CN104211670A - 一种烷基吡喃酮类化合物及其制备方法和用途 - Google Patents
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Abstract
本发明涉及一种烷基吡喃酮类化合物及其制备方法和用途。该烷基吡喃酮类化合物属于活性吡喃酮类化合物，并且含有一个α-吡喃酮结构。其制备方法通过发酵培养棘孢木霉(Trichodermaasperellum)，获取菌丝体内代谢产物的粗提物，从中分离纯化出该化合物。目前尚未见该化合物的化学结构及癌细胞增殖抑制活性的报道，经试验证实，该化合物可作为癌细胞增殖抑制剂或抗肿瘤剂。
Description
技术领域
本发明涉及一种烷基吡喃酮类化合物及其制备方法和用途。
背景技术
烷基吡喃酮类化合物(Alkyl pyrones)是吡喃酮类化合物的一类衍生物，结构特征是含有六元环不饱和内酯，常被报道具有广泛的生物活性，如细胞毒性作用、神经毒性作用和植物毒性作用等。本发明人研究得知，棘孢木霉(Trichoderma asperellum) IBPT-2 (2012年10月30日保藏在武汉大学中国典型培养物保藏中心，保藏编号是：CCTCC NO：M 2012438)菌丝体内代谢产物的粗提物有较好的癌细胞增殖抑制活性，遂对其活性成分进行研究。研究发现所示烷基吡喃酮类化合物具有抗肿瘤活性，目前尚未见该化合物的化学结构及癌细胞增殖抑制活性的报道，因此市场上也尚未见有与此相关的药物。
发明内容
本发明的目的在于提供一种烷基吡喃酮类化合物及其制备方法和用途，该化合物具有抑制癌细胞增殖活性。其结构式为：
。
其结构特征是：含有一个α-吡喃酮结构。
本发明还提供了所述化合物的制备方法：发酵培养棘孢木霉(Trichoderma asperellum)，获取菌丝体，进行破碎萃取处理后，得到菌丝体内代谢产物粗提物，然后从粗提物中分离纯化出该化合物。
所述棘孢木霉(Trichoderma asperellum)为棘孢木霉(Trichoderma asperellum) IBPT-2，已于2012年10月30日保藏在中国典型培养物保藏中心，地址：中国 武汉 武汉大学，保藏编号是：CCTCC NO：M 2012438。
本发明还保护了所述的化合物在制备癌细胞增殖抑制剂中的用途。所述癌细胞优选为人淋巴癌细胞RAJI。及该化合物在制备抗肿瘤药物中的用途。
本发明的显著优点：研究所示烷基吡喃酮类化合物属于活性吡喃酮类化合物，并且含有一个α-吡喃酮结构。所述烷基吡喃酮类化合物具有抗肿瘤活性，目前尚未见该化合物的化学结构及癌细胞增殖抑制活性的报道，因此市场上也尚未见有与此相关的药物。
具体实施方式
在如下的实施例中所指的化合物的化学结构：
实施例1该化合物的发酵生产及分离精制
1发酵生产
生产菌的发酵培养：按培养微生物的常规方法，取棘孢木霉(Trichoderma asperellum) (2012年10月30日保藏在武汉大学中国典型培养物保藏中心，保藏编号是：CCTCC NO：M 2012438)适量，接种到PDA固体斜面培养基上在28℃培养箱中培养4天。
取斜面培养4天的菌株适量，接种到装有400mL培养液[培养基组成(克/升)：甘露醇20.0，酵母膏3.0，麦芽糖20.0，味精10.0，葡萄糖10.0，KH2PO4 0.5，MgSO4 0.3]的1000 mL锥形瓶中，28℃静止培养30天后，获得菌丝体和发酵液。
2 浸膏的获得
发酵完成后，用纱布将菌丝体和发酵液分离。用含丙酮与水4:1的溶液浸泡溶解菌丝体细胞壁，超声辅助破碎，用多层纱布过滤得到菌丝体的丙酮粗提物。菌丝体破碎后得到的丙酮粗提物旋转蒸发除去丙酮，直至剩下粗提物的水溶液。按体积比为1:2加入乙酸乙酯，连续萃取两遍，合并后减压浓缩至干，得到菌丝体内代谢产物的乙酸乙酯浸膏。
3 化合物的分离精制
该浸膏通过100-200目硅胶拌样后固体上样，以石油醚：二氯甲烷：甲醇为洗脱液用减压硅胶色谱柱梯度洗脱。洗脱液经过活性跟踪（对人黑色素瘤细胞株A375抑制），得到活性组分D (二氯甲烷-甲醇v/v 30:1洗脱物)，然后以石油醚：二氯甲烷：甲醇梯度组分为洗脱液，进一步通过加压硅胶柱层析梯度洗脱，得到的活性亚组分D2(二氯甲烷-甲醇为20:1的洗脱物)通过氯仿-甲醇(v/v 2:1)为溶剂进行Sephadex LH-20凝胶柱层析，再经过RP-18反相硅胶柱层析以甲醇-水(v/v 3:2)为溶剂洗脱，最后通过半制备液相色谱(1010型ODS-A，10×250 mm，5μm)：分离流速为5 mL.min-1，流动相为60%乙腈，得到所示化合物(21.3 mg，t R 17.63min)。
