CN111153883B - 一种混元萜类化合物Verruculide B4及其制备方法和应用 - Google Patents
一种混元萜类化合物Verruculide B4及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及天然产物与医药技术领域，公开了一种混元萜类化合物Verruculide B4及其制备方法和应用。本发明所述混元萜类化合物Verruculide B4具有式(I)所示结构。本发明对真菌(Penicillium sp.)SCS‑KFD09代谢产物研究过程中，获得了一个混元萜类化合物Verruculide B4，其具有较强的蛋白络氨酸激酶1B(PTP1B)抑制活性，且无细胞毒活性，是开发高效、低毒的抗2型糖尿病的理想药物先导化合物。
Description
技术领域
本发明涉及天然产物与医药技术领域，具体涉及一种混元萜类化合物Verruculide B4及其制备方法和应用。
背景技术
糖尿病是一种常见的代谢内分泌疾病，基本病理生理为绝对或相对胰岛素不足和胰高血糖素活性增高所引起的代谢紊乱。糖尿病是当前世界上威胁全球人类健康最主要的非传染性疾病之一。糖尿病主要有两种类型，l型糖尿病(胰岛素依赖型)和II型糖尿病(非胰岛素依赖型)，其中II型糖尿病占糖尿病患者总数的90％以上。具国际糖尿病联盟统计，2011年全球糖尿病患者约有3.7亿，而到2030年全球将有近5.7亿糖尿病患者，其中80％在发展中国家。2009年中国卫生部门给出的糖尿病患者人数是9200万，到2013年这个数字变为1.14亿人，四年间中国多出2200万糖尿病病人，平均每年增长550万例，每天增长1.5万例。
蛋白酪氨酸磷酸酶1B(Protein Tyrosine Phosphatase1 B,PTP1B)是一种非跨膜蛋白酪氨酸磷酸水解酶，位于胞浆内质网，与蛋白络氨酸激酶(Protein Tyrosine Kinase,PTK)共同维持着络氨酸蛋白磷酸化的平衡，参与细胞信号转导。PTP1B是胰岛素信号转导通路中的关键的负调节蛋白，它的过度表达会导致胰岛素受体无法与胰岛素结合，进而引起胰岛素抵抗，导致体内胰岛素含量相对降低，这被认为是导致II型糖尿病的重要原因之一。PTP1B抑制剂通过阻断胰岛素刺激的胰岛素受体(IR)的酪氨酸磷酸化，进而影响胰岛素受体(IRS-1)的磷酸化，使类胰岛素和胰岛素增敏，降低血糖。同时，其能使瘦素信号增强，诱导脂肪代谢水平升高，体重下降，因此，PTP1B是开发新型抗糖尿病药物的作用靶点，这为II型糖尿病的治疗提供了新的思路。
由于海洋环境的特殊性(高盐度、高压、低温、寡营养等)，造就了海洋真菌独特的适应机制和代谢机制。从1953年分离鉴定了第一个海洋真菌天然产物cephalosporin N到目前为止，海洋真菌天然产物已经发现2000余个。其中脱氢二酮哌嗪生物碱halimide的化学衍生物plinabulin已结束II期临床研究，并于2015年第三季度开始在美国和中国进行III期临床研究，用于治疗转移性的晚期非小细胞肺癌，是20个海洋药物之一。
目前用于糖尿病的混元萜类化合物种类仍然不多，且很少属于海洋真菌天然产物，同时PTP1B抑制活性也需要进一步提高。
发明内容
有鉴于此，本发明的目的在于提供一种混元萜类化合物Verruculide B4，是的所述混元萜类化合物Verruculide B4来源于海洋真菌的代谢产物，并具备极高的PTP1B抑制活性；
本发明的另外一个目的在于提供上述混元萜类化合物Verruculide B4的制备方法和在制备治疗糖尿病药物中的应用。
为了实现上述目的，本发明提供如下技术方案：
一种混元萜类化合物Verruculide B4，具备式(I)所示结构：
本发明所述混元萜类化合物Verruculide B4首次分离于青霉属真菌(Penicillium sp.)SCS-KFD09的发酵培养物，该菌为已有研究报道的菌株(Kong,F.D.；Ma,Q.Y.；Huang,S.Z.；Wang,P.；Wang,J.F.；Zhou,L.M.；Yuan,J.Z.；Dai,H.F.；Zhao,Y.X.Chrodrimanins K–N and Related Meroterpenoids from the Fungus Penicilliumsp.SCS-KFD09 Isolated from a Marine Worm,Sipunculus nudus.Journal of NaturalProducts,2017,80:1039-1047.)。
同时，本发明还提供了如何从SCS-KFD09的发酵培养物中分离获得所述混元萜类化合物Verruculide B4的方法，包括：
步骤1、获得青霉属真菌SCS-KFD09的发酵培养物，发酵培养物经过乙酸乙酯萃取，浓缩乙酸乙酯后得到浸膏；
