重量比为3:1的比例加入赋形剂,制成胶囊。
8.取化合物1–16任其一或任意组合,按其与赋形剂重量比为5:1的比例加入赋形剂,制成颗粒剂。
Claims (8)
2.权利要求1所述的式(I)的化合物草豆蔻醇B1–B16(1–16)任其一或任意组合在制备降血糖药物或保健食品中的应用。
3.权利要求1所述的式(I)的化合物草豆蔻醇B1–B16(1–16)任其一或任意组合在制备GPa、PTP1B及α-葡萄糖苷酶抑制剂中的应用。
4.制备权利要求1所述的式(I)化合物草豆蔻醇B1–B16(1–16)的方法,该方法包括:取草豆蔻的干燥种子,粉碎,用90%乙醇回流提取两次,每次2h,合并乙醇提液,减压回收乙醇得浸膏,浸膏分散在水中后用乙酸乙酯萃取,随后浓缩的到乙酸乙酯萃取部分;然后将乙酸乙酯萃取部分过硅胶柱层析,以甲醇-氯仿(0:100、2:98、5:95、10:90、20:80和100:0,v/v)为洗脱剂梯度洗脱得到Fr.A-1~Fr.A-8八个流分;流分Fr.A-6经MCI CHP 20P gel柱层析(甲醇-水,30:70、40:60、50:50、70:30和100:0)得到五个亚流分Fr.A-6-1~Fr.A-6-5;Fr.A-6-2经硅胶柱层析(MeOH-CHCl3,5:95和10:90)得到五个亚流分Fr.A-6-2-1~Fr.A-6-2-5;Fr.A-6-2-4经Sephadex LH-20(氯仿-甲醇,50:50)、硅胶柱层析(MeOH-CHCl3, 15:85)和半制备高效液相(MeCN-H2O, 35:65, 3.0 mL/min,Agilent XDB-C18柱,9.4 × 250 mm, 5 μm)得到化合物6, 7, 8和11,Fr. A-6-4 经Rp-C18柱层析(甲醇-水,40:60、50:50、60:40、70:30和100:0)得到七个亚流分Fr. A-6-4-1‒Fr. A-6-4-7;Fr. A-6-4-3经Sephadex LH-20(氯仿-甲醇,50:50)、硅胶柱层析(MeOH-CHCl3, 6:94;acetone-CHCl3, 65:35)和半制备高效液相(MeCN-H2O, 35:65, 3.0 mL/min,Agilent XDB-C18柱,9.4 × 250 mm, 5 μm)得到化合物9, 10, 12, 13和14;Fr. A-6-4-6经Rp-C18柱层析(甲醇-水,40:60、50:50、60:40和70:30)、Sephadex LH-20(氯仿-甲醇,50:50)、硅胶柱层析(MeOH-CHCl3, 10:90)和半制备高效液相(MeCN-H2O,40:60, 3.0 mL/min,Agilent XDB-C18柱,9.4 × 250 mm, 5 μm)得到化合物1,2, 15和16;Fr. A-6-5经Rp-C18柱层析(甲醇-水,40:60、50:50、60:40和70:30)、SephadexLH-20(氯仿-甲醇,50:50)、硅胶柱层析(MeOH-CHCl3, 5:95, 10:90;acetone-CHCl3, 40:60)和半制备高效液相(MeCN-H2O,40:60, 3.0 mL/min,Agilent XDB-C18柱,9.4 × 250mm, 5 μm)得到化合物3, 4和5。
5.一种药物组合物,其特征在于,所述药物组合物包括权利要求1 所述的式(I) 化合物草豆蔻醇B1–B16(1–16)的至少一种或任意组合和药学上可接受的载体或赋型剂。
6.权利要求5所述的药物组合物在制备降血糖药物或保健食品中的应用。
7.权利要求5所述的药物组合物在制备GPa、PTP1B及α-葡萄糖苷酶抑制剂中的应用。
8.制备权利要求5所述的药物组合物的方法,按照权利要求3的方法制备得到化合物草豆蔻醇B1–B16(1–16),再以化合物1-16的至少一种或任意组合为原料加入一定比例的可药用载体或赋形剂。
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CN113929698B (zh) * | 2021-11-23 | 2023-08-04 | 中国科学院昆明植物研究所 | 二芳基庚烷二聚体及其药物组合物与其制备方法和应用 |
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