CN116574079A - 一类二芳基庚烷及其制备方法和应用 - Google Patents
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Abstract
本发明提供了一类二芳基庚烷及其制备方法和应用,属于药物技术领域。本发明通过活性导向及LC‑MS分析从山柰中分离得到了5个结构新颖且可以促进GLP‑1分泌和抑制GPa和α‑葡萄糖苷酶活性的二芳基庚烷kaemgalangins A‑E(1‑5),对于山柰的应用以及新的降血糖药物或功能食品、保健食品的开发具有重要意义。
Description
技术领域
本发明属于药物技术领域,具体涉及一类二芳基庚烷及其制备方法和应用,更具体地,涉及5个二芳基庚烷kaemgalangins A-E(1-5),以及化合物1-5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、功能食品或保健食品中的应用。
背景技术
糖尿病是一种严重的慢性代谢性疾病,可分为1型糖尿病(T1DM)、2型糖尿病(T2DM)和妊娠糖尿病(GDM),其中2型糖尿病患者占糖尿病患者总数的90%以上。目前,临床上治疗糖尿病的药物主要有胰岛素增敏剂、促进胰岛素分泌类药物、抑制碳水化合物吸收药物、胰岛素、酶靶点调节剂、以及其他药物如钠/葡萄糖共转运蛋白2(sodium-glucosetransport protein 2,SGLT2)抑制剂等。然而,各种各样的副作用(如急性低血糖、体重增加、皮肤不良反应、酮症酸中毒、周围神经病变及感染等)限制了上述糖尿病药物的应用。因此,寻找新的糖尿病治疗药物很有必要。
目前寻找可调控血糖水平的药物靶点是糖尿病治疗的一大热点,这些靶点包括受体和酶。其中,胰高血糖素样肽1(Glucagon-like peptide 1,GLP-1)能以葡萄糖依赖的方式刺激胰岛素分泌,抑制胃排空、食物摄入和胰高血糖素分泌,降低糖尿病患者空腹和餐后血糖。肝脏葡萄糖生成增加是T2DM发病的主要原因之一,肝脏葡萄糖产生与糖异生、糖原分解、糖酵解、糖原生成之间的平衡密切相关,糖原磷酸化酶GP由2个亚基GPa(具有催化活性的形式)和GPb(非催化活性的形式)组成,是控制糖原分解的关键酶。因此,抑制GPa可以抑制糖原分解,有利于控制肝脏葡萄糖生成,维持葡萄糖稳态。α-葡萄糖苷酶抑制剂是水解食物中碳水化合物的关键酶,抑制α-葡萄糖苷酶可抑制人体对葡萄糖的吸收来降低患者的餐后血糖。蛋白酪氨酸磷酸酶1B(PTP1B)是胰岛素信号传导的负调节因子,还能抑制瘦素信号的传导,实验证明,PTP1B基因敲除的小鼠,不仅胰岛素敏感性增强,而且在高脂饮食下也不出现肥胖及胰岛素抵抗。目前大多数GLP-1受体激动剂存在成本高、注射给药、胃肠道和胰腺方面的副作用等缺点,因此,从天然药物中寻找更多的GLP-1受体激动剂具有重要意义。
我国药用植物种类丰富,其安全有效性经过长期的实践使用得到了验证,这为寻找药用植物中的降血糖相关酶抑制剂提供了重要基础。山柰为姜科植物山柰Kaempferiagalanga L.的干燥根茎,可理气、利尿、芳香开胃、杀虫、缓解焦虑等,用于治疗高血压、胸腹痛、头痛、风湿、消化不良等。山柰化学成分多样,包括挥发油、萜类、二芳基庚烷、黄酮、环肽等化学成分,药理作用广泛,可抗氧化、抗炎镇痛、驱虫、抗癌、抗血栓、抗结核、抗血管生成、镇静等。Mahmud ZA等人首次报道了山柰提取物在小鼠体内的潜在降血糖活性,通过口服葡萄糖耐量实验研究结果显示,山柰甲醇提取物和氯仿萃取部位在给小鼠过量葡萄糖30min后均能很好的抑制小鼠的血糖升高,抑制率分别为61.2%和89.6%,显示出比阳性药物格列本脲(34.8%)更显著的抑制作用。然而,山柰中的抗糖尿病成分尚未完全清楚。
因此,进一步分析并开发山柰中的抗糖尿病成分,对于山柰的应用以及新的降血糖药物或功能食品、保健食品的开发具有重要意义。
发明内容
针对上述不足,本发明提供了一类二芳基庚烷及其制备方法和应用。本发明通过活性导向及LC-MS分析从山柰中分离得到了5个结构新颖且可以促进GLP-1分泌和抑制GPa和α-葡萄糖苷酶活性的二芳基庚烷kaemgalangins A-E(1-5),对于山柰的应用以及新的降血糖药物或功能食品、保健食品的开发具有重要意义。
为了实现上述发明目的,本发明的技术方案如下:
一方面,本发明提供了一类二芳基庚烷,所述的二芳基庚烷为如下结构式所示的化合物1-5,即kaemgalangins A-E(1-5),
