CN115403590A - 一种口山酮类化合物及其分离方法和应用 - Google Patents
一种口山酮类化合物及其分离方法和应用 Download PDFInfo
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- CN115403590A CN115403590A CN202211001161.3A CN202211001161A CN115403590A CN 115403590 A CN115403590 A CN 115403590A CN 202211001161 A CN202211001161 A CN 202211001161A CN 115403590 A CN115403590 A CN 115403590A
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- compound
- crude extract
- culture medium
- xanthone
- austocystin
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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Abstract
本发明提供了一种新的口山酮类化合物及其分离方法和应用,该口山酮类化合物是从内生真菌Aspergillus puniceus中分离得到。利用正相硅胶柱层析法和半制备液相色谱法对该菌的发酵产物进行分离,得到1个口山酮类化合物1,通过NMR、MS、X‑ray等技术鉴定其化学结构,经检索为新化合物,命名为austocystin R。还分离得到一个已知口山酮类化合物2(austocystin D),2个口山酮类化合物经α‑葡萄糖苷酶和PTP1B抑制活性测试,其中化合物1(austocystin R)在浓度为1μg/ml时,具有不同程度的抑制活性。本发明的化合物制备方法简单,且化合物austocystin R同时具有良好的α‑葡萄糖苷酶和PTP1B抑制作用,其中对PTP1B的抑制活性强于阳性药,可作为抗糖尿病双靶点的先导化合物,具有较好的应用前景。
Description
技术领域
本发明涉及一种内生真菌提取物,具体为一种口山酮类化合物及其分离方法和应用。
背景技术
药用植物中蕴含着大量的内生真菌,这些内生真菌与宿主之间具有紧密的生态关系,产生的次生代谢产物在病虫害的生物防治、医药工业上的用途和范围逐渐增大,成为寻找新的天然活性产物的重要方向[Strobel G,Daisy B,Castillo U,et al.Naturalproducts from endophytic microorganisms.Journal Of Natural Products.2004,67(2):257-268.]。文献研究表明,内生真菌Aspergillus puniceus中含有二酮哌嗪生物碱和口山酮两类结构新颖的化合物[Liang X,Zhang X,Lu X,et al.Diketopiperazine-TypeAlkaloids from a Deep-Sea-Derived Aspergillus puniceus Fungus and TheirEffects on Liver X Receptor alpha.Journal of Natural Products.2019,82(6):1558-1564.]。口山酮广泛存在于植物中,而微生物中报道相对较少,植物来源的口山酮被报道具有保肝、抗肿瘤、治疗心血管疾病等多种活性[Jiang DJ,Dai Z,LiYJ.Pharmacological effects of xanthones as cardiovascular protectiveagents.Cardiovasc Drug Rev.2004.22:91-102.]。
