CN113929698B - 二芳基庚烷二聚体及其药物组合物与其制备方法和应用 - Google Patents
二芳基庚烷二聚体及其药物组合物与其制备方法和应用 Download PDFInfo
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Abstract
本发明提供结构式(I)所示10个新的二芳基庚烷二聚体,草豆蔻醇C1−C10(katsumadainols C1−C10,1–10),以其为活性成份的药物组合物,及其它们的制备方法和应用,属于药物技术领域。本发明的化合物可显著促进GLP‑1分泌,同时具有GPa、PTP1B和α‑葡萄糖苷酶抑制活性,能够与可药用载体或赋型剂组成药物组合物,能够用于制备降血糖药物或保健食品。
Description
技术领域:
本发明属于药物技术领域。具体地,涉及10个新的二芳基庚烷二聚体,草豆蔻醇C1-C10(katsumadainols C1-C10,1-10),以化合物1-10为有效成分的药物组合物,它们的制备方法,及其在制备GLP-1促泌剂药物中的应用,在制备GPa、PTP1B和α-葡萄糖苷酶抑制剂药物中的应用,和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(Type 2diabetes mellitus,T2DM)作为一种复杂的代谢性疾病,已成为世界性的重大健康问题。由于长期高血糖,2型糖尿病常导致严重的并发症,如视网膜病变、肾病、高血压等。目前,市场上有7种口服降糖药,包括双胍类、α-葡萄糖苷酶抑制剂、胰岛素分泌剂、胰岛素增敏剂、胰高血糖素样肽-1(GLP-1)受体激动剂、二肽基肽酶-4(DPP4)抑制剂和钠-葡萄糖协同转运体-2(SGLT-2)抑制剂,然而,各种各样的副作用(如急性低血糖、体重增加、胃肠不适和肝毒性)限制了它们的应用。因此,具有高效、低血糖风险的抗糖尿病新药仍需努力研究。目前,多采用药物组合疗法治疗2型糖尿病,例如:Qtrilmet和Trijardy XR是SGLT-2抑制剂、DPP4抑制剂和盐酸二甲双胍的组合,与单靶点药物相比具有明显的治疗优势。因此,具有多种靶点的化合物在寻找新的抗糖尿病候选药物方面具有重要价值。
胰高血糖素样肽1(Glucagon-like peptide 1,GLP-1)是肠内分泌上皮L细胞分泌的一种肠促胰岛素激素,能以葡萄糖依赖的方式刺激胰岛素分泌,降低胰高血糖素分泌。目前市面上有GLP-1受体激动剂和DPP-4抑制剂两种类型的GLP-1受体激动剂,而大多数GLP-1受体激动剂为肽类似物,存在成本高、注射给药、胃肠道和胰腺方面的副作用等缺点,而且现有的DPP4抑制药物均为人工合成化合物,存在选择性低、安全性差的问题。因此从天然产物中寻找GLP-1受体激动剂具有重要意义。
糖原磷酸化酶a(Glycogen phosphorylase a,GPa)负责控制糖原降解速率,并在催化糖原磷酸水解形成葡萄糖-1-磷酸中起着关键作用。已有几种类型的GPa抑制剂在糖尿病动物和临床试验中显示出降糖作用,但尚未被批准为新药。PTP1B通过激活的胰岛素受体去磷酸化负调控胰岛素作用,是开发抗糖尿病药物的另一个有前景的治疗靶点。然而,PTP1B抑制剂的膜通透性差,对与PTP1B最相似的蛋白T细胞蛋白酪氨酸磷酸酶(TCPTP)的选择性弱,严重阻碍了其临床应用。α-葡萄糖苷酶抑制剂(如阿卡波糖、米格列醇和沃格利波糖)是很有前途的降糖药,可单独或与其他类型药物联合使用,但具有不可避免的副作用,如不良胃肠道副作用和体重增加。
在中国使用了数千年的传统中药是探索新的抗糖尿病药物的重要来源。草豆蔻(Alpinia katsumadai)是我国著名的香料,在传统中药中常用来治疗呕吐、胃病、炎症等疾病。目前以从草豆蔻中分离得到了二芳基庚烷、黄酮、单萜、倍半萜、二苯乙烯等多种类型的化合物,其中一些化合物具有止吐、平喘、抗胃溃疡、抗增殖、抗病毒、抗氧化、抗炎、抗菌等生物活性。Lee等人报道草豆蔻的甲醇提取物具有α-葡萄糖苷酶抑制活性,但是活性成分尚不明确。在我们的前期研究发现草豆蔻干燥种子的乙醇提取物对db/db小鼠显示降血糖活性,活性导向分离得到了10个结构新颖且可以促进GLP-1分泌和抑制GPa、PTP1B及α-葡萄糖苷酶活性的二苯基庚烷二聚体,草豆蔻醇C1-C10(katsumadainols C1-C10,1-10)。
迄今为止,现有技术无草豆蔻醇C1-C10(katsumadainols C1-C10,1-10)的报道,也没有化合物1-10及其药物组合物作为GLP-1促泌剂以及GPa、PTP1B和α-葡萄糖苷酶抑制剂的报道,及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C1-C10(katsumadainols C1-C10,1-10),化合物1-10及其药物组合物作为GLP-1促泌剂以及GPa、PTP1B和α-葡萄糖苷酶抑制剂,及其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)所示的二芳基庚烷二聚体化合物1-10,即草豆蔻醇C1-C10(katsumadainols C1-C10,),
