CN116082358B - 一类4-羟基-2-吡啶酮生物碱类衍生物及其制备方法和在制备抗肿瘤药物中的应用 - Google Patents
一类4-羟基-2-吡啶酮生物碱类衍生物及其制备方法和在制备抗肿瘤药物中的应用 Download PDFInfo
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- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 19
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
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- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 claims description 3
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract
本发明公开了一类4‑羟基‑2‑吡啶酮生物碱类衍生物及其制备方法和在制备抗肿瘤药物中的应用。本发明从节菱孢Arthrinium sp.ZSDS1‑F3中制备得到两个具有抗肿瘤活性的化合物1和2，其结构式如式(Ⅰ)所示。实验证明，化合物1和2具有良好的抗肿瘤活性，可用于开发抗肿瘤药物。本发明为开发新的抗肿瘤药物提供了备选化合物，对我国海洋微生物药物资源的开发具有重要意义。
Description
技术领域
本发明属于天然药物技术领域，具体涉及4-羟基-2-吡啶酮生物碱类衍生物及其制备方法和在制备抗肿瘤药物中的应用。
背景技术
肿瘤是一类严重影响人类生命健康的疾病，其致死率居高不下，仅次于心脑血管疾病。目前随着人口老龄化的加剧以及环境污染等不利因素的影响，肿瘤对人类的威胁有进一步加剧的趋势。具有高度物种多样性的海洋真菌能够产生结构新颖的次生代谢产物，是发现新型抗肿瘤药物先导化合物的重要资源。加强对抗肿瘤活性生产菌株的开发研究，对筛选发掘具有抗肿瘤活性的天然产物及药源先导化合物研发具有重要意义。
发明内容
本发明的第一个目的是提供一类4-羟基-2-吡啶酮生物碱类衍生物或其药用盐，所述的4-羟基-2-吡啶酮生物碱类衍生物的结构式如式1-2任一所示。
本发明的第二个目的是提供一种制备上述的4-羟基-2-吡啶酮生物碱类衍生物的方法，所述的4-羟基-2-吡啶酮生物碱类衍生物是从节菱孢Arthrinium sp.ZSDS1-F3的发酵培养物中分离制备得到的。
优选的，所述的制备方法，具体步骤如下：
1)制备节菱孢Arthrinium sp.ZSDS1-F3的发酵培养物；
2)对发酵培养物进行离心，得上清发酵液和沉淀菌丝体；上清发酵液用乙酸乙酯萃取，乙酸乙酯萃取液减压浓缩得到发酵液浸膏；沉淀菌丝体用丙酮水溶液超声浸提，提取液经减压蒸馏后，再用乙酸乙酯萃取，乙酸乙酯萃取液减压浓缩得到菌丝体浸膏；合并发酵液浸膏和菌丝体浸膏，再用石油醚反复萃取，除去油脂部分，得到粗浸膏；粗浸膏用正相硅胶柱层析分离，采用CH2Cl2–MeOH按体积分数0-100％进行梯度洗脱顺序得到组分7个组分fr1～fr7；将CH2Cl2–MeOH按体积比95:5洗脱得到的组分fr4经Sephadex LH-20柱层析，以甲醇为洗脱剂，洗脱纯化后，根据薄层层析结果分析，获得6个馏分fr4-1～fr4-6；收集以二氯甲烷：甲醇＝10：1v/v作为展开剂位移值在0.4-0.6范围内的馏分fr4-3，馏分fr4-3以210、290和340nm波长做检测、采用4mL/min的流速，以乙腈：水体积比为55:45进行等梯度洗脱进行半制备高效液相分离，收集保留时间为19.2min的组分，得到化合物2，收集保留时间为28.3min的组分，得到化合物1。