。
另一方面,本发明提供了上述二芳基庚烷的制备方法,所述的制备方法包括以下步骤:
(1)将山柰的干燥根茎粉碎后,采用乙醇室温浸泡提取,得到粗提物;
(2)将上述步骤(1)制备得到的粗提取采用乙酸乙酯萃取,浓缩,经硅胶柱层析,以丙酮-石油醚为洗脱剂进行梯度洗脱,硅胶柱层析,以甲醇-氯仿混合溶剂进行梯度洗脱,硅胶柱层析,以丙酮-氯仿混合溶剂、甲醇-氯仿混合溶剂进行梯度洗脱,得到流分;
(3)将上述步骤(2)制备的流分经反相RP C18柱层析、Sephadex LH-20分离、高效液相、凝胶柱层析、硅胶柱层析或HPLC制备得到上述二芳基庚烷。
具体地,步骤(1)中所述的乙醇的浓度为75-95%,优选为90%。
具体地,步骤(2)中所述的洗脱剂丙酮-石油醚的梯度为5:95~100:0。
具体地,步骤(2)中所述的洗脱剂甲醇-氯仿的梯度为2:98~100:0。
具体地,步骤(2)中所述的洗脱剂丙酮-氯仿的梯度为10:90~40:60,甲醇-氯仿的梯度为10:90~100:0。
在某些实施例中,本发明所述的二芳基庚烷的制备方法包括以下步骤:将山柰的干燥根茎粉碎,用90%乙醇室温浸泡提取3次,每次48h,合并乙醇提取液,减压回收乙醇得粗提物,粗提物分散在水中后用乙酸乙酯萃取,随后浓缩得到乙酸乙酯萃取部分,乙酸乙酯萃取部分经过硅胶柱层析,以丙酮-石油醚(5:95~100: 0,v/v)为洗脱剂梯度洗脱得到流分Fr. 1~Fr. 10;取Fr.8通过硅胶柱层析,以甲醇-氯仿混合溶剂(2:98~100:0)进行梯度洗脱,得到9个流分:Fr.8-1~Fr.8-9;取Fr.8-7通过硅胶柱层析,依次以丙酮-氯仿混合溶剂(10:90~40:60)、甲醇-氯仿混合溶剂(10:90~100:0)进行梯度洗脱,得到3个流分:Fr.8-7-1~Fr.8-7-3;Fr.8-7-1经过反相RP C18柱层析(MeOH-H2O, 30:70~90:10)、Sephadex LH-20(MeOH-CHCl3,50:50)分离,之后分别经过半制备高效液相(MeOH-H2O, 37:67)、(MeCN-H2O, 20:80)和(MeOH-H2O, 47:53)得到化合物1、4和5;Fr.8-7-2经过多次反相C18柱层析、凝胶柱层析以及硅胶柱层析,最后经过半制备HPLC(MeOH-H2O, 45:65)纯化,得到化合物3;Fr.8-7-3经过多次反相C18柱层析、硅胶柱层析、半制备HPLC(MeOH-H2O, 28:72)纯化得到化合物2。
又一方面,本发明提供了上述二芳基庚烷在制备GLP-1促泌剂药物中的应用。
又一方面,本发明提供了一种GLP-1促泌剂药物,所述的药物包含上述二芳基庚烷。
又一方面,本发明提供了上述二芳基庚烷在制备GPa和α-葡萄糖苷酶抑制剂药物中的应用。
又一方面,本发明提供了一种GPa和α-葡萄糖苷酶抑制剂药物,所述的药物包含上述二芳基庚烷。
又一方面,本发明提供了上述二芳基庚烷在制备降血糖药物、功能食品或保健食品中的应用。
又一方面,本发明提供了一种降血糖药物、功能食品或保健食品,所述的降血糖药物、功能食品或保健食品中包含上述二芳基庚烷。
又一方面,本发明提供了一种药物组合物,所述药物组合物包含上述二芳基庚烷和药学上可接受的载体或赋型剂。
具体地,所述的药学上可接受的载体或赋型剂包括但不限于:稀释剂、赋形剂、填充剂、润湿剂、崩解剂、矫味剂和粘合剂。
具体地,所述的药物组合物包括但不限于胶囊、片剂、锭剂、丸剂、滴丸、栓剂、喷雾、乳膏、贴剂等形式。
又一方面,本发明提供了上述药物组合物在制备GLP-1促泌剂药物中的应用。
又一方面,本发明提供了上述药物组合物在制备GPa和α-葡萄糖苷酶抑制剂药物中的应用。
又一方面,本发明提供了上述药物组合物在制备降血糖药物中的应用。
又一方面,本发明提供了上述药物组合物的制备方法,所述的制备方法包括以下步骤:以上述二芳基庚烷为原料,加入药学上可接受的载体或赋型剂。所述的药学上可接受的载体或赋型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。
在某些实施例中,本发明所述的二芳基庚烷用作GLP-1促泌剂以及GPa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1-5,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。将本发明所述的药物组合物以单位体重服用量的形式使用。本发明所述的药物可经注射(静注、肌注)和口服两种形式给药。