糖尿病已成为继心脑血管疾病和肿瘤后影响人类健康的第三大疾病,全世界患者高达4.63亿,其中90%的糖尿病为2型糖尿病。2型糖尿病是以胰岛素抵抗和/或胰岛素细胞功能衰竭为主要特征的一系列代谢紊乱综合征,常伴随多种急慢性并发症。80%的2型糖尿病患者同时伴有肥胖症[中华医学会糖尿病学分会.中国2型糖尿病防治指南(2020年版).中华糖尿病杂志,2021,13(4):315-409.]。但现阶段药物无法有效阻止胰岛β细胞的坏死,且副作用较多,如长期服用降糖药二甲双胍、α-葡萄糖苷酶抑制剂易使糖尿病患者产生腹胀、恶心、呕吐等严重的胃肠道副反应,甚至对患者的肾脏和肝脏造成严重损伤[康文艺,张丽,宋艳丽.滇丁香中抑制α-葡萄糖苷酶活性成分研究.中国中药杂志,2009,34(4):406-409.]。采用多靶点药物治疗可提高治疗效果,避免联合用药产生的一些不良的相互作用,具有较大的研究价值。
发明内容
本发明提供一种口山酮类化合物及其分离方法和应用,该方法具有产品收率高、质量好、操作简单、环境友好等优点。
本发明的技术方案是,该化合物命名为austocystin R,具体结构式如下化合物1,
进一步地,化合物1是从内生真菌Aspergillus puniceus中分离得到的。
本发明还涉及所述口山酮类化合物的分离方法,其特征在于,包括以下步骤:
S1、将Aspergillus puniceus菌株接入马铃薯葡萄糖琼脂培养基(PDA固体培养基)中复苏,培养得到种子菌块,挑选种子菌块接入马铃薯葡萄糖水培养基(PDB培养基)中培养得到种子液;再将种子液接种到马铃薯葡萄糖水培养基(PDB培养基)中摇床培养得到发酵产物;
S2、将S1中的发酵产物过滤得到菌丝体和发酵液;菌丝体干燥后加入丙酮浸泡,超声提取得到粗提物1,发酵液采用乙酸乙酯萃取得到粗提物2;将粗提物1和粗提物2合并后得到发酵粗提物;
S3、将S2所得发酵粗提物和正相硅胶混合拌成粉末,通过正相硅胶柱干法上样、湿法过柱,采用二氯甲烷-甲醇混合液进行梯度洗脱,共得到8个流份Fr.A~G;将流份Fr.C利用半制备高效液相色谱仪进行分离,色谱柱采用C18反相柱,流动相为乙腈/水体积比为70:30的混合溶剂,在保留时间为12分钟处收集峰,即得到化合物1。在15分钟处收集峰,即得到化合物2。
进一步地,S1中PDA固体培养基中培养时间为3~5天;PDB发酵培养基中培养时间为3~5天;PDB培养基中培养时间为14~20天,在28~30℃,以100~120 rpm进行摇床培养。
进一步地,S2中菌丝体处理时,在45℃条件下干燥,加入丙酮浸泡过夜,在35~45℃超声提取30~40min,超声功率为60~80W,反复提取3次得到粗提物1;发酵液采用乙酸乙酯萃取3遍后得到粗提物2。
进一步地,S3中发酵粗提物和200~300目的正相硅胶按1:1的比例制备粉末。
进一步地,S3梯度洗脱时依次采用二氯甲烷-甲醇体积比为100:0、50:1、40:1、30:1、10:1、5:1、1:1、0:1共8种洗脱液依次进行洗脱,得到8个流份Fr.A~G。
本发明还涉及所述口山酮类化合物在制备治疗糖尿病药物中的应用。
进一步地,口山酮类化合物的浓度为1μg/mL。
本发明还涉及所述口山酮类化合物在抑制α-葡萄糖苷酶和/或PTP1B中的应用。
α-葡萄糖苷酶和PTP1B是其重要的靶酶,其中α-葡萄糖苷酶抑制剂可抑制小肠内α-葡萄糖苷酶的活性,延缓或抑制葡萄糖在肠道的吸收,从而有效降低餐后高血糖;PTP1B可通过介导内质网(ER)应激引起胰岛素抵抗,通过强化瘦素信号来提高脂肪代谢水平,进而降低体质量,通过PTP1B抑制剂可能减轻甚至逆转肥胖症患者对胰岛素和瘦素的抵抗,对于伴有肥胖的2型糖尿病患者的治疗具有重大意义。
