CN116064244B - 一种海洋曲霉菌ITBBc1及其分离的三联苯类化合物和应用 - Google Patents
一种海洋曲霉菌ITBBc1及其分离的三联苯类化合物和应用 Download PDFInfo
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Abstract
本发明公开了一种海洋曲霉菌Aspergillus sp.ITBBc1,其特征是:它的保藏编号为GDMCC No:62723,保藏日期为2022年08月23日,保藏单位为广东省微生物菌种保藏中心,保藏地址为中国广州,还公开了一种具有磷酸二酯酶PDE4D抑制活性的三联苯类化合物,所述三联苯类化合物为海洋曲霉素A、亮白曲霉素C或亮白曲霉素A,以及该三联苯类化合物的制备方法和其在制备具有磷酸二酯酶PDE4D抑制活性的PDE4D抑制剂中的应用或在制备具有预防和/或治疗神经系统病症、炎症性疾病、呼吸系统疾病、代谢性疾病或心血管疾病效果的药物中的应用。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种海洋曲霉菌ITBBc1及其分离的三联苯类化合物和应用,尤其还涉及一种从海洋曲霉菌ITBBc1中分离的三联苯类化合物海洋曲霉素A以及亮白曲霉素A和亮白曲霉素C在磷酸二酯酶PDE4抑制剂研发中的新用途及其制备方法和应用。
背景技术
cAMP和cGMP广泛存在于有机体细胞中,它们对细胞生命活动的调节功能发挥了极其重要的作用,一旦其浓度失衡将导致机体多种疾病的发生。磷酸二酯酶家族(Phosphodiesterases,PDEs)是机体内唯一能水解cAMP或cGMP的酶类,参与体内多种生理或病理过程,并且被证实是有效的药物靶点。基于PDE的底物特异性、组织分布、催化结构域的同源性及对抑制剂的敏感性等,PDEs可分为11个家族(PDE1~11)。迄今为止,针对不同类型的PDE研发的抑制剂药物已多达十余个被批准上市,其适应症主要为男性勃起功能障碍、肺动脉高压、心力衰竭、慢性阻塞性肺病和银屑病等,其中最为成功的药物是PDE5抑制剂西地那非,俗称“伟哥”,在上市后每年销售额均超过十亿美元。这些PDE抑制剂的成功运用激励着科学家研发更多高效的选择性PDE抑制剂及其适应症。
磷酸二酯酶-4(PDE4)是主要的cAMP特异性水解酶,目前是治疗中枢神经系统、炎症性和呼吸系统疾病药物研发的重要靶点。它主要有4个亚型,包括PDE4A~D,其中PDE4D在大脑额叶皮层中高效表达,是参与大脑记忆巩固过程的主要PDE4亚型,已上市的治疗精神压抑药物咯利普兰(Rolipram)就是一种典型的PDE4D抑制剂。一些被用于治疗心脑血管疾病的天然产物,譬如茶碱和罂粟碱,也是PDE的抑制剂。尽管过去10多年已发现了大量结构各异的小分子PDE4抑制剂,但是剂量限制性毒副作用严重限制了它们的使用。因此亟需寻找更高效低毒性的新型PDE4抑制剂。
自然界作为活性天然产物的重要来源孕育了数以亿计的生命有机体。在过去的几十年里,绝大多数抗感染、抗肿瘤药物都源于生命体产生的天然产物及其衍生物,如吗啡、奎宁、青霉素、阿司匹林、紫杉醇、青蒿素。其中,微生物由于能够产生一系列活性显著且具有成药潜力的天然产物而备受关注。特殊环境中的微生物是尚未得到有效重视和充分利用的微生物资源,是发现具有新颖结构和独特作用机制的创新药物的重要来源。
发明内容
本发明的目的在于提供一种海洋曲霉菌Aspergillus sp.ITBBc1。
