CN103923075A - 新型链状二萜类化合物的制备与应用 - Google Patents
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Abstract
本发明涉及六个新型链状二萜类化合物的制备方法及应用，包括该类成分从山楝中分离，体外试验证实这六个新型链状二萜类化合物具有显著细胞毒活性，可作为抗肿瘤药物的应用。
Description
技术领域
本发明涉及六个新型链状二萜类化合物的制备方法及应用，包括该类成分从山楝中分离，体外试验证实这六个新型链状二萜类化合物具有显著细胞毒活性，可作为抗肿瘤药物的应用。
背景技术：
肿瘤是目前危害人民生命和健康的严重疾病之一，目前，治疗癌症的方法主要包括手术、放疗、化疗、免疫治疗、中医中药治疗等多种。化疗主要依靠化学药物，而化学药物产生的耐药性以及毒副作用，亟待新型抗肿瘤药物的发现。天然药物富含多种结构新颖且活性显著的抗肿瘤化合物，引起世界范围的广泛关注。因此，从天然药物中寻找高效、低毒的抗癌活性成分一直是化学家和药理学家关注热点。山楝为(Aphanamixis polystachya)为楝科(Meliaceae)山楝属(Aphanamixis)植物，主要分布于广东、广西、云南等省的低海拔至中海拔山地沟谷密林或疏林中。文献报道该植物提取物具有昆虫拒食、防护剂的作用。我们在前期的体外抗肿瘤实验筛选时发现，其醇提取物具有显著性的抗肿瘤活性。通过深入研究，确定了抗肿瘤活性部位，并确定了该活性部位主要由6个新颖的二萜类成分组成，这些成分为：Aphanamixin A(1)，Aphanamixin B(2)，Aphanamixin C(3)，Aphanamixin D(4)，Aphanamixin E(5)，Aphanamixin F(6)。迄今为止，这些研究成果尚未有专利或文献报道。
本发明的有益效果和意义在于：本发明之目的在于充分利用我国丰富的山楝植物资源，深入进行研究开发，明确该该植物有效部位的组成及其制剂的临床应用，即该药用植物提取物由8二萜类成分组成，该提取物具有显著的体外抗肿瘤活性，以期为临床提供一种抗癌的现代中药制剂。
发明内容
1.本实验室利用现代分离技术和结构测定手段对楝科山楝属山楝抗肿瘤活性部位进行化学成分研究过程中，从中分离得到8个二萜类成分，分别为Aphanamixin A(1)，Aphanamixin B(2)，Aphanamixin C(3)，Aphanamixin D(4)，Aphanamixin E(5)，Aphanamixin F(6)。
附图说明
图1化合物1-6的化学结构
具体实施方式
根据本发明所公开的技术内容，本领域技术人员将很清楚本发明的其他实施方案，下述实施方案仅作示例。在不违反本发明主旨及范围的情况下，可对本发明进行各种改变和改进。这些改变和改进均应在本发明的保护范围之内。
实施案例(一)
取山楝茎皮2Kg，阴干后粉碎，醇类溶剂进行提取。提取液经浓缩至无醇味后，得到提取液。提取液经有机溶剂分配法进行萃取，分别采用石油醚、氯仿和乙酸乙酯进行萃取，浓缩萃取液后得分别到萃取部位B、C、D。其中部位C经体外实验发现具有显著地抗肿瘤活性，结果见表2。进一步对部位C进行系统分离，利用薄层色谱发对部位C进行分离条件选择，经过大量实验发现在石油醚-乙酸乙酯体系下，分离效果较好。以此，利用硅胶柱色谱进行粗分离，经过柱色谱粗分离后共收集8个流份(Fr.I-VIII)。Fr.II经凝胶柱色谱分离，氯仿∶甲醇1∶1体系洗脱，收集洗脱液，浓缩后得到不同的流份。利用高效液相色谱法对不同流份进行分离，采用甲醇-水不同体积比的溶剂进行洗脱，收集液相色谱图中为单峰的色谱峰，浓缩收集的洗脱液，得到化合物1；化合物2-8分别从Fr.III-Fr.VIII中分离得到，分离流程同化合物1。应用波谱学技术对化合物的结构进行鉴定，结果化合物1-6均为结构新颖的二萜类化合物。它们的化学结构见图1，波谱数据见表1和表2。
表1化合物1-3的核磁共振波谱数据
表2化合物4-6的核磁共振波谱数据
实施案例(二)
取对数生长期的细胞以每孔3×103～5×103个细胞接种于96孔板中培养24h后，小心吸出原培养基，加入含有不同浓度化合物(0.9375、1.875、3.75、7.5、15.0、30μmol·mL-1)的培养基200μL，对照组加入RPMI1640或DMEM培养基200μL。每组各设3个平行孔。将96孔板置37℃、5％CO2的恒温培养箱中培养48h。然后于每孔中加入20μLMTT(5mg·mL-1)，再培养2～3h，弃上清液，每孔加入150μL DMSO，振荡15min，应用酶标仪于570nm处测OD值，再计算出化合物的IC50。为确保结果的可靠性及实验的稳定性，所有实验在相同条件下重复进行3次。测试结果如表3。
表3山楝活性部位及化合物的抗肿瘤活性
a阳性药 。
Claims (8)
1.制备六个新型链状二萜类化合物的方法，该方法包括如下步骤：
(1)山楝乙醇提取物用氯仿和/或甲醇溶解；
(2)将步骤(1)中所得的溶液经硅胶柱色谱分离，依次用石油醚，石油醚-乙酸乙酯(9∶1)，石油醚-乙酸乙酯(4∶1)，石油醚-乙酸乙酯(2∶1)洗脱，洗脱液浓缩，依次得到不同极性的洗脱物；
(3)将步骤(2)中得到的洗脱物，溶解后经凝胶柱层析，用氯仿∶甲醇的体积比为1∶1的溶剂进行洗脱，并收集洗脱液；
(4)将步骤(3)中的洗脱液浓缩，经色谱检识合并，进一步得到不同的流份；
(5)将步骤(4)所得流份进行高效液相色谱分离，利用水∶甲醇不同体积比的混合溶剂进行洗脱，得到本发明中的六个新型化合物。
2.根据权利要求1所述，采用MTT法进行体外抗肿瘤实验，所用的五种细胞株分别为HepG2、KB-3-1、NCI-H460、MCF-7、A-549。
3.根据权利2要求的方法，上述步骤中所使用的凝胶柱为Sephadex LH-20柱。
4.根据权利2要求的方法，所述方法中高效液相色谱为分析型液相色谱或制备型液相色谱，配备半制备型色谱柱或制备型色谱柱。
5.权利要求1所述组合物具有显著的抑制肿瘤细胞生长活性，该提取物及其制剂可用于抗肿瘤药物的制备。
6.一种具有抗肿瘤的组合物，含有只有一种权利要求1的化合物。
7.权利要求1所述组合物在制备辅助治疗癌症有关疾病的保健品中的应用。
8.根据权利要求5所述的抗肿瘤的药物，其特征在于：所述的药物为胶囊(软胶囊)、颗粒剂(干混悬剂)、片剂(分散片、泡腾片、咀嚼片、口崩片)、溶液剂(糖浆)、丸剂(浓缩丸、滴丸、微丸)，或者为注射剂型。
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