步骤2、所述浸膏经正相硅胶色谱柱，用石油醚/乙酸乙酯作为洗脱剂，从体积比为9:1到1:0进行梯度洗脱，收集石油醚/乙酸乙酯体积比为8:1的洗脱馏分，经反相硅胶色谱柱洗脱，收集的馏分以甲醇：水＝85:15再经HPLC半制备分离得到Verruculide B4。
其中，所述发酵培养物由SCS-KFD09接种发酵培养基静置培养后30天获得；所述发酵培养基每升含有麦芽糖20g、味精10g、KH2PO4 0.5g、MgSO4·7H2O 0.3g、葡萄糖10g、酵母膏3g、玉米浆1g、甘露醇20g、海盐33g，余量水，pH 6.5。
采用p-NPP法检测目标化合物对PTP1B的活性，结果显示，化合物对PTP1B的抑制活性IC50为4.5μM，与阳性药Na3VO4的IC503.4μM较为接近；同时采用参考文献MTT法测定Verruculide B4对4种人体肿瘤细胞株(SGC-7901,K562,Hela和A549)的细胞毒活性，发现其在100μM浓度下无抑制作用；上述试验结果提示其能被用于制备低毒高效的PTP1B抑制相关的糖尿病药物。
基于此，本发明提出了所述混元萜类化合物Verruculide B4在制备治疗糖尿病药物中的应用。所述药物可以是药剂领域中的任何剂型，所述药物的剂型为片剂、胶囊或注射液。
根据应用，本发明还提出了一种治疗糖尿病的药物，其包含所述混元萜类化合物Verruculide B4和药学上可接受的载体。
由以上技术方案可知，本发明对真菌(Penicillium sp.)SCS-KFD09代谢产物研究过程中，获得了一个混元萜类化合物Verruculide B4，其具有较强的蛋白络氨酸激酶1B(PTP1B)抑制活性，且无细胞毒活性，是开发高效、低毒的抗2型糖尿病的理想药物先导化合物。
附图说明
图1所示为Verruculide B4的1H NMR谱图；
图2所示为Verruculide B4的13C NMR谱图。
具体实施方式
本发明公开了一种混元萜类化合物Verruculide B4及其制备方法和应用，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明所述混元萜类化合物Verruculide B4及其制备方法和应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的混元萜类化合物Verruculide B4及其制备方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
以下就本发明所提供的一种混元萜类化合物Verruculide B4及其制备方法和应用做进一步说明。
实施例1：混元萜类化合物Verruculide B4的制备和分离
1、配制培养基：按1L配方(麦芽糖20g，味精10g，KH2PO4 0.5g，MgSO4·7H2O 0.3g，葡萄糖10g，酵母膏3g，玉米浆1g，甘露醇20g，海盐33g，pH 6.5，余量水)配制发酵培养基30L，分装到1L容量的三角瓶中，每瓶300mL培养基，共100瓶，121℃高温灭菌。
2、发酵培养：将青霉属(Penicillium)sp.SCS-KFD09接入上述培养基中，室温静置培养30天。
3、萃取：发酵培养物用三倍体积乙酸乙酯萃取后减压浓缩得浸膏20.8g。
4、混元萜的分离：上述浸膏经正相硅胶色谱柱，用石油醚/乙酸乙酯作为洗脱剂，从体积比为9:1到1:0进行梯度洗脱，收集石油醚/乙酸乙酯体积比为为8:1的洗脱馏分，经反相C-18硅胶柱洗脱，收集的馏分再经HPLC(甲醇：水＝85:15)半制备分离得到混元萜类化合物verruculide B4(10.6mg，13min)。
5、混元萜的结果鉴定：混元萜的质谱、核磁和旋光数据与文献中(Bai,T.；Quan,Z.；Zhai,R.；Awakawa,T.；Matsuda,Y.；Abe,I.Elucidation and heterologousreconstitution of chrodrimanin B biosynthesis.Organic letters,2018,20:7504-7508.)一致，确证混元萜verruculide B4结构，核磁相关结果见表1和图1-2。
表1混元萜verruculide B4的1H和13C NMR核磁归属(溶剂为DMSO-d6)
实施例2：混元萜verruculide B4的PTP1B抑制活性测定