本发明另外还提供了制备所述的式(I)化合物1-10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。Fr.A-7(50g)经MCI CHP 20P gel柱层析(甲醇-水,30:70、40:60、50:50、70:30、100:0,v/v)得到了Fr.A-7-1~Fr.A-7-6。Fr.A-7-2(15g)经硅胶柱层析(MeOH-CHCl3,10:90和20:80)得到了Fr.A-7-2a~Fr.A-7-2e。Fr.A-7-2c(5g)经Sephadex LH-20(氯仿-甲醇,50:50)、硅胶柱层析(MeOH-CHCl3,15:85)、反相Rp-C18柱层析(MeOH-H2O,50:50,60:40,70:30)和半制备高效液相(Agilent XDB-C18柱,MeOH-H2O,65:35;手性柱Opti-C1-5柱,MeCN-H2O,35:65)得到化合物6(52mg),8(184mg)和9(88mg)。Fr.A-7-2d(3g)经过反复的硅胶柱层析(MeOH-CHCl3,10:90)、SephadexLH-20柱层析(MeOH-CHCl3,50:50)和半制备高效液相(Agilent XDB-C18柱,MeCN-H2O,38:62)纯化得到化合物7(10mg)和10(47mg)。Fr.A-7-3(10g)经过反相Rp-C18柱层析(MeOH-H2O,40:60~100:0)、硅胶柱层析(MeOH-CHCl3,5:95)、Sephadex LH-20柱层析(MeOH-CHCl3,50:5)和半制备高效液相(Agilent XDB-C18柱,MeCN-H2O,38:62;Opti-/>C1-5柱,MeOH-H2O,75:25)纯化得到化合物3(7mg)、4(16mg)和5(13mg)。Fr.A-7-4(8g)经过反复的反相Rp-C18柱层析(MeOH-H2O,40:60~100:0)、硅胶柱层析(MeOH-CHCl3,8:92)、Sephadex LH-20柱层析(MeOH-CHCl3,50:5)和半制备高效液相(Agilent XDB-C18柱,MeCN-H2O,45:55;Opti-C1-5柱,MeOH-H2O,80:20)纯化得到化合物1(300mg)和2(180mg)。
本发明提供了上述技术方案所述化合物1-10在制备GLP-1促泌剂药物中的应用。
本发明提供了上述技术方案所述化合物1-10在制备GPa、PTP1B和α-葡萄糖苷酶抑制剂药物中的应用。
本发明提供了上述技术方案所述化合物1-10在制备降血糖药物或保健食品中的应用。
本发明提供了一种药物组合物,所述药物组合物包括上述技术方案所述化合物1-10中的至少一种和药学上可接受的载体或赋型剂。
本发明提供了上述技术方案所述药物组合物在制备GLP-1促泌剂药物中的应用。
本发明提供了上述技术方案所述药物组合物在制备GPa、PTP1B和α-葡萄糖苷酶抑制剂药物中的应用。
本发明提供了上述技术方案所述药物组合物在制备降血糖药物或保健食品中的应用。
制备含化合物1-10的药物组合物的方法是,以化合物1-10中的至少一种为原料,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1-10用作GLP-1促泌剂以及GPa、PTP1B和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1-10,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。
与现有技术相比,本发明具备如下的优益性:
1.本发明提供了一类新的二芳基庚烷二聚体,为首次报道的新化合物。
2.本发明从草豆蔻中分离得到10个新的二芳基庚烷二聚体1-10,在浓度为25.0和12.5μmol/L时,化合物1-5和7-10明显地刺激STC-1细胞中GLP-1的分泌。化合物1-4具有明显的GPa抑制活性,其IC50值为18.0-31.3μmol/L;化合物1-5具有明显的α-葡萄糖苷酶抑制活性,其IC50值小于20μmol/L;同时化合物1-5和10还具有明显的PTP1B抑制活性,其IC50值在35.5至80.1μmol/L之间。本发明表明草豆蔻中二芳基庚烷二聚体具有降血糖作用。
3.本发明化合物同时具有促GLP-1分泌活性和GPa、α-葡萄糖苷酶和PTP1B抑制活性,是一类新颖的多靶点降血糖活性分子。
4.本发明的制备方法简单易行,操作方便,得率较高,环保安全,具有较高的可行性。