本发明的目的还在于提供一种具有磷酸二酯酶PDE4D抑制活性的三联苯类化合物及其制备方法。
本发明的最后一个目的在于提供上述三联苯类化合物在制备具有磷酸二酯酶PDE4D抑制活性的PDE4D抑制剂中的应用。
本发明的上述第一个目的可以通过以下技术方案来实现:一种海洋曲霉菌Aspergillus sp.ITBBc1,它的保藏编号为GDMCC No:62723,保藏日期为2022年08月23日,保藏单位为广东省微生物菌种保藏中心,保藏地址为中国广州。
保藏编号为GDMCC No:62723的海洋曲霉菌Aspergillus sp.ITBBc1是从海南南海海域采集的硬珊瑚上分离得到,并经ITS基因序列鉴定为曲霉菌(Aspergillus sp.)。
该菌株命名为Aspergillus sp.ITBBc1,保藏单位:广东省微生物菌种保藏中心,保藏地址:广州市先烈中路100号大院59号楼5楼,广东省科学院微生物研究所,保藏日期为2022年08月23日,保藏编号为GDMCC No:62723。
本发明上述的第二个目的可以通过以下技术方案来实现:一种具有磷酸二酯酶PDE4D抑制活性的三联苯类化合物,所述三联苯类化合物为海洋曲霉素A、亮白曲霉素C或亮白曲霉素A,所述海洋曲霉素A、亮白曲霉素C或亮白曲霉素A通过上述的海洋曲霉菌Aspergillus sp.ITBBc1发酵产生,其中所述海洋曲霉素A、亮白曲霉素C或亮白曲霉素A的化学结构式分别如下式(Ⅰ)、(Ⅱ)或(Ⅲ)所示:
其中海洋曲霉素A是一种新的三联苯类化合物,该化合物的结构式是C25H25O4,实测分子量为389.1752([M+H]+分子离子峰,其[M+H]+理论分子量为389.1747)。
所述的三联苯类化合物海洋曲霉素A是通过保藏号为GDMCC No:62723的海洋曲霉菌Aspergillus sp.ITBBc1发酵产生的,该化合物具有较强的磷酸二酯酶PDE4D抑制活性。
亮白曲霉素C,该化合物(Ⅱ)的结构式是C21H18O6,实测分子量为367.1154([M+H]+分子离子峰,其[M+H]+理论分子量为367.1176)。
亮白曲霉素A,该化合物(Ⅲ)的结构式是C20H16O6,实测分子量为353.1017([M+H]+分子离子峰,其[M+H]+理论分子量为353.1020)。
亮白曲霉素C和亮白曲霉素A也是通过保藏号为GDMCC No:62723的海洋曲霉菌Aspergillus sp.ITBBc1发酵产生的,二者也具有极强的磷酸二酯酶PDE4D抑制活性。
上述具有磷酸二酯酶PDE4D抑制活性的海洋曲霉素A、亮白曲霉素A和亮白曲霉素C的制备方法,包括以下步骤:
(1)将上述的曲霉菌Aspergillus sp.ITBBc1经土豆培养基平板活化后接种于ME液体培养基中,26~32℃、140~200r/min振荡培养3~4d,获得种子液,取种子液接种到大米培养基中,26~32℃静置发酵35~50天,得到发酵物;
(2)用等体积的乙酸乙酯浸提发酵物,将乙酸乙酯浸提液减压浓缩至干,得到发酵提取物;
(3)对发酵提取物进行正相硅胶柱层析,用体积比为100:1、50:1、25:1、10:1、5:1、2:1、1:1、0:1的石油醚-乙酸乙酯梯度洗脱,得到馏分A、B、C、D、E、F、G和H;
(4)对馏分E进行ODS反相柱层析、Sephadex LH-20凝胶柱层析和正相硅胶柱层析分离纯化,得到海洋曲霉素A;
(5)对馏分F进行ODS反相柱层析、Sephadex LH-20凝胶柱层析和半制备HPLC纯化,得到亮白曲霉素C;