本发明公开了一种口山酮类化合物(化合物1austocystin R),其产自内生真菌Aspergillus puniceus,利用正相硅胶柱层析法和半制备液相色谱法制备得到,制备方法简单,通过NMR、MS、X-ray等技术鉴定其化学结构,经检索为新化合物。经α-葡萄糖苷酶和PTP1B抑制活性测试,在浓度为1μg/ml时,化合物1(austocystin R)同时具有较好的α-葡萄糖苷酶(抑制率为40.09%)和PTP1B(抑制率为71.06%)抑制作用,其中对PTP1B的抑制活性强于阳性药(抑制率为52.65%),可作为抗糖尿病双靶点的先导化合物,具有较好的应用前景。
本发明提供的化合物1(austocystin R),能够同时抑制α-葡萄糖苷酶和PTP1B两个靶点,一方面可降低餐后血糖,另一方面可增强胰岛素的敏感性,有利于降低肥胖型2型糖尿病患者的体质量。
附图说明
图1为化合物1的结构式;
图2化合物1的HMBC和1H-1H COSY相关图;
图3为化合物1的X-Ray结构;
图4为化合物1的1H-NMR图(溶剂为DMSO-d6);
图5为化合物1的1H-NMR图(溶剂为MeOD-d4);
图6为化合物1的13C-NMR图(溶剂为DMSO-d6);
图7为化合物1的DEPT135图(溶剂为DMSO-d6);
图8为化合物1的1H-1H COSY图(溶剂为DMSO-d6);
图9为化合物1的HSQC图(溶剂为DMSO-d6);
图10为化合物1的HMBC图(溶剂为DMSO-d6);
图11为化合物1的NOESY图(溶剂为DMSO-d6)。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。
除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。除非特别说明,本发明所用试剂和材料均为市购。内生真菌Aspergillus puniceus可从市面上购买,本发明中是从明舟生物公司(商品货号:163488)购买获得。
实施例1:
将冻藏的该株真菌Aspergillus puniceus接入PDA固体培养基中复苏,培养3天后得到种子菌块,挑选0.5cm×0.5cm大小的种子菌块分别接入3瓶(500mL锥形瓶,每瓶中培养基装样量150mL)PDB发酵培养基中培养3天得到种子液;吸取2mL种子液到500mL锥形瓶中(每瓶PDB培养基装样量150mL),共接种30瓶。在28~30℃,120rpm条件下摇床培养14天后得到发酵产物。
上述发酵产物过滤得到菌丝体和发酵液;菌丝体经45℃条件下干燥后加入丙酮浸泡过夜,超声(45℃、60W)提取30min,反复提取3次得到粗提物1,发酵液采用乙酸乙酯萃取3遍后得到粗提物2;将粗提物1和粗提物2合并后得到发酵粗提物5g。
发酵粗提物和正相硅胶(200~300目)1:1的比例,将发酵粗提物样品拌成粉末。通过正相硅胶柱(10cm×70cm),干法上样、湿法过柱,采用二氯甲烷-甲醇(体积比,100:0、50:1、40:1、30:1、10:1、5:1、1:1、0:1)梯度洗脱,共得到8个流份Fr.A~G。将流份Fr.C采用二氯甲烷-甲醇体积比40:1洗脱,利用半制备高效液相色谱仪进行分离,色谱柱采用C18反相柱,流动相为乙腈/水体积比为70:30的混合溶剂,在保留时间为12分钟处收集峰,即得到化合物1(9mg)。在15分钟处收集峰,即得到化合物2。
实施例2:化合物1和2的结构的鉴定
化合物1:结晶状(二氯甲烷)。旋光数据[α]25 D+7.4°(c 0.10,甲醇),UV(甲醇)λmax=203,252,280,350nm;由高分辨质谱HR-ESI-MS:m/z 451.0989[M+Na]+(计算值为:451.1000),确定其分子式为C22H20O9,不饱和度为13。在1H-NMR谱中(表1),化合物1显示两个活泼质子信号δH 12.18(br.s,1-OH)和11.63(br.s,8-OH),两个烯烃质子信号δH 5.63(d,J=2.8Hz,H-3')和6.78(d,J=2.3Hz,H-4'),两个苯环邻位取代的质子信号δH 7.82(d,J=8.5Hz,H-6)和6.83(d,J=8.5Hz,H-7),两个甲基的质子信号δH 1.31(s,H-4”)和1.21(s,H-5”)。