优选的，所述的节菱孢Arthrinium sp.ZSDS1-F3的发酵培养物是将节菱孢Arthrinium sp.ZSDS1-F3接入发酵培养基中发酵得到，所述的发酵培养基，每升含有：山梨醇20g，麦芽糖20g，味精10g，蛋白胨3g，磷酸二氢钾0.5g，硫酸镁0.3g，溶剂为水。
本发明的第三个目的是提供一种上述的4-羟基-2-吡啶酮生物碱类衍生物或其药用盐在制备抗肿瘤药物中的应用。
优选的，所述的抗肿瘤药物为抗前列腺癌、肺癌或肝癌的药物。
优选的，当为化合物1时，所述的抗肿瘤药物为抗前列腺癌的药物。
本发明的第四个目的是提供一种抗肿瘤药物，所述的抗肿瘤药物包含有效量的作为活性成分的上述式1-2任一所示的4-羟基-2-吡啶酮生物碱类衍生物或其药用盐，和药学上可以接受的载体。
本发明的第五个目的是提供节菱孢Arthrinium sp.ZSDS1-F3在制备4-羟基-2-吡啶酮生物碱类衍生物中的应用。
与现有技术相比，本发明具有如下有益效果：
本发明提供了一类结构新颖的4-羟基-2-吡啶酮生物碱类衍生物，该类化合物具有显著的抗肿瘤活性。其中，化合物1对前列腺癌、肺癌和肝癌具有显著的抑制活性，IC50值分别为0.53μM、3.48μM和4.78μM；特别是化合物1对前列腺癌的抗肿瘤细胞活性IC50值强于阳性药。化合物2对肝癌具有显著的抑制活性，IC50值为4.12μM。化合物1和2良好的抗肿瘤活性，可以做为抗肿瘤药物开发的先导化合物，对我国海洋微生物药物资源的开发具有重要意义。
本发明的节菱孢Arthrinium sp.ZSDS1-F3，于2013年12月20日保藏于中国微生物菌种保藏管理委员会普通微生物中心(CGMCC)，地址：北京市朝阳区北辰西路1号院，中科院微生物研究所，邮编：100101，保藏编号为CGMCC No.8652。该菌株公开于专利申请号：CN201410021280.4，发明名称：吡啶酮生物碱类化合物及其制备方法和在制备抗肿瘤药物中的应用中。
附图说明
图1为化合物1和2主要的1H-1H COSY,HMBC和NOESY信息。
图2为化合物1的X-Ray单晶图。
图3为不同浓度下化合物1和2对三种肿瘤细胞株的增殖抑制活性。
具体实施方式
下面结合具体实施例对本发明作出进一步地详细阐述，所述实施例只用于解释本发明，并非用于限定本发明的范围。下述实施例中所使用的试验方法如无特殊说明，均为常规方法；所使用的材料、试剂等，如无特殊说明，为可从商业途径得到的试剂和材料。
实施例1：化合物1和2的制备及结构鉴定
1、制备节菱孢Arthrinium sp.ZSDS1-F3的发酵培养物
每1000mL培养基是这样配制的：取山梨醇20g，麦芽糖20g，味精10g，蛋白胨3g，磷酸二氢钾0.5g，硫酸镁0.3g，然后溶于适量的水中，用水定容至1000mL，121℃高温灭菌30min，备用。将节菱孢Arthrinium sp.ZSDS1-F3接种到上述培养基中，28℃条件下摇床培养3天，得种子培养液，再以体积比5％的种子培养液接种到上述60L的培养基中，28℃条件下摇床培养12天，得到节菱孢Arthrinium sp.ZSDS1-F3的发酵产物。
2、化合物1和2的分离纯化