与现有技术相比,本发明的积极和有益效果在于:
1.本发明提供了一类新的二芳基庚烷,为首次报道的新化合物。
2.本发明从山柰中分离得到5个新的二芳基庚烷,在浓度为50.0μM时,化合物1-5均能明显地刺激NCI-H716细胞中GLP-1的分泌;化合物1具有中等的GPa抑制活性,在200μM时抑制率为63.6%;化合物1、5具有明显的α-葡萄糖苷酶抑制活性,其IC50值分别为45.3和116.0μM。本发明表明山柰中的单体二芳基庚烷具有潜在降糖作用。
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1-5对NCI-H716细胞中GLP-1分泌的促进作用,胆酸(Cholicacid)用作阳性对照,数值用平均值±标准偏差表示(n=3)。
实施方式
下面结合具体实施例,对本发明作进一步详细的阐述,下述实施例不用于限制本发明,仅用于说明本发明。以下实施例中所使用的实验方法如无特殊说明,实施例中未注明具体条件的实验方法,通常按照常规条件,下述实施例中所使用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1.化合物1-5的制备
将山柰的干燥根茎粉碎,用90%乙醇室温浸泡提取3次,每次48h,合并乙醇提取液,减压回收乙醇得粗提物,粗提物分散在水中后用乙酸乙酯萃取,随后浓缩得到乙酸乙酯萃取部分,乙酸乙酯萃取部分经过硅胶柱层析,以丙酮-石油醚(5:95~100: 0,v/v)为洗脱剂梯度洗脱得到流分Fr.1~Fr.10;Fr.8(52g)通过硅胶柱层析,以甲醇-氯仿混合溶剂(2:98~100:0)进行梯度洗脱,得到9个流分:Fr.8-1~Fr.8-9;Fr.8-7通过硅胶柱层析,依次以丙酮-氯仿混合溶剂(10:90~40:60)、甲醇-氯仿混合溶剂(10:90~100:0)进行梯度洗脱,得到3个流分:Fr.8-7-1~Fr.8-7-3;Fr.8-7-1经过反相RP C18柱层析(MeOH-H2O, 30:70~90:10)、Sephadex LH-20(MeOH-CHCl3,50:50)分离,之后分别经过半制备高效液相(MeOH-H2O,37:67)、(MeCN-H2O, 20:80)和(MeOH-H2O, 47:53)得到化合物1、4和5;Fr.8-7-2经过多次反相C18柱层析、凝胶柱层析以及硅胶柱层析,最后经过半制备HPLC(MeOH-H2O, 45:65)纯化,得到化合物3;Fr. 8-7-3经过多次反相C18柱层析、硅胶柱层析、半制备HPLC(MeOH-H2O, 28:72)纯化得到化合物2。
化合物1-5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AppliedPhotophysics圆二色谱仪(Agilent, Santa Clara, United States)测定;核磁共振谱(1D和2D NMR)用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)购自临沂市海祥化工有限公司(中国临沂)、烟台新诺新材料技术有限公司(中国烟台市)。
Kaemgalangin A(1)
分子式:C19H22O5
分子量:330
性状:无色胶状固体
HRESIMSm/z:331.1557 [M + H]+ (calcd. for C19H23O5, m/z 331.1540);
UV (MeOH) λ max (log ε):195 (3.80), 223 (3.07), 280 (2.62) nm;
IR (KBr) v max: 3247, 2937, 1601, 1516,1459,1380, 1245, 1027, 824 cm–1;
ECD (c 0.05, MeOH) λ max (Δε): 202 (-7.48), 216 (+1.53), 228 (-0.03),243 (+2.16) nm;
-100.2 (c 0.1, MeOH);
1HNMR和13CNMR(DEPT)数据见表1。
Kaemgalangin B(2)
分子式:C20H24O7
分子量:376
性状:无色胶状固体
HRESIMS m/z: 399.1399 [M + Na]+ (calcd. for C20H24O7Na, m/z 399.1414);
UV (MeOH) λ max (log ε): 196 (3.96), 224 (3.23), 278 (2.74) nm;