在13C-NMR和DEPT135谱中(表1),显示22个碳信号,包括14个烯基或芳香族碳信号、2个甲基碳信号、1个羰基碳信号、3个连氧碳信号、1个半缩醛碳信号和1个亚甲基碳信号。这些数据与austocystin类型化合物F02Z-1593J[路新华,郑智慧,可爱兵,等.一株真菌产生的强抗癌活性新的山酮类化合物及其作用机制的研究.2008年中国药学会学术年会暨第八届中国药师周论文集.2008]数据非常相似,但是文献中的化合物F02Z-1593J没有确定最终的立体构型,特别是C-1”的构型。仔细比较化合物1和化合物F02Z-1593J的1H-NMR数据,发现H-1”和H-2”的化学位移和偶合常数有区别,我们换用和文献一致的氘代溶剂(氘代甲醇),同样发现2个化合物的H-1”和H-2”的化学位移和偶合常数有区别,说明这2个化合物的C-1”的构型不同,通过HMBC和1H-1H COSY谱(图2),验证了化合物1的平面结构,为了进一步解析其立体结构,我们首次培养出austocystin类型化合物的单晶(图3),根据X-Ray单晶测定(Cu靶)结果(CCDC编号为2184354),Flack和Hooft常数分别为0.14(13)和0.14(12),确定C-1'、C-2'、C-1”的构型均为R(图1)。我们命名它为austocystin R。
表1.化合物1的1H-NMR(400MHz)和13C-NMR(100MHz)数据(溶剂为DMSO-d6)
化合物2:通过与文献(Liang X,Huang Z H,Ma X,et al.Mycotoxins asinhibitors of protein tyrosine phosphatases from the deep-sea-derived fungusAspergillus puniceus SCSIO z021.Bioorganic Chemistry,2020,107:104571.)的核磁共振数据比对,发现化合物2为已知化合物austocystin D。
实施例3
实施例3-1:萄糖苷酶抑制活性测试
α-葡萄糖苷酶的测定方法参照文献[Tao Y,Zhang Y,Cheng Y,et al.Rapidscreening and identification ofα-glucosidase inhibitors from mulberry leavesusing enzyme-immobilized magnetic beads coupled with HPLC/MS and NMR[J].Biomed Chromatogr,2013,27(2):148-155.]进行。将实施例1所得化合物1(浓度为3μg/mL,溶剂为DMSO)和化合物2(浓度为3μg/mL,溶剂为DMSO)各40μL分别加入到40μL反应缓冲溶液(PBS)中,加入20μLα-葡萄糖苷酶溶液(2U/mL)混合在每个孔中,使用37℃的块加热器预热反应混合物15min,加入20μL反应底物PNPG(5mM),于37℃条件下反应15min,加入Na2CO3溶液(80μL,0.2M)以停止反应。在405nm处记录吸光度。设置酶活性组(酶+反应缓冲液+底物)、酶空白组(反应缓冲液+反应底物)、样品组(样品+反应缓冲液+酶+反应底物)、样品空白组(样品+反应缓冲液+反应底物),以阿卡波糖溶液作为阳性对照。
实施例3-2:PTP1B抑制活性测试