(6)对馏分G进行ODS反相柱层析、Sephadex LH-20凝胶柱层析和半制备HPLC纯化,得到亮白曲霉素A。
在上述具有磷酸二酯酶PDE4D抑制活性的海洋曲霉素A、亮白曲霉素A和亮白曲霉素C的制备方法中:
优选的,步骤(1)中所述土豆培养基为常规培养基,由以下组分组成:马铃薯200~300g,葡萄糖20~30g,琼脂15~20g,水1L。
优选的,步骤(1)中所述的ME液体培养基中含有以下质量的组分:麦芽提取物9~12g、蔗糖8~14g、蛋白胨1~2g,水1L。
优选的,步骤(1)中所述的大米培养基由以下组分组成:大米30g,水45mL。
优选的,步骤(2)中用等体积的乙酸乙酯浸提萃取发酵液3~5次,减压浓缩的温度为45~60℃。
优选的,步骤(4)~(6)中采用的ODS反相柱层析、Sephadex LH-20凝胶柱层析、正相硅胶柱层析、半制备HPLC纯化均为本领域常规商品或常规方法。
本发明提供的具有磷酸二酯酶PDE4D抑制活性的三联苯类化合物的制备方法,该制备方法工艺简洁,绿色环保,成本低。
本发明上述的第三个目的可以通过以下技术方案来实现:上述三联苯类化合物在制备具有磷酸二酯酶PDE4D抑制活性的PDE4D抑制剂中的应用。
进一步的,还可以将三联苯类化合物在制备具有预防和/或治疗神经系统病症、炎症性疾病、呼吸系统疾病、代谢性疾病或心血管疾病效果的药物中的应用。
优选的,所述的PDE4D抑制剂应用于治疗神经系统病症如帕金森症、老年痴呆症、精神分裂症、精神障碍症、抑郁症、亨廷顿舞蹈病、缺血性中风、创伤性脑损伤、年龄相关记忆障碍等,呼吸系统病症如慢性阻塞性肺病、哮喘、肺炎等,炎症性疾病如银屑病与银屑病关节炎、轻中度湿疹、过敏性皮炎、非酒精性脂肪性肝炎等,代谢性疾病如II型糖尿病,心血管疾病如高血压以及多发性骨纤维营养不良、痉挛等。
与现有技术相比,本发明具有如下优点:
(1)本发明如式(I)所示结构的三联苯类化合物海洋曲霉素A未见从自然界中分离得到过,结构未见报道过,是一个新结构化合物;
(2)本发明如式(Ⅱ)和(Ⅲ)所示结构的亮白曲霉素C和亮白曲霉素A具有高效的磷酸二酯酶PDE4D抑制活性,磷酸二酯酶抑制活性未见报道过,具有新用途;
(3)本发明提供的海洋曲霉素A、亮白曲霉素C和亮白曲霉素A均来源于自然界生物体尤其是海洋曲霉菌Aspergillus sp.ITBBc1,副作用低,活性优;
(4)本发明提供的曲霉菌Aspergillus sp.ITBBc1生产海洋曲霉素A、亮白曲霉素C和亮白曲霉素A的原料易得,工艺绿色环保,成本低,适合用作药物生产;
(5)本发明通过酶活性抑制实验表明具有如式(I)、(Ⅱ)和(Ⅲ)所示结构的化合物具有优异的磷酸二酯酶PDE4D抑制活性,它们作为磷酸二酯酶抑制剂,可作为用于治疗神经系统病症如帕金森症、老年痴呆症、精神分裂症、精神障碍症、抑郁症、亨廷顿舞蹈病、缺血性中风、创伤性脑损伤、年龄相关记忆障碍等,呼吸系统病症如慢性阻塞性肺病、哮喘、肺炎等,炎症性疾病如银屑病与银屑病关节炎、轻中度湿疹、过敏性皮炎、非酒精性脂肪性肝炎等,代谢性疾病如II型糖尿病,心血管疾病如高血压以及多发性骨纤维营养不良、痉挛等的药物;
(6)本发明针对生境特殊、种类丰富的海南南海珊瑚共附生微生物产生的具有PDE4D抑制活性的天然产物进行挖掘,为天然来源的高效低毒性新型PDE4抑制药物研发提供新分子资源,具有极大的应用价值和开发潜力。
附图说明
图1是实施例1中菌株ITBBc1在PDA培养基平板上培养7d时的菌落特征;