将上述节菱孢Arthrinium sp.ZSDS1-F3的发酵产物，以3600rpm离心，得上清发酵液和沉淀菌丝体。上清发酵液用乙酸乙酯等体积萃取3次，乙酸乙酯萃取液在低于40℃减压浓缩得发酵液浸膏；沉淀菌丝体用体积分数为85％的丙酮水溶液超声浸提，提取液经减压蒸馏后，再用乙酸乙酯反复萃取三次，乙酸乙酯萃取液在低于40℃下减压浓缩得菌丝体浸膏；合并发酵液浸膏和菌丝体浸膏，再用石油醚溶剂反复萃取三次，除去油脂部分，最后得约54.7g粗浸膏。该粗浸膏用正相硅胶柱层析分离，经拌样、干法装柱后，采用CH2Cl2-MeOH(0-100％,v/v)梯度洗脱顺序得7个组分(fr1～fr7)。组分fr4(CH2Cl2:MeOH＝95:5v/v洗脱的组分)经Sephadex LH-20柱层析，以甲醇为洗脱剂，洗脱纯化后，根据薄层层析结果分析，获得6个馏分(fr4-1～fr4-6)；收集以二氯甲烷：甲醇＝10：1v/v作为展开剂位移值在0.4-0.6范围内的馏分fr4-3，馏分fr4-3以210、290和340nm波长做检测、采用4mL/min的流速，以乙腈：水(55:45,v/v)进行等梯度洗脱进行半制备高效液相分离，HPLC(YMC-pack ODS-A,10×250mm,5μm)，得到化合物2(4.1mg，保留时间tR 19.2min)和化合物1(3.1mg，保留时间tR28.3min)。
3、化合物1和2的结构鉴定
对获得的化合物1和2进行核磁共振(NMR)、质谱(MS)、旋光(OR)、单晶衍射(X-Ray)等数据测试，从而确定化合物的化学结构。
新化合物1结构鉴定：无色晶体，高分辨质谱HRESIMS m/z 468.1991[M+Na]+(calcd for C24H31NNaO7,468.1993)，建议分子式为C24H31NO7；1H和13C NMR数据见表1，化合物1的NMR数据与已知化合物N-hydroxyapiosporamide的NMR数据非常相似，只有部分(环己烷片段)信号不同：13C NMR图谱中化合物1的C-21和C-22化学位移相对于已知化合物N-hydroxyapiosporamide向低场移动，表明环己烷片段中三元环氧打开，变为邻位二醇结构。此外，H-23与C-20的关键HMBC相关信号，表明C-20和C-23通过氧原子醚键相连。进一步通过X-Ray证明上述推断的正确性，同时确定了整个分子的绝对构型为3R 5S 8R 9R10R 20S21S 22S 23S，为结构崭新的化合物，命名为arthpyrone M。化合物1主要的COSY和HMBC相关信息见图1，化合物1的单晶X-Ray图见图2。
新化合物2结构鉴定：淡黄色油状物，高分辨质谱HRESIMS m/z 452.2040[M+Na]+(calcd for C24H31NNaO6,430.2043)，建议分子式为C24H31NO6；1H和13C NMR数据见表1，化合物2的NMR数据与化合物1的NMR数据非常相似，同样不同核磁数据主要发生在环己烷片段之处：二维核磁谱图COSY中可以发现关键的H-20/H2-25/H2-24/H-23/H-22自选耦合体系。HMBC中发现H-23和H2-25与羰基碳信号C-21的关键相关信号。经检索，化合物2为崭新结构，命名为arthpyrone N。化合物2主要的COSY和HMBC相关信息见图1。
表1.化合物1和2的1H和13C NMR数据(CD3OD,500MHz)
根据以上理化数据分析可知，化合物1和化合物2的具体结构如式(Ⅰ)所示。
实施例2：化合物1和2的抗肿瘤活性检测
采用国际通用的肿瘤细胞株，即：人前列腺癌细胞(C42B)、人肺癌细胞(H446)、人肝癌细胞(HepG2)。以抗肿瘤药物5-氟尿嘧啶(5-FU)、恩杂鲁胺(Enzalutamide)、顺铂(DDP)、阿霉素(DOX)作为阳性对照。试验方法为国际通用的CCK-8法。