采用p-NPP法检测目标化合物对PTP1B的活性，活性测试方法参考文献(Kong,F.D.；Fan,P.；Zhou,L.M.；Ma,Q.Y.；Xie,Q.Y.；Zheng,H.Z.；Zheng,Z.H.；Zhang,R.S.；Yuan,J.Z.；Zhang,R.S.；Dai,H.F.；Luo,D.Q.Penerpenes A–D,Four Indole Terpenoids withPotent Protein Tyrosine Phosphatase Inhibitory Activity from the Marine-Derived Fungus Penicillium sp.KFD28.Organic letters.2019,21:4864-4867)。化合物对PTP1B的抑制活性IC50为4.5μM(阳性药Na3VO4的IC50为3.4μM)。同时采用参考文献MTT法(Sheng-Zhuo Huang,Qing-Yun Ma,Fan-Dong Kong,Zhi-Kai Guo,Cai-Hong Cai,Li-LiHu,Li-Man Zhou,Qi Wang,Hao-Fu Dai,Wen-Li Mei,You Xing Zhao.Lanostane-typetriterpenoids from the fruiting body of Ganodermacalidophilum.Phytochemistry,2017,143:104-110.)测定Verruculide B4对4种人体肿瘤细胞株(SGC-7901,K562,Hela,and A549)的细胞毒活性，发现其在100μM浓度下无抑制作用，提示其能被改造用于制备低毒高效的PTP1B抑制相关的糖尿病药物。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，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 (1)
1.混元萜类化合物Verruculide B4的制备方法，其特征在于，包括：
步骤1、获得青霉属真菌SCS-KFD09的发酵培养物，发酵培养物经过乙酸乙酯萃取，浓缩乙酸乙酯后得到浸膏；所述发酵培养物由SCS-KFD09接种发酵培养基培养后获得；所述发酵培养基每升含有麦芽糖20g、味精10g、KH2PO4 0.5g、MgSO4·7H2O 0.3g、葡萄糖10g、酵母膏3g、玉米浆1g、甘露醇20g、海盐33g，余量水，pH 6.5
步骤2、所述浸膏经正相硅胶色谱柱，用石油醚/乙酸乙酯作为洗脱剂，从体积比为9:1到0：1进行梯度洗脱，收集石油醚/乙酸乙酯体积比为8:1的洗脱馏分，经反相硅胶色谱柱洗脱，收集的馏分以甲醇：水＝85:15再经HPLC半制备分离得到Verruculide B4；
所述Verruculide B4具备式(I)所示结构：
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Non-Patent Citations (5)
| Title |
|---|
| Chrodrimanins K−N and Related Meroterpenoids from the Fungus Penicillium sp. SCS-KFD09 Isolated from a Marine Worm, Sipunculus nudus;Fan-Dong Kong et al.;《Journal of Natural Products》;20170217;第80卷;第1039-1047页 * |
| Elucidation and Heterologous Reconstitution of Chrodrimanin B Biosynthesis;Tongxuan Bai et al.;《Organic Letters》;20181112;第20卷;第7504-7508页 * |
| Tongxuan Bai et al..Elucidation and Heterologous Reconstitution of Chrodrimanin B Biosynthesis.《Organic Letters》.2018,第20卷第7504-7508页. * |
| Verruculides A and B, two new protein tyrosine phosphatase 1B inhibitors from an Indonesian ascidian-derived Penicillium verruculosum;Hiroyuki Yamazaki et al.;《Bioorganic & Medicinal Chemistry Letters》;20150614;第25卷;第3087-3090页 * |
| 海洋动物来源真菌代谢产物结构及其生物活性研究;孔凡栋等;《中国菌物学会2018年学术年会》;20180811;第200页 * |
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