图2是实施例1中菌株ITBBc1的ITS序列系统发育树;
图3是实施例4中化合物(Ⅰ)的高分辨质谱;
图4是实施例4中化合物(Ⅰ)的1H一维核磁共振谱;
图5是实施例4中化合物(Ⅰ)的13C一维核磁共振谱;
图6是实施例4中化合物(Ⅰ)的DEPT135一维核磁共振谱;
图7是实施例4中化合物(Ⅰ)的HSQC二维核磁共振谱;
图8是实施例4中化合物(Ⅰ)的HMBC二维核磁共振谱;
图9是实施例4中化合物(Ⅰ)的1H-1H COSY二维核磁共振谱;
图10是实施例4中化合物(Ⅰ)的ROESY二维核磁共振谱;
图11是实施例4中化合物(Ⅱ)的高分辨质谱;
图12是实施例4中化合物(Ⅱ)的1H一维核磁共振谱;
图13是实施例4中化合物(Ⅲ)的高分辨质谱;
图14是实施例4中化合物(Ⅲ)的1H一维核磁共振谱。
具体实施方式
下面实施例中,高分辨质谱仪为Agilent 6210TOF LC-MS质谱仪(美国Agilent公司)。超导核磁共振波谱仪为BrukerAVIII-500(德国Bruker公司)。Waters 1525型高效液相色谱仪,配备分析型色谱柱(Waters XBridge C18,150mm×2.1mm,3.5μm)和半制备型色谱柱(Waters XBridge C18,250mm×10mm,5μm)(美国Waters公司)。分析型薄层层析硅胶板(GF254)和正相层析柱硅胶(45–75μm)均为青岛海洋化工厂产品。Sephadex LH-20为瑞典Pharmacia Biotech公司产品。ODS反相硅胶为日本Nacalai Tesque公司产品。色谱甲醇为天津康科德公司产品。水为双重蒸馏水,其他试剂均为分析纯。磷酸二酯酶PED4D抑制活性测试实验参照Bioorganic&Medicinal Chemistry Letters,2019,29:2150-2152(Dualfunctional cholinesterase and PDE4D inhibitors for the treatment ofAlzheimer’s disease:Design,synthesis and evaluation of tacrine-pyrazolo[3,4-b]pyridine hybrids.Tingting Pan,Shishun Xie,Yan Zhou,Jinhui Hu,Haibin Luo,Xingshu Li,Ling Huang)。阳性药Rolipram购自海口盛京科技有限公司。
实施例1菌株分离与鉴定
从海南南海海域采集的硬珊瑚上分离得到共附生真菌菌株ITBBc1,该菌株在PDA培养基平板上,菌落白色至淡黄色,反面白色,边缘不规则,表面颗粒状孢子粉呈散状分布,气生菌丝少,PDA平板中未见可溶性色素(如图1所示)。经ITS基因序列测序、BLAST对比分析和MEGA5.0构建系统发育树(如图2所示),将该菌株鉴定为曲霉菌(Aspergillus sp.),并命名为Aspergillus sp.ITBBc1,保藏编号为GDMCC No:62723,保藏日期为2022年08月23日,保藏单位:广东省微生物菌种保藏中心,保藏地址:广州市先烈中路100号大院59号楼5楼,广东省科学院微生物研究所。
该菌株的ITS基因序列为:
TGCGGAAGGATCATTACCGAGTGCTGGGCCCTCTGGGTCCAACCTCCCACCCGTGTCTATTGTACCTTGTTGCTTCGGCGGGCCCGCCGTTTTCGAACGGCCGCCGGGGAGGCCTCGCGCCCCCGGGCCCGCGCCCGCCGAAGACCCCAACATGAACGCTGTTCTGAAAGTATGCAGTCTGAGTTTGATTATCATAATCAGTTAAAACTTTCAACAACGGATCTCTTGGTTCCGGCATCGATGAAGAACGCAGCGAAATGCGATAAGTAATGTGAATTGCAGAATTCAGTGAATCATCGAGTCTTTGAACGCACATTGCGCCCCCTGGTATTCCGGGGGGCATGCCTGTCCGAGCGTCATTGCTGCCCTCAAGCACGGCTTGTGTGTTGGGCCCCCGTCCCCGGTTCTCCCCGGGGACGGGCCCGAAAGGCAGCGGCGGCACCGCGTCCGATCCTCGAGCGTATGGGGCTTTGTCACCCGCTCTGTAGGCCCGGCCGGCGCCAGCCGACACCCCAACTTTATTTTTCTAAGGTTGACCTCGGATCAGGTAGGGATACCCGCTGAACTTAAGCATA575。
实施例2菌株Aspergillus sp.ITBBc1的发酵及其发酵提取物样品的获取
将实施例1所得菌株Aspergillus sp.ITBBc1经土豆培养基平板活化,接种于ME液体培养基中,28℃、160r/min振荡培养4天,获得种子液。取15mL种子液接种到大米培养基中进行发酵,28℃静置培养45天。发酵完成后,加入等体积的乙酸乙酯浸提,重复提取4次,合并乙酸乙酯提取液,于45℃下减压浓缩得到发酵提取物。所述ME培养基由以下按重量体积比计的组分组成:麦芽提取物10.0g/L、蔗糖10.0g/L、蛋白胨1.0g/L。所述大米固体培养基由以下组分组成:大米30g,水45mL。
实施例3化合物的分离
将实施例2所得发酵提取物进行正相硅胶柱层析,采用石油醚-乙酸乙酯(体积比分别为100:1、50:1、25:1、10:1、5:1、2:1、1:1、0:1)进行梯度洗脱,得到A、B、C、D、E、F、G、H共8个馏分。
对馏分E进行ODS反相柱层析、Sephadex LH-20凝胶和正相硅胶柱层析分离纯化得到新结构化合物(Ⅰ)。
对馏分F进行ODS反相柱层析、Sephadex LH-20凝胶柱层析和半制备HPLC纯化得化合物(Ⅱ)。
对馏分G进行ODS反相柱层析、Sephadex LH-20凝胶柱层析和半制备HPLC纯化得化合物(Ⅲ)。
实施例4化合物的结构鉴定
化合物(Ⅰ)的结构通过高分辨质谱【实测分子量为389.1752([M+H]+分子离子峰,其[M+H]+理论分子量为389.1747),推出分子式为C25H25O4】(如图3所示)、核磁共振(包括一维、二维NMR实验)(如图4-图10所示)等多种波谱学手段确定,为未报道过的具有新结构的三联苯类化合物,命名为海洋曲霉素A。
化合物(Ⅱ)的结构通过高分辨质谱【实测分子量为367.1154([M+H]+分子离子峰,其[M+H]+理论分子量为367.1176),推出分子式为C21H18O6】(如图11所示)、氢(1H)核磁共振(如图12所示)波谱学手段确定为已知结构的三联苯类化合物亮白曲霉素C(candidusinC)。
化合物(Ⅲ)的结构通过高分辨质谱【实测分子量为353.1017([M+H]+分子离子峰,其[M+H]+理论分子量为353.1020),推出分子式为C20H16O6】(如图13所示)、氢(1H)核磁共振(如图14所示)波谱学手段确定为已知结构的三联苯类化合物亮白曲霉素A(candidusinA)。