IR (KBr) v max: 3435, 1614,1518, 1451, 1382, 1274, 1237, 1051, 821 cm–1;
ECD (c 0.04, MeOH) λ max(Δε): 201 (-18.67), 215 (2.51), 230 (-3.50),247 (3.16) nm;
-70.1 (c 0.09, MeOH);
1H-NMR和13C-NMR(DEPT)数据见表2。
Kaemgalangin C(3)
分子式:C29H32O10
分子量:540
性状:无色胶状固体
HRESIMS m/z563.1906 [M + Na]+ (calcd. for C29H32O10Na, m/z 563.1888);
UV (MeOH) λ max (log ε): 200 (4.06), 218 (3.41), 229 (3.48),250 (2.70),279 (3.27),312 (3.05) nm;
IR (KBr) v max: 3431, 2925, 2853, 1681, 1595, 1516, 1464, 1428, 1385,1272, 1128, 1031, 816 cm–1;
ECD (c 0.04, MeOH) λ max (Δε): 196 (+18.93), 236 (-2.20), 247 (+1.86),265 (+0.93), 312 (+3.25) nm;
–4.6 (c 0.08, MeOH);
1H-NMR和13C-NMR(DEPT)数据见表2。
Kaemgalangin D(4)
分子式:C20H26O6
分子量:362
性状:无色胶状固体
HRESIMS m/z385.1644 [M + Na]+ (calcd. for C20H26O6Na, m/z 385.1622);
UV (MeOH) λ max (log ε): 214 (3.17), 224 (3.25), 249 (2.41),282 (2.84)nm;
+15.7 (c 0.06, MeOH);
1H-NMR和13C-NMR(DEPT)数据见表3。
Kaemgalangin E(5)
分子式:C19H24O5
分子量:332
性状:无色胶状固体
HRESIMS m/z331.1541 [M – H]– (calcd for C19H23O5, m/z 331.1551);
UV (MeOH) λ max (log ε): 218 (3.15), 223 (3.16), 252 (2.28),282 (2.72)nm;
–11.5 (c 0.08, MeOH);
1H-NMR和13C-NMR(DEPT)数据见表3。
实施例2.化合物促GLP-1分泌以及GPa、PTP1B和α-葡萄糖苷酶抑制活性
1.材料和方法
1.1.材料
NCI-H716细胞购买于中国科学院细胞库(上海);人源GLP-1 ELISA试剂盒购买于Signalway Antibody (Maryland, USA);α-葡萄糖苷酶(G5003-100UN)和GPa(P1261-10MG)购买于Sigma Aldrich(St. Louis, MO, USA);PTP1B (10304-H07E)购自Sino Biological(Wayne, PA, USA);阿卡波糖购买自北京百灵威科技有限公司;正钒酸钠购买自萨恩化学技术有限公司。
1.2.仪器
Flex Station 3台式多功能酶标仪购买自Bio-Rad Laboratories公司;FlexA-200全波长酶标分析仪购买自杭州奥盛仪器有限公司;分析天平ME104E购买自梅特勒-托利多仪器(上海)有限公司;电热恒温培养箱 (DHP-9082)购买自上海一恒科技有限公司。
1.3.实验过程
GLP-1分泌实验:实验按照文献报道(Biochem. Biophys. Res. Commun. 2013,435, 165-170)并加以调整后进行。将NCl-H716细胞用含有10%FBS和1%PS的RPMI-1640培养基在37℃和5% CO2饱和湿度的培养箱中培养;当细胞生长到80-90%时,将稀释好的细胞悬液接种于24孔板中(5×105个/每孔),分化两天;每孔加入KRBH工作液III饥饿1h;每孔加含化合物的KRBH工作液IV饥饿2h,收集上清液;用人源GLP-1 ELISA试剂盒检测上清液中的GLP-1含量。
