CN115215881A - 唐古特瑞香中制备的愈创木烷型倍半萜类化合物及其制备方法和应用 - Google Patents
唐古特瑞香中制备的愈创木烷型倍半萜类化合物及其制备方法和应用 Download PDFInfo
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Abstract
唐古特瑞香中制备的愈创木烷型倍半萜类化合物及其制备方法和应用，属于医药技术领域，具体涉及如下所示，从植物唐古特瑞香中制备得到的新的愈创木烷型倍半萜类化合物及这类化合物在抗炎方面的应用。进一步的，所述愈创木烷型倍半萜类化合物或包含上述化合物的药物组合物在制备抑制LPS诱导的BV‑2细胞炎症药物中的应用。本发明的优点在于，所述化合物均为新化合物，结构新颖，且均为立体构型确定的光学纯化合物，同时其抗炎活性强，具有进一步开发的价值。
Description
技术领域
本发明属于医药技术领域，具体涉及植物唐古特瑞香中制备得到的新的愈创木烷型倍半萜类化合物及这类化合物在抗炎方面的应用。
背景技术
唐古特瑞香：唐古特瑞香[Daphne tangutica Maxim.]，为瑞香科瑞香属的常绿灌木。唐古特瑞香主要分布于山西、陕西、甘肃、青海、四川、贵州、云南、西藏。生于海拔1000-3800米的润湿林中。1977年版《中国药典》及《陕西中药志》记载黄瑞香、唐古特瑞香和凹叶瑞香可用作祖师麻入药。目前市售制剂有注射液、片剂、贴剂等，临床上主要用于治疗跌打损伤、风湿性关节炎及止痛等。
炎症(inflammation)：机体对于刺激的一种防御反应，表现为红、肿、热、痛和功能障碍。炎症分为两类，可以是感染引起的感染性炎症，也可以不是由于感染引起的非感染性炎症。例如对人体自身组织的攻击、发生在透明组织的炎症等等。神经退行性疾病(Neurodegenerative diseases)与炎症：神经退行性疾病是由于大脑和脊髓的神经元丧失而引起的一类不可逆转的神经系统疾病，特征表现为发作迟缓和选择性神经元的功能障碍。大脑中的慢性炎症环境是阿尔茨海默病、帕金森病等神经退行性疾病的标志。
发明内容
本发明的目的在于提供一种从唐古特瑞香中制备得到的愈创木烷型倍半萜类化合物，以及其在抑制神经炎症方面的应用。
本发明所述从瑞香科瑞香属植物唐古特瑞香[Daphne tangutica Maxim.]中分离得到的新愈创木烷型倍半萜类化合物为如下所示结构中任一种：
本发明的所述愈创木烷型倍半萜类化合物的制备技术方案包括如下步骤：
取干燥的唐古特瑞香全草以乙醇提取，合并提取液浓缩得浸膏，浸膏采用乙酸乙酯萃取并将所得组分经硅胶柱色谱，以二氯甲烷-甲醇系统100:0-0:100进行等度梯度洗脱，共收集到四个组分Fr.A-Fr.D；
流份Fr.B经HP20柱色谱，以乙醇-水系统0:100-90:10进行梯度洗脱，得三个组分Fr.B1-Fr.B3；
利用ODS柱色谱将组分Fr.B1-Fr.B3以乙醇-水系统10:90-90:10进行梯度洗脱，得5个组分Fr.R1-Fr.R5；
所得组分Fr.R3经硅胶柱色谱以石油醚-乙酸乙酯系统100:1-10:1在TLC分析的基础上得到15个亚组分Fr.R3-1-Fr.R3-15；
在制备性反相高效液相色谱上使用乙腈-水的流动相来分离Fr.R3-2、Fr.R3-5和Fr.R3-7得到化合物1-12。
上述制备方法中，采用的唐古特瑞香为瑞香科瑞香属植物唐古特瑞香[Daphanetangutica Maxim]。
干燥的唐古特瑞香全草以70％-80％工业乙醇回流提取2-3次，每次2-3h。
在制备性反相高效液相色谱上以55:45-35:65的乙腈-水流动相分离Fr.R3-2、Fr.R3-5和Fr.R3-7。
所得化合物经过系统结构鉴定结果如下：
利用高分辨质谱，一维NMR、二维NMR、计算ECD及X单晶衍射方法对化合物1-12的结构鉴定，相应谱图如图1-15所示。
Tanguticatin A(1):白色块状结晶；
+88.5(c 0.20,MeOH)；HRESIMS(m/z287.1249[M+Na]+,calcd 287.1254)确定分子式为C15H20O4；通过分析tanguticatin A的1HNMR、13C NMR、HMQC谱、HMBC谱、计算ECD及X射线单晶衍射，确定了tanguticatin A的结构，为一个新化合物。
Tanguticatin B(2):无色油状物；