附图说明:
图1为本发明化合物1-10的结构式示意图;
图2.为本发明化合物1-5和7-10对STC-1细胞中GLP-1分泌的促进作用,油酰乙醇胺(Oleoyl ethanolamine,OEA)用作阳性对照.数值用平均值±标准偏差表示(n=3);
图3.为本发明化合物1-10的GPa,α-葡萄糖苷酶、PTP1B、TCPTP和DPP4抑制实验.CP-91149、阿卡波糖、正钒酸钠和西他列汀分别是GPa、α-葡萄糖苷酶、PTP1B/TCPTP和DPP4抑制实验的阳性对照。
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草豆蔻醇C1-C10(katsumadainols C1-C10,1-10)制备方法、结构鉴定、药理作用,以及本发明的制备方法及药物组成,但不以此试验例和实施例来限定本发明。
实施例1:
化合物1-10的制备:
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。Fr.A-7(50g)经MCI CHP 20P gel柱层析(甲醇-水,30:70、40:60、50:50、70:30、100:0,v/v)得到了Fr.A-7-1~Fr.A-7-6。Fr.A-7-2(15g)经硅胶柱层析(MeOH-CHCl3,10:90和20:80)得到了Fr.A-7-2a~Fr.A-7-2e。Fr.A-7-2c(5g)经Sephadex LH-20(氯仿-甲醇,50:50)、硅胶柱层析(MeOH-CHCl3,15:85)、反相Rp-C18柱层析(MeOH-H2O,50:50,60:40,70:30)和半制备高效液相(Agilent XDB-C18柱,MeOH-H2O,65:35;手性柱Opti-C1-5柱,MeCN-H2O,35:65)得到化合物6(52mg),8(184mg)和9(88mg)。Fr.A-7-2d(3g)经过反复的硅胶柱层析(MeOH-CHCl3,10:90)、Sephadex LH-20柱层析(MeOH-CHCl3,50:50)和半制备高效液相(AgilentXDB-C18柱,MeCN-H2O,38:62)纯化得到化合物7(10mg)和10(47mg)。Fr.A-7-3(10g)经过反相Rp-C18柱层析(MeOH-H2O,40:60~100:0)、硅胶柱层析(MeOH-CHCl3,5:95)、Sephadex LH-20柱层析(MeOH-CHCl3,50:5)和半制备高效液相(Agilent XDB-C18柱,MeCN-H2O,38:62;Opti-C1-5柱,MeOH-H2O,75:25)纯化得到化合物3(7mg)、4(16mg)和5(13mg)。Fr.A-7-4(8g)经过反复的反相Rp-C18柱层析(MeOH-H2O,40:60~100:0)、硅胶柱层析(MeOH-CHCl3,8:92)、Sephadex LH-20柱层析(MeOH-CHCl3,50:5)和半制备高效液相(Agilent XDB-C18柱,MeCN-H2O,45:55;Opti-/>C1-5柱,MeOH-H2O,80:20)纯化得到化合物1(300mg)和2(180mg)。
化合物1-10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;X-射线晶体分析是使用Cu Kα靶在Bruker D8 QUEST仪器(Bruker,Karlsruher,Germany)测定。ECD谱由AppliedPhotophysics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)。CHP20PMCI凝胶购自Mitsubishi Chemical Corporation(Tokyo,Japan)。
草豆蔻醇C1(1)
分子式:C38H40O6,
分子量:592
性状:浅黄色粉末
HRESIMSm/z:591.2756[M-H]-(calcd.for C38H39O6,591.2752);
UV(MeOH)λmax(logε):223(3.62),268(3.42)nm
IR(KBr)vmax:3392,1612,1514,1446,1363,1233,1132,1050cm-1;
ECD(c 0.03,MeOH)λmax(Δε):212(-0.70),221(+2.38),237(-0.45),263(+0.60),288(-1.52)nm
(c 0.12,MeOH);
1HNMR和13CNMR(DEPT)数据见表1和2。
草豆蔻醇C2(2)
分子式:C38H40O6
分子量:592
性状:浅黄色粉末
HRESIMS m/z:591.2760[M-H]-(calcd.for C38H39O6,591.2752);
UV(MeOH)λmax(logε):221(3.47),265(3.24)nm;