化合物 无色晶体，正离子HR-ESI-MS m/z: 203.0702 [M+Na]+，分子式C10H12O3；1H和13C-NMR等NMR数据见表1。
表1化合物的1H和13C-NMR数据(500和125MHz，in DMSO-d 6)
1) 本表信号归属基于DEPT、HMQC及HMQC图谱解析结果。碳信号的多重度利用DEPT方法确定。
2) 此栏中的数字和代号分别代表在1H-1H COSY谱中与相应行中的1H给出耦合相关信号的1H核。
3) 此栏中的数字和代号分别代表在HMBC谱中与相应行中的1H给出耦合相关信号的13C核。
实施例2 体外抗肿瘤活性的测试
1 实验样品及实验方法
被测样品溶液的配制：测试样品为上述实施1中分离精制的化合物纯品。精密称取适量样品，加入50 μL DMSO，紫外照射一小时后，加入950 μL含有10% FBS的细胞培养液，得到了含有5% DMSO的1 mg.mL-1样品原液。用细胞培养液进行稀释，分别得到浓度为0.1、0.05、0.02、0.01 mg.mL-1的样品。
细胞系及细胞的继代培养采用人淋巴癌细胞RAJI细胞系。细胞用含10% FBS的RPMI-1640培养基，在37℃于通入5%二氧化碳的培养箱中继代培养。
癌细胞增殖抑制活性测试方法
取处于对数生长期的肿瘤细胞，用含10% FBS的培养液稀释，将细胞密度调至每毫升2×105的细胞悬液。在96孔板四周铺满PBS缓冲液，再把细胞悬液按每孔100 μL接种于96孔板中，留两个不加细胞悬浊液，只加细胞培养液作为给药组与对照组的空白孔。将接种完的96孔板放入37C，5% CO2的培养箱中培养24 h。待细胞贴壁后，吸去上清，每孔加入稀释好的样品100 μL，设置5% DMSO溶液的培养基作为对照组继续培养24 h。小心吸去上清液，每孔加1 mg.mL-1的MTT溶液100 μL，37℃培养4小时后，每分钟2000 转离心8分钟，用移液枪小心吸去上清液。每孔加入DMSO 100 μL，37℃摇床振荡，至结晶完全溶解后，酶标仪测定570 nm处测每孔OD值。取四孔平均OD值，按细胞增殖抑制率IR(%)=(OD对照-OD样品)/OD对照×100%计算，根据bliss法计算样品半数抑制率IC50。
2. 实验结果
细胞增殖抑制活性测试结果
在MTT法测试中，该化合物对人淋巴癌细胞RAJI细胞株的增殖抑制结果：IC50=82.6μM。
3. 结论
化合物具有明显的肿瘤细胞增殖抑制作用，可作为制备癌细胞增殖抑制剂或抗肿瘤剂用于抗肿瘤的研究。
Claims (5)
- 化合物。
- 一种如权利要求1所述化合物的制备方法，其特征在于：发酵培养棘孢木霉(Trichoderma asperellum)，获取菌丝体内代谢产物的粗提物，从中分离纯化出该化合物；所述棘孢木霉(Trichoderma asperellum)为棘孢木霉(Trichoderma asperellum) IBPT-2，已于2012年10月30日保藏在中国典型培养物保藏中心，保藏编号是：CCTCC NO：M 2012438。
- 权利要求1所述的化合物在制备癌细胞增殖抑制剂中的用途。
- 根据权利要求3所述化合物的用途，其特征在于：所述癌细胞为人淋巴癌细胞RAJI。
- 权利要求1所述的化合物在制备抗肿瘤药物中的用途。
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| CN107602555A (zh) * | 2017-10-27 | 2018-01-19 | 河南工业大学 | 一种咪唑类含硒吡喃酮化合物的合成及应用 |
| CN110840878A (zh) * | 2019-11-05 | 2020-02-28 | 牡丹江医学院 | 一种用于治疗银屑病的化合物及其制备方法 |
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