-90.5(c 0.20,MeOH)；HRESIMS(m/z235.1689[M+H]+,calcd for C15H23O2,235.1693)确定分子式为C15H23O2；通过分析tanguticatin B的1H NMR、13C NMR、HMQC谱、HMBC谱及计算ECD，确定了tanguticatin B的结构，为一个新化合物。
Tanguticatin C(3):无色油状物；
+90.0(c 0.20,MeOH)；HRESIMS(m/z235.1638[M+H]+,calcd for C15H23O2,235.1693)确定分子式为C15H23O2；通过分析tanguticatin C的1H NMR、13C NMR、HMQC谱、HMBC谱及计算ECD，确定了tanguticatin C的结构，为一个新化合物。
Tanguticatin D(4):无色油状物；
-88.5(c 0.20,MeOH)；HRESIMS(m/z255.1361[M+Na]+,calcd for C15H20NaO2,255.1356)确定分子式为C15H20O2；通过分析tanguticatin D的1H NMR、13C NMR、HMQC谱、HMBC谱及计算ECD，确定了tanguticatin D的结构，为一个新化合物。
Tanguticatin E(5):无色油状物；
+30(c 0.20,MeOH)；HRESIMS(m/z287.1619[M+Na]+,calcd for C16H24NaO3,287.1618)确定分子式为C16H24O3；通过分析tanguticatin E的1H NMR、13C NMR、HMQC谱、HMBC谱及计算ECD，确定了tanguticatin E的结构，为一个新化合物。
Tanguticatin F(6):无色油状物；
-28(c 0.20,MeOH)；HRESIMS(m/z271.1213[M+Na]+,calcd for C15H20NaO3,271.1305)确定分子式为C15H20O3；通过分析tanguticatin F的1H NMR、13C NMR、HMQC谱、HMBC谱及计算ECD，确定了tanguticatin F的结构，为一个新化合物。
Tanguticatin G(7):无色油状物；
-37.0(c 0.20,MeOH)；HRESIMS(m/z277.1399[M+H]+,calcd for C16H21O4,277.1434)确定分子式为C16H20O4；通过分析tanguticatin G的1H NMR、13C NMR、HMQC谱、HMBC谱及计算ECD，确定了tanguticatin G的结构，为一个新化合物。
Tanguticatin H(8):无色块晶；
+39.2(c 0.10,MeOH)；HRESIMS(299.1259[M+Na]+,calcd for C16H20NaO4,299.1254)确定分子式为C16H20O4；通过分析tanguticatin H的1H NMR、13C NMR、HMQC谱、HMBC谱、计算ECD及X射线单晶衍射，确定了tanguticatin H的结构，为一个新化合物。
Tanguticatin I(9):无色块晶；
-39.8(c 0.10,MeOH)；HRESIMS(m/z235.1687[M+H]+,calcd for C15H23O2,235.1693确定分子式为C15H22O2；通过分析tanguticatin I的1H NMR、13C NMR、HMQC谱、HMBC谱、计算ECD及X射线单晶衍射，确定了tanguticatin I的结构，为一个新化合物。
Tanguticatin J(10):无色油状；
-83.0(c 0.30,MeOH)；HRESIMS(m/z287.1615[M+Na]+,calcd for C15H20NaO2,287.1618)确定分子式为C16H24O3；通过分析tanguticatin J的1H NMR、13C NMR、HMQC谱、HMBC谱、计算ECD，确定了tanguticatin J的结构，为一个新化合物。
Tanguticatin K(11):无色油状；
+85.0(c 0.30,MeOH)；HRESIMS(m/z255.1361[M+Na]+,calcd for C15H20NaO2,255.1356)确定分子式为C15H20O2；通过分析tanguticatin K的1H NMR、13C NMR、HMQC谱、HMBC谱、计算ECD，确定了tanguticatin K的结构，为一个新化合物。