GPa、α-葡萄糖苷酶、PTP1B抑制实验:按照已报道文献(Ind. Crop. Prod. 2020,144, 112028)和(Chin. J. Chem. 2021, 39,3051-3063)中的方法进行。
2.结果:
在浓度为50μM时评价了化合物1-5刺激NCl-H716细胞中GLP-1分泌情况。如图1所示,在浓度为50μM时,化合物均显示出了明显的促GLP-1分泌作用,促泌率在826.9%至1738.3%之间。
在浓度200μM和100μM时,测试了化合物1-5对GPa的抑制活性。如表4所示,化合物1对GPa具有中等强度的抑制作用,在浓度为200μM时,其抑制率为63.6%。
如表4所示,化合物1、5对α-葡萄糖苷酶具有明显的抑制活性,其抑制活性优于阳性阿卡波糖(IC50:392.0μM),其IC50分别为45.3μM和116.0μM。
在200μM时,所有的化合物对PTP1B的抑制活性都较弱。
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抑制实验的阳性对照。
3.结论:
本发明从山柰中分离得到5个新的二芳基庚烷,在浓度为50μM时,化合物均显示出明显的促GLP-1分泌作用,促泌率在826.9%至1738.3%之间;化合物1对GPa具有中等强度的抑制作用,在浓度为200μM时,其抑制率为63.6%;化合物1、5具有明显的α-葡萄糖苷酶抑制活性,其IC50分别为45.3μM和116.0μM。本发明表明山柰中的二芳基庚烷具有降血糖作用。
实施例3.制剂实施例
1.取化合物1-5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1-5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1-5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1-5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1-5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1-5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1-5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1-5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。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (10)
1.一类二芳基庚烷,其特征在于:所述的二芳基庚烷为如下结构式所示的化合物1-5,
。
2.一种权利要求1所述的二芳基庚烷的制备方法,其特征在于:所述的制备方法包括以下步骤:
(1)将山柰的干燥根茎粉碎后,采用乙醇室温浸泡提取,得到粗提物;
(2)将上述步骤(1)制备得到的粗提取采用乙酸乙酯萃取,浓缩,经硅胶柱层析,以丙酮-石油醚为洗脱剂进行梯度洗脱,硅胶柱层析,以甲醇-氯仿混合溶剂进行梯度洗脱,硅胶柱层析,以丙酮-氯仿混合溶剂、甲醇-氯仿混合溶剂进行梯度洗脱,得到流分;
(3)将上述步骤(2)制备的流分经反相RP C18柱层析、Sephadex LH-20分离、高效液相、凝胶柱层析、硅胶柱层析或HPLC制备得到权利要求1所述的二芳基庚烷。
3.权利要求1所述的二芳基庚烷在制备GLP-1促泌剂药物中的应用。
4.权利要求1所述的二芳基庚烷在制备GPa和α-葡萄糖苷酶抑制剂药物中的应用。
5.权利要求1所述的二芳基庚烷在制备降血糖药物、功能食品或保健食品中的应用。
6.一种药物组合物,其特征在于:所述药物组合物包含权利要求1所述的二芳基庚烷和药学上可接受的载体或赋型剂。
7.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。
8.权利要求6所述的药物组合物在制备GPa和α-葡萄糖苷酶抑制剂药物中的应用。
9.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。
10.一种权利要求6所述的药物组合物的制备方法,其特征在于:所述的制备方法包括以下步骤:以权利要求1所述的二芳基庚烷为原料,加入药学上可接受的载体或赋型剂。
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