PTP1B的测定方法参照文献[Xu J,Cao J Q,Yue J Y,et al.New triterpenoidsfrom acorns of Quercus liaotungensis and their inhibitory activity againstα-glucosidase,α-amylase and protein-tyrosine phosphatase 1B.J Funct Foods,2018,41:232-239;哈及尼沙,阿卜杜热合曼·努如拉,李改茹,等.榅桲籽的化学成分及其PTP1B抑制活性.药学学报,2019,54(3):510-513.]进行。将化合物1(浓度为21μg/mL,溶剂为DMSO)和化合物2(浓度为21μg/mL,溶剂为DMSO)各10μL分别加入到170μL反应缓冲溶液中,其由50mM柠檬酸(pH 7.4),50mM NaCl,2mM二硫代糖醇(DTT),1.1mM EDTA组成,加入20μL重组PTP1B溶液(1mg/mL,1μL)混合在每个孔中,使用37℃的块加热器预热反应混合物15min,加入10μL反应底物对硝基苯基磷酸酯pNPP(33mM),于37℃条件下反应15min,加入NaOH溶液(10μL,0.1M)以停止反应。在405nm处记录吸光度。设置酶活性组(酶+反应缓冲液+底物)、酶空白组(反应缓冲液+反应底物)、样品组(样品+反应缓冲液+酶+反应底物)、样品空白组(样品+反应缓冲液+反应底物),以正钒酸钠水溶液作为阳性对照。
化合物1和2对α-葡萄糖苷酶和PTP1B抑制活性结果见表2。
表2
上述的实施例仅为本发明的优选技术方案,而不应视为对于本发明的限制,本申请中的实施例及实施例中的特征在不冲突的情况下,可以相互任意组合。本发明的保护范围应以权利要求记载的技术方案,包括权利要求记载的技术方案中技术特征的等同替换方案为保护范围。即在此范围内的等同替换改进,也在本发明的保护范围之内。
Claims (10)
2.根据权利要求1所述的口山酮类化合物,其特征在于:化合物1是从内生真菌Aspergillus puniceus中分离得到的。
3.权利要求1或2所述口山酮类化合物的分离方法,其特征在于,包括以下步骤:
S1、将Aspergillus puniceus菌株接入马铃薯葡萄糖琼脂培养基(PDA固体培养基)中复苏,培养得到种子菌块,挑选种子菌块接入马铃薯葡萄糖水培养基(PDB培养基)中培养得到种子液;再将种子液接种到PDB培养基中摇床培养得到发酵产物;
S2、将S1中的发酵产物过滤得到菌丝体和发酵液;菌丝体干燥后加入丙酮浸泡,超声提取得到粗提物1,发酵液采用乙酸乙酯萃取得到粗提物2;将粗提物1和粗提物2合并后得到发酵粗提物;
S3、将S2所得发酵粗提物和正相硅胶混合拌成粉末,通过正相硅胶柱干法上样、湿法过柱,采用二氯甲烷-甲醇混合液进行梯度洗脱,共得到8个流份Fr.A~G;将流份Fr.C利用半制备高效液相色谱仪进行分离,色谱柱采用C18反相柱,流动相为乙腈/水体积比为70:30的混合溶剂,在保留时间为12分钟处收集峰,即得到化合物1。
4.根据权利要求3所述的分离方法,其特征在于:S1中PDA固体培养基中培养时间为3~5天;PDB发酵培养基中培养时间为3~5天;PDB培养基中培养时间为14~20天,在28~30℃,以100~120rpm进行摇床培养。
5.根据权利要求3所述的分离方法,其特征在于:S2中菌丝体处理时,在45℃条件下干燥,加入丙酮浸泡过夜,在35~45℃超声提取30~40min,超声功率为60~80W,反复提取3次得到粗提物1;发酵液采用乙酸乙酯萃取3遍后得到粗提物2。
6.根据权利要求3所述的分离方法,其特征在于:S3中发酵粗提物和200~300目的正相硅胶按质量比1:1的比例制备粉末。
7.根据权利要求3所述的分离方法,其特征在于:S3梯度洗脱时依次采用二氯甲烷-甲醇体积比为100:0、50:1、40:1、30:1、10:1、5:1、1:1、0:1共8种洗脱液依次进行洗脱,依次得到8个流份Fr.A~G。
8.根据权利要求1或2所述口山酮类化合物1在制备治疗糖尿病药物中的应用。
9.根据权利要求8所述的应用,其特征在于:口山酮类化合物1的浓度为1μg/mL。
10.根据权利要求1或2所述口山酮类化合物1在抑制α-葡萄糖苷酶和/或PTP1B中的应用。
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