IR(KBr)νmax:3402,1612,1514,1446,1364,1235,1172,1050cm-1;
ECD(c 0.03,MeOH)λmax(Δε):212(-0.70),221(+2.38),237(-0.45),263(+0.60),288(-1.52)nm;
(c 0.12,MeOH);
1H-NMR和13C-NMR(DEPT)数据见表1和2。
草豆蔻醇C3(3)
分子式:C38H40O6
分子量:592
性状:浅黄色粉末
HRESIMS m/z593.2893[M+H]+(calcd.for C38H41O6,593.2898);
UV(MeOH)λmax(logε):225(3.54),266(3.27)nm;
IR(KBr)νmax:3425,1613,1514,1446,1368,1231,1172,1077,831cm-1;
ECD(c 0.08,MeOH)λmax(Δε):212(+2.48),222(-4.72),239(+1.91),287(+4.08)nm;
(c 0.14,MeOH);
1H-NMR和13C-NMR(DEPT)数据见表1和2。
草豆蔻醇C4(4)
分子式:C25H28O6,
分子量:424
性状:浅黄色粉末
HRESIMS m/z591.2748[M-H]-(calcd.for C38H39O6,591.2752);
UV(MeOH)λmax(logε):225(3.48),265(3.28)nm;
IR(KBr)νmax:3423,1613,1514,1445,1365,1231,1171,1076cm-1;
ECD(c 0.08,MeOH)λmax(Δε):230(+3.24),265(-7.63)nm;
(c 0.12,MeOH);
1H-NMR和13C-NMR(DEPT)数据见表1和2。
草豆蔻醇C5(5)
分子式:C40H44O8
分子量:652
性状:浅黄色粉末
HRESIMS m/z651.2971[M-H]-(calcd.for C40H43O8,651.2963);
UV(MeOH)λmax(logε):226(3.40),263(3.19)nm;
IR(KBr)νmax:3413,1707,1612,1514,1440,1344,1260,1234,1171,1104,1067cm-1;
ECD(c 0.08,MeOH)λmax(Δε):216(-0.37),230(+0.24),261(-1.52)nm;
(c 0.10,MeOH);
1H-NMR和13C-NMR(DEPT)数据见表1和2。
草豆蔻醇C6(6)
分子式:C38H42O7,
分子量:610
性状:浅黄色粉末
HRESIMS m/z609.2855[M-H]-(calcd.for C38H41O7,609.2858);
UV(MeOH)λmax(logε):226(3.55),278(2.77)nm;
IR(KBr)νmax:3395,1613,1514,1450,1369,1240,1174,1046cm-1;
ECD(c 0.08,MeOH)λmax(Δε):202(-1.73),206(+1.05),220(-0.28),238(+0.81),268(-0.20)nm;
(c 0.15,MeOH);
1H-NMR和13C-NMR(DEPT)数据见表1和3。
草豆蔻醇C7(7)
分子式:C38H42O7,
分子量:610
性状:浅黄色粉末
HRESIMS m/z609.2849[M-H]-(calcd.for C38H41O7,609.2858);
UV(MeOH)λmax(logε):225(3.50),278(2.87)nm;
IR(KBr)νmax:3440,1632,1614,1515,1449,1384,1237,1173,1056cm-1;
ECD(c 0.10,MeOH)λmax(Δε):208(-3.22),236(-2.04),284(-0.53)nm;
(c 0.11,MeOH);
1H-NMR和13C-NMR(DEPT)数据见表1和3。
草豆蔻醇C8(8)
分子式:C38H42O7,
分子量:610
性状:浅黄色粉末
HRESIMS m/z609.2867[M-H]-(calcd.for C38H41O7,609.2858);
UV(MeOH)λmax(logε):226(3.42),279(2.77)nm;
IR(KBr)νmax:3442,1634,1615,1514,1454,1384,1241,1173,1047cm-1;
ECD(c 0.10,MeOH)λmax(Δε):204(-3.35),221(-1.82),236(-1.44),271(+0.53)nm;
(c 0.22,MeOH);
1H-NMR和13C-NMR(DEPT)数据见表1和3。
草豆蔻醇C9(9)
分子式:C38H42O7,
分子量:610