Tanguticatin L(12):无色油状；
-19.7(c 0.10,MeOH)；HRESIMS(m/z233.1510[M+H]+,calcd for C15H21O2,233.1536)确定分子式为C15H20O2；通过分析tanguticatin L的1H NMR、13C NMR、HMQC谱、HMBC谱、计算ECD，确定了tanguticatin L的结构，为一个新化合物。
表1化合物1-3的1H NMR数据(600MHz,in CDCl3,δin ppm,J in Hz)
表2化合物4-6的1H NMR数据(600MHz,in CDCl3,δin ppm,J in Hz)
表3化合物7-9的1H NMR数据(600MHz,in CDCl3,δin ppm,J in Hz)
表4化合物10-12的1H NMR数据(600MHz,in CDCl3,δin ppm,J in Hz)
表5化合物1-6的13C NMR数据(150MHz,in CDCl3,δin ppm,J in Hz)
表6化合物1-6的13C NMR数据(150MHz,in CDCl3,δin ppm,J in Hz)
对本发明所述12个新化合物的抗神经炎症活性进行了考察，其中化合物1-12均展现良好的抗炎活性，因此本发明所述的新愈创木烷型倍半萜类化合物具有进一步开发预防和治疗神经炎症药物的前景。
一种药物组合物，包含上述从唐古特瑞香中制备得到的愈创木烷型倍半萜类化合物或其在药学上可接受的盐和药学上可接受的载体或赋形剂。
本发明还提供所述从唐古特瑞香中制备得到的愈创木烷型倍半萜类化合物或包含上述化合物的药物组合物在制备抑制神经炎症药物中的应用。
本发明还提供所述从唐古特瑞香中制备得到的愈创木烷型倍半萜类化合物或包含上述化合物的药物组合物在制备抑制LPS诱导的BV-2细胞炎症药物中的应用。
一种唐古特瑞香提取物，包含所述愈创木烷型倍半萜类化合物，应用于制备抑制神经炎症药物中。
本发明的优点在于，所述化合物均为新化合物，结构新颖，且均为立体构型确定的光学纯化合物，同时其抗炎活性强，具有进一步开发的价值。
附图说明
图1化合物1的HRESIMS、1H、13C-NMR和HMBC谱；
图2化合物2的HRESIMS、1H、13C-NMR和HMBC谱；
图3化合物3的HRESIMS、1H、13C-NMR和HMBC谱；
图4化合物4的HRESIMS、1H、13C-NMR和HMBC谱；
图5化合物5的HRESIMS、1H、13C-NMR和HMBC谱；
图6化合物6的HRESIMS、1H、13C-NMR和HMBC谱；
图7化合物7的HRESIMS、1H、13C-NMR和HMBC谱；
图8化合物8的HRESIMS、1H、13C-NMR和HMBC谱；
图9化合物9的HRESIMS、1H、13C-NMR和HMBC谱；
图10化合物10的HRESIMS、1H、13C-NMR和HMBC谱；
图11化合物11的HRESIMS、1H、13C-NMR和HMBC谱；
图12化合物12的HRESIMS、1H、13C-NMR和HMBC谱；
图13化合物1、8、9的X单晶数据图；
图14化合物1-12的HMBC相关；
图15化合物1-12的实测与计算ECD谱图；
图16化合物1-12在体外抑制LPS诱导的小鼠小胶质细胞BV-2细胞炎症作用。对照组相比于模型组的NO产物浓度###P<0.001；实验组相比于模型组的细胞存活百分比*P<0.1,**P<0.05,***P<0.001。
具体实施方式
下面所列实施例有助于本领域技术人员更好地理解本发明，但不以任何方式限制本发明。
实施例1
化合物1-12的制备方法，具体操作如下：
取干燥的唐古特瑞香全草以80％工业乙醇回流提取，2次，每次2h，合并提取液浓缩得浸膏，浸膏采用乙酸乙酯萃取并将所得组分经硅胶柱色谱，以二氯甲烷-甲醇系统100:0,90:10,80:20,70:30,60:40,50:50,40:60,30:70,20:80,10:90,0:100(v/v)进行等度梯度洗脱，共收集到四个组分Fr.A-Fr.D；
流份Fr.B经HP20柱色谱，以乙醇-水系统0:100,10:90,20:80,30:70,40:60,50:50,60:40,70:30,80:20,90:10(v/v)进行梯度洗脱，得三个组分Fr.B1-Fr.B3；