化合物(Ⅰ)、(Ⅱ)和(Ⅲ)的1H、13C核磁共振波谱数据如下表1所示:
表1实施例3-4中化合物(Ⅰ)、(Ⅱ)和(Ⅲ)的核磁共振数据及归属
结构式如下:
实施例5化合物(Ⅰ)、(Ⅱ)和(Ⅲ)的磷酸二酯酶PED4D抑制活性测试
5.1活性测试方法
在EP管中加入58μL合适浓度的[8-3H]-cAMP,测试组加入2μL不同的化合物溶液(用倍半稀释法稀释化合物,用DMSO稀释9个浓度),阴性对照组和空白对照组中分别加入2μLDMSO,阳性对照组中加入2μL40μM(终浓度为0.8μM)Rolipram的DMSO溶液,混匀。
测试组、阳性对照组和阴性对照组中都分别加入40μL合适浓度的磷酸二酯酶PDE4D蛋白溶液(均用Assay Buffer稀释),空白对照组中加入40μL空白Assay buffer。
将整个反应体系溶液混匀后,室温静置反应15min。然后按顺序加入200μL0.2M硫酸锌溶液和200μL 0.2M氢氧化钡溶液停止反应。随后将体系混匀后的离心管离心6min(转速为14800rpm)。离心完成后,吸取430μL反应体系的上清液,加入到装有1.8mL闪烁液的6mL闪烁管中,盖上闪烁管盖子,再将其涡旋混匀,最后用液体闪烁计数仪测定上清液的放射性,通过计算确定化合物对磷酸二酯酶PDE4D的抑制活性,上述测试重复三次。使用GraphPad Prism 5.1软件处理数据,绘制化合物浓度-蛋白抑制率曲线,作非线性回归拟合后计算出IC50。
5.2活性评价结果
实施例3-4中的化合物(Ⅰ)、(Ⅱ)和(Ⅲ)均对磷酸二酯酶PED4D具有优异的抑制活性(如表2所示),其中新结构化合物(Ⅰ)抑制磷酸二酯酶PED4D活性的IC50值为5.543±0.24μmol/L,化合物(Ⅱ)和化合物(Ⅲ)抑制磷酸二酯酶PED4D活性的IC50值分别为1.378和0.719μmol/L,它们的活性与阳性药物Rolipram的抑制活性相当,表明化合物(Ⅰ)、(Ⅱ)和(Ⅲ)具有开发成磷酸二酯酶PED4抑制剂的良好前景。天然来源的PDE4抑制剂非常稀有,本发明提供的3个三联苯类化合物为自然界来源的磷酸二酯酶PDE4抑制剂的研发提供了非常有前景的先导模板结构。
表2实施例3-5中化合物(Ⅰ)、(Ⅱ)和(Ⅲ)的磷酸二酯酶PED4D抑制活性结果
供试样品 | IC50(μmol/L) |
化合物(Ⅰ) | 5.543±0.24 |
化合物(Ⅱ) | 1.378 |
化合物(Ⅲ) | 0.719 |
阳性药Rolipram | 0.588±0.057 |
上面列举一部分具体实施例对本发明进行说明,有必要在此指出的是上下具体实施例只用于对本发明作进一步的说明,不代表对本发明保护范围的限制。其他人根据本发明作出的一些非本质的修改和调整仍属于本发明的保护范围。
Claims (2)
1.一种海洋曲霉菌(Aspergillus sp.)ITBBc1,其特征是:它的保藏编号为GDMCC No:62723,保藏日期为2022年08月23日,保藏单位为广东省微生物菌种保藏中心,保藏地址为中国广州。
2.一种具有磷酸二酯酶PDE4D抑制活性的三联苯类化合物,其特征是:所述三联苯类化合物为海洋曲霉素A,所述海洋曲霉素A通过权利要求1所述的海洋曲霉菌(Aspergillussp.)ITBBc1发酵产生,其中所述海洋曲霉素A的化学结构式如下式(Ⅰ)所示:
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