性状:浅黄色粉末
HRESIMS m/z609.2864[M-H]-(calcd.for C38H41O7,609.2858);
UV(MeOH)λmax(logε):226(3.48),280(2.90)nm;
IR(KBr)νmax:3442,1633,1615,1515,1454,1384,1242,1172,1049cm-1;
ECD(c 0.10,MeOH)λmax(Δε):207(+2.34),237(+1.60),283(+0.39)nm;
(c 0.06,MeOH);
1H-NMR和13C-NMR(DEPT)数据见表1和3。
草豆蔻醇C10(10)
分子式:C38H42O7,
分子量:610
性状:浅黄色粉末
HRESIMS m/z609.2841[M-H]-(calcd.for C38H41O7,609.2858);
UV(MeOH)λmax(logε):225(3.56),278(2.98)nm;
IR(KBr)vmax:3432,1625,1516,1450,1384,1148and 1115cm-1;
IR(KBr)νmax:3443,1634,1615,1515,1454,1384,1229,1173,1058cm-1;
(c 0.15,MeOH);
1H-NMR和13C-NMR(DEPT)数据见表1和3。
表1化合物1-10的13C NMR(150MHz,CD3OD)数据a
aRecorded in 100MHz.
表2.化合物1-5的1H NMR(600MHz,CD3OD,δin ppm,J in Hz)数据.
表3.化合物6-10的1H NMR(600MHz,CD3OD,δin ppm,J in Hz)数据.
aRecorded in 400MHz.
实施例2:
化合物促GLP-1分泌以及GPa、PTP1B、TCPTP和α-葡萄糖苷酶抑制活性。
1材料和方法
1.1材料
STC-1细胞购自美国ATCC;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 JerseyUSA);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);牛血清购自上海龙田生物技术有限公司(上海);小鼠GLP-1酶联免疫吸附测定试剂盒购自北京太阳生物科技有限公司科技有限公司(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
GLP-1分泌实验:将用STC-1细胞用含有10%胎牛血清和1%青霉素/链霉素的培养基在37℃和5%CO2饱和湿度的培养箱中培养。将细胞浓度为1×106个/每孔的细胞接种于24孔板中继续培养24h。细胞融合度达到80%-90%后,用含0.1%(w/v)无脂肪酸BSA的Krebs-Ringer碳酸氢盐缓冲液(KRB:134.5mM NaCl,10mM Hepes,3.6mM KCl,5mM NaHCO3,1.5mMCaCl2,0.5mM NaH2PO4,0.5mM MgCl2)饥饿1h,然后再用不同浓度待测化合物处理的含有0.1%(w/v)无脂肪酸BSA和55.5mM葡萄糖的Krebs-Ringer碳酸氢盐缓冲液孵育1h。处理结束后,在4℃800g下离心5min,收集上清液,然后用小鼠GLP-1ELISA试剂盒检测上清液中的GLP-1含量。
GPa抑制实验:前期准备:将1.19g Hepes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。
α-葡萄糖苷酶抑制实验: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20μL 5.0mM 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。
PTP1B抑制实验:工作缓冲液(working buffer,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10μL 100mM 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。
2.结果:
在浓度为25.0和12.5μmol/L时评价了化合物1-5和7-10刺激STC-1细胞中GLP-1分泌情况。在用不同浓度的化合物处理后,与对照组相比,化合物明显的增加了GLP-1分泌(图2和表4)。化合物1-5和7-10明显的刺激GLP-1分泌,当浓度为25.0μmol/L时,促泌率在267.5%至433.1%之间,当浓度为25.0μmol/L时,促泌率在117.8%至348.2%之间,强于阳性油酰乙醇胺(77.5%,25.0μmol/L)。
表4.化合物对STC-1细胞GLP-1分泌的促进作用
a促泌率表示为GLP-1含量较对照组增加的百分比.