利用ODS柱色谱将组分Fr.B1-Fr.B3以乙醇-水系统10:90,20:80,30:70,40:60,50:50,60:40,70:30,80:20,90:10(v/v)进行梯度洗脱，得5个组分Fr.R1-Fr.R5；
所得组分Fr.R3经硅胶柱色谱以石油醚-乙酸乙酯系统100:1,80:1,60:1,40:1,20:1,10:1(v/v)在TLC分析的基础上得到15个亚组分Fr.R3-1-Fr.R3-15；
在制备性反相高效液相色谱上使用乙腈-水55:45-35:65的流动相来分离Fr.R3-2、Fr.R3-5和Fr.R3-7得到化合物1-12(化合物1-4采用55:45，化合物2-8采用45:55，化合物9-12采用35:65)。化合物1-12的量分别为11.2mg,3.2mg,5.6mg,4.3mg,3.1mg,1.8mg,10.0mg,18.7mg,21.2mg,30.0mg,1.5mg,1.6mg。
实施例2
化合物1-12的抗神经炎症的活性考察：
用Griess法检测LPS诱导的BV-2细胞内的NO产物含量。BV-2细胞系置于含10％胎牛血清以及1％双抗的DMEM培养基内，37℃，5％CO2的培养箱中进行培养。稳定传代培养至对数生长的细胞用于实验。取对数生长期的BV-2小胶质瘤细胞以5×103个/孔的密度接种于96孔板中，待细胞生长至60％时加入10μM的受试化合物，共培养1h后观察细胞生长状态良好，加入10μg/mL的LPS，24h后取上清液用NO试剂盒检测NO浓度。利用紫外分光光度计(Thermo Scientific Multiskan MK3，上海，中国)在540nm处测定吸光度。结果显示，多数化合物表现出比阳性药地塞米松更好的抗炎作用，如图16所示。
Claims (10)
1.唐古特瑞香中制备的愈创木烷型倍半萜类化合物，其特征在于，其为如下所示结构中任一种：
2.根据权利要求1所述的唐古特瑞香中制备的愈创木烷型倍半萜类化合物，其特征在于，所述化合物由瑞香科瑞香属植物唐古特瑞香[Daphne tangutica Maxim.]中分离得到。
3.一种权利要求1或2所述唐古特瑞香中制备的愈创木烷型倍半萜类化合物的制备方法，其特征在于，包括如下步骤：
取干燥的唐古特瑞香全草以乙醇提取，合并提取液浓缩得浸膏，浸膏采用乙酸乙酯萃取并将所得组分经硅胶柱色谱，以二氯甲烷-甲醇系统100:0-0:100进行等度梯度洗脱，共收集到四个组分Fr.A-Fr.D；
流份Fr.B经HP20柱色谱，以乙醇-水系统0:100-90:10进行梯度洗脱，得三个组分Fr.B1-Fr.B3；
利用ODS柱色谱将组分Fr.B1-Fr.B3以乙醇-水系统10:90-90:10进行梯度洗脱，得5个组分Fr.R1-Fr.R5；
所得组分Fr.R3经硅胶柱色谱以石油醚-乙酸乙酯系统100:1-10:1在TLC分析的基础上得到15个亚组分Fr.R3-1-Fr.R3-15；
在制备性反相高效液相色谱上使用乙腈-水的流动相来分离Fr.R3-2、Fr.R3-5和Fr.R3-7得到化合物1-12。
4.根据权利要求3所述唐古特瑞香中制备的愈创木烷型倍半萜类化合物的制备方法，其特征在于，采用的唐古特瑞香为瑞香科瑞香属植物唐古特瑞香[Daphane tanguticaMaxim]。
5.根据权利要求3所述唐古特瑞香中制备的愈创木烷型倍半萜类化合物的制备方法，其特征在于，干燥的唐古特瑞香全草以70％-80％工业乙醇回流提取2-3次，每次2-3h。
6.根据权利要求3所述唐古特瑞香中制备的愈创木烷型倍半萜类化合物的制备方法，其特征在于，在制备性反相高效液相色谱上以55:45-35:65的乙腈-水流动相分离Fr.R3-2、Fr.R3-5和Fr.R3-7。
7.一种药物组合物，其特征在于，包含权利要求1或2所述的唐古特瑞香中制备得到的愈创木烷型倍半萜类化合物或其在药学上可接受的盐和药学上可接受的载体或赋形剂。
8.一种唐古特瑞香提取物，其特征在于，包含权利要求1或2所述愈创木烷型倍半萜类化合物，应用于制备抑制神经炎症药物中。
9.权利要求1或2所述唐古特瑞香中制备得到的愈创木烷型倍半萜类化合物或权利要求7所述药物组合物在制备抑制神经炎症药物中的应用。
10.权利要求1或2所述唐古特瑞香中制备得到的愈创木烷型倍半萜类化合物或权利要求7所述药物组合物在制备抑制LPS诱导的BV-2细胞炎症药物中的应用。
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