化合物1和2对上述三种肿瘤细胞的抑制活性数据如表2和图3所示。
表2.化合物1和2对四株肿瘤细胞的增殖抑制作用(IC50,μM)
上述实验结果表明，化合物1和2作为结构新颖的4-羟基-2-吡啶酮生物碱类衍生物，具有显著的抗肿瘤活性；特别是化合物1对前列腺癌肿瘤表现出显著的抗肿瘤活性，体外抗肿瘤细胞活性IC50值强于阳性药，可以做为抗肿瘤药物开发的先导化合物。对我国海洋微生物药物资源的开发具有重要意义。
以上仅是本发明的优选实施方式，应当指出的是，上述优选实施方式不应视为对本发明的限制，本发明的保护范围应当以权利要求所限定的范围为准。对于本技术领域的普通技术人员来说，在不脱离本发明的精神和范围内，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (8)
1.4-羟基-2-吡啶酮生物碱类衍生物或其药用盐，其结构式如式1-2任一所示：
2.一种制备权利要求1所述的4-羟基-2-吡啶酮生物碱类衍生物的方法，其特征在于，所述的4-羟基-2-吡啶酮生物碱类衍生物是从节菱孢Arthrinium sp.ZSDS1-F3的发酵培养物中分离制备得到的；具体步骤如下：
1)制备节菱孢Arthrinium sp.ZSDS1-F3的发酵培养物；
2)对发酵培养物进行离心，得上清发酵液和沉淀菌丝体；上清发酵液用乙酸乙酯萃取，乙酸乙酯萃取液减压浓缩得到发酵液浸膏；沉淀菌丝体用丙酮水溶液超声浸提，提取液经减压蒸馏后，再用乙酸乙酯萃取，乙酸乙酯萃取液减压浓缩得到菌丝体浸膏；合并发酵液浸膏和菌丝体浸膏，再用石油醚反复萃取，除去油脂部分，得到粗浸膏；粗浸膏用正相硅胶柱层析分离，采用CH2Cl2-MeOH按体积分数0-100％进行梯度洗脱顺序得到组分7个组分fr1～fr7；将CH2Cl2-MeOH按体积比95:5洗脱得到的组分fr4经Sephadex LH-20柱层析，以甲醇为洗脱剂，洗脱纯化后，根据薄层层析结果分析，获得6个馏分fr4-1～fr4-6；收集以二氯甲烷：甲醇＝10：1v/v作为展开剂位移值在0.4-0.6范围内的馏分fr4-3，馏分fr4-3以210、290和340nm波长做检测、采用4mL/min的流速，以乙腈：水体积比为55:45进行等梯度洗脱进行半制备高效液相分离，收集保留时间为19.2min的组分，得到化合物2，收集保留时间为28.3min的组分，得到化合物1。
3.根据权利要求2所述的制备方法，其特征在于，所述的节菱孢Arthrinium sp.ZSDS1-F3的发酵培养物是将节菱孢Arthrinium sp.ZSDS1-F3接入发酵培养基中发酵得到，所述的发酵培养基，每升含有：山梨醇20g，麦芽糖20g，味精10g，蛋白胨3g，磷酸二氢钾0.5g，硫酸镁0.3g，溶剂为水。
4.权利要求1所述的4-羟基-2-吡啶酮生物碱类衍生物或其药用盐在制备抗肿瘤药物中的应用。
5.根据权利要求4所述的应用，其特征在于，所述的抗肿瘤药物为抗前列腺癌、肺癌或肝癌的药物。
6.根据权利要求5所述的应用，其特征在于，当为化合物1时，所述的抗肿瘤药物为抗前列腺癌的药物。
7.一种抗肿瘤药物，其特征在于，包含有效量的作为活性成分的权利要求1中式1-2任一所示的4-羟基-2-吡啶酮生物碱类衍生物或其药用盐，和药学上可以接受的载体。
8.节菱孢Arthrinium sp.ZSDS1-F3在制备权利要求1所述的4-羟基-2-吡啶酮生物碱类衍生物中的应用。
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