在浓度200和100μmol/L时,测试了化合物1-10对GPa的抑制活性。如图3所示,除了化合物7之外,所有的化合物对显示了明显的抑制活性,当浓度为200μmol/L时,其抑制率超过了65%。特别是化合物1-4在浓度为200μmol/L时其抑制率甚至超过了80%。进一步研究各活性化合物的剂量-效应关系,得到各自的IC50值(表5)。化合物1-4对GPa具有明显的抑制活性,其IC50值在18.0至31.3μmol/L之间;化合物5、6和8-10对GPa具有适中的抑制活性,其IC50值在119.3至165.3μmol/L之间。
化合物1-10对α-葡萄糖苷酶具有明显的抑制活性,当浓度为200μmol/L时,其抑制活性优于阳性阿卡波糖,抑制率高于60%。在所有的化合物中,化合物1对α-葡萄糖苷酶的抑制活性最好,其IC50值为6.9μmol/L,是阿卡波糖(IC50:180.2μmol/L)的26倍左右。化合物2-5对α-葡萄糖苷酶也具有明显的抑制活性,其IC50分别为12.0、17.5、18.2和11.2μmol/L,是阳性对照的10至16倍。此外,化合物6-10具有适中的α-葡萄糖苷酶抑制活性,其IC50值分别为90.0-171.2μmol/L。
除了化合物3和6之外,所有化合物均对PTP1B有明显抑制作用,但对TCPTP活性较弱,表明它们对PTP1B和TCPTP抑制具有选择性。化合物1-5和10对PTP1B具有较好的抑制活性,其IC50值为35.5~80.1μmol/L,约为阳性对照正钒酸钠(IC50:200.1μmol/L)的2至6倍。同时,化合物7-9展示了适中的PTP1B抑制活性,其IC50值分别为109.4、173.2和116.6μmol/L。
在200μmol/L时,所有的化合物对DPP4的抑制活性都较弱。
表5.化合物1-10对GPa、α-葡萄糖苷酶、PTP1B和TCPTP的抑制活性a
a数值用平均值±标准偏差表示(n=3).b CP-91149是GPa抑制试验的阳性对照;c阿卡波糖是α-葡萄糖苷酶抑制实验的阳性对照;d正钒酸钠是PTP1B和TCPTP抑制实验的阳性对照。
3、结论:
本发明从草豆蔻中分离得到10个新的二芳基庚烷二聚体,在浓度为25.0和12.5μmol/L时,化合物1-5和7-10明显地刺激STC-1细胞中GLP-1的分泌。化合物1-4具有明显的GPa抑制活性,其IC50值为18.0-31.3μmol/L;化合物1-5具有明显的α-葡萄糖苷酶抑制活性,其IC50值低于20μmol/L;同时化合物1-5和10还具有明显的PTP1B抑制活性,其IC50值在35.5至80.1μmol/L之间。本发明表明草豆蔻中二芳基庚烷二聚体具有降血糖作用。
实施例3:
制剂实施例:
1.取化合物1-10任其一或其任意组合,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1-10任其一或其任意组合,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1-10任其一或其任意组合,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1-10任其一或其任意组合,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1-10任其一或其任意组合,按常规口服液制法制成口服液。
6.取化合物1-10任其一或其任意组合,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1-10任其一或其任意组合,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1-10任其一或其任意组合,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 (10)
1.如下结构式所示的二芳基庚烷二聚体化合物2–10,
2.权利要求1所述的二芳基庚烷二聚体化合物2-10的制备方法,其特征在于,该方法包括以下步骤: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;Fr.A-7经MCI CHP 20P gel柱层析(甲醇-水,30:70、40:60、50:50、70:30、100:0,v/v)得到了Fr.A-7-1~Fr.A-7-6;Fr.A-7-2经硅胶柱层析(MeOH-CHCl3,10:90和20:80)得到了Fr.A-7-2a~Fr.A-7-2e;Fr.A-7-2c经Sephadex LH-20(氯仿-甲醇,50:50)、硅胶柱层析(MeOH-CHCl3,15:85)、反相Rp-C18柱层析(MeOH-H2O,50:50,60:40,70:30)和半制备高效液相(Agilent XDB-C18柱,MeOH-H2O,65:35;手性柱C1-5柱,MeCN-H2O,35:65)得到化合物6,8和9;Fr.A-7-2d经过反复的硅胶柱层析(MeOH-CHCl3,10:90)、Sephadex LH-20柱层析(MeOH-CHCl3,50:50)和半制备高效液相(Agilent XDB-C18柱,MeCN-H2O,38:62)纯化得到化合物7和10;Fr.A-7-3经过反相Rp-C18柱层析(MeOH-H2O,40:60~100:0)、硅胶柱层析(MeOH-CHCl3,5:95)、Sephadex LH-20柱层析(MeOH-CHCl3,50:5)和半制备高效液相(Agilent XDB-C18柱,MeCN-H2O,38:62;C1-5柱,MeOH-H2O,75:25)纯化得到化合物3、4和5;Fr.A-7-4经过反复的反相Rp-C18柱层析(MeOH-H2O,40:60~100:0)、硅胶柱层析(MeOH-CHCl3,8:92)、Sephadex LH-20柱层析(MeOH-CHCl3,50:5)和半制备高效液相(Agilent XDB-C18柱,MeCN-H2O,45:55;C1-5柱,MeOH-H2O,80:20)纯化得到化合物2。
3.权利要求1所述的二芳基庚烷二聚体化合物2–10在制备GLP-1促泌剂药物中的应用。
4.权利要求1所述的二芳基庚烷二聚体化合物2–10在制备GPa、PTP1B和α-葡萄糖苷酶抑制剂药物中的应用。
5.权利要求1所述的二芳基庚烷二聚体化合物2–10在制备降血糖药物中的应用。
6.一种药物组合物,其特征在于,所述药物组合物包括权利要求1所述的二芳基庚烷二聚体化合物2-10的至少一种和药学上可接受的载体。
7.制备权利要求6所述的药物组合物的方法,其特征在于,该方法包括以下步骤: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(Fr.A)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;Fr.A-7经MCI CHP 20P gel柱层析(甲醇-水,30:70、40:60、50:50、70:30、100:0,v/v)得到了Fr.A-7-1~Fr.A-7-6;Fr.A-7-2经硅胶柱层析(MeOH-CHCl3,10:90和20:80)得到了Fr.A-7-2a~Fr.A-7-2e;Fr.A-7-2c经Sephadex LH-20(氯仿-甲醇,50:50)、硅胶柱层析(MeOH-CHCl3,15:85)、反相Rp-C18柱层析(MeOH-H2O,50:50,60:40,70:30)和半制备高效液相(Agilent XDB-C18柱,MeOH-H2O,65:35;手性柱C1-5柱,MeCN-H2O,35:65)得到化合物6,8和9;Fr.A-7-2d经过反复的硅胶柱层析(MeOH-CHCl3,10:90)、Sephadex LH-20柱层析(MeOH-CHCl3,50:50)和半制备高效液相(Agilent XDB-C18柱,MeCN-H2O,38:62)纯化得到化合物7和10;Fr.A-7-3经过反相Rp-C18柱层析(MeOH-H2O,40:60~100:0)、硅胶柱层析(MeOH-CHCl3,5:95)、Sephadex LH-20柱层析(MeOH-CHCl3,50:5)和半制备高效液相(Agilent XDB-C18柱,MeCN-H2O,38:62;C1-5柱,MeOH-H2O,75:25)纯化得到化合物3、4和5;Fr.A-7-4经过反复的反相Rp-C18柱层析(MeOH-H2O,40:60~100:0)、硅胶柱层析(MeOH-CHCl3,8:92)、Sephadex LH-20柱层析(MeOH-CHCl3,50:5)和半制备高效液相(Agilent XDB-C18柱,MeCN-H2O,45:55;C1-5柱,MeOH-H2O,80:20)纯化得到化合物2,再以化合物2–10的至少一种或其任意组合为原料加入一定比例的可药用载体。
8.权利要求6所述的药物组合物在制备GLP-1促泌剂药物中的应用。
9.权利要求6所述的药物组合物在制备GPa、PTP1B和α-葡萄糖苷酶抑制剂药物中的应用。
10.权利要求6所述的药物组合物在制备降血糖药物中的应用。
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