CN110452247B - 一种杂萜化合物及其制备方法和应用 - Google Patents
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Abstract
本发明公开了一种杂萜化合物及其制备方法和应用,属于海洋真菌活性成分分析技术领域。所述杂萜化合物的分子式为C25H34O5,其制备方法包括:将经活化的篮状菌属真菌(Talaromyces purpureogenus CX11)接种到培养液中发酵培养;再分离得到菌丝体和发酵液,其中菌丝体加入有机溶剂中浸提,然后用乙酸乙酯或氯仿对浸提液进行萃取;或者,用乙酸乙酯或氯仿对发酵液进行萃取;萃取液经浓缩、分离纯化后,制得杂萜化合物。本发明从海洋篮状菌属真菌的发酵培养物中提取、分离获得了一种具有新颖结构的杂萜化合物,该化合物具有较好的抗病毒活性,可用于制备抗病毒药物,具有良好的开发前景。
Description
技术领域
本发明涉及海洋真菌活性成分分析技术领域,具体涉及一种杂萜化合物及其制备方法和应用。
背景技术
海洋微生物相对于陆地微生物而言,能够耐受海洋特有的如高盐、高压、低氧、低光照等极端条件,生活环境的特异性导致海洋微生物在物种、基因组成和生态功能上的多样性。海洋环境的特殊性加上海洋微生物资源获取技术的进步又给海洋微生物源天然药源化合物的研究带了前所未有的机遇。
海洋微生物中的海洋真菌是活性次级代谢产物的丰富的来源,海洋真菌的次级代谢产物70-80%具有生物活性,包括小分子内脂化合物;真菌毒素;对中枢神经系统有抑制活性的新物质;1-十二醇、不饱和烃、酸、酯;可抑制植物和人的真菌病毒作用于真菌细胞壁合成新靶位的脂肽类抗生素。以海洋真菌为原料发现具有特定结构类型的天然产物对于海洋药物的研发具有重要意义。
如专利文献CN 108485987 A公开了从威海附近海域的底泥中分离一株对多株病原菌均有抗菌活性的海洋真菌WH4-2,经ITS全序列分析鉴定为柄篮状菌,该菌具有高效的抗副溶血弧菌活性,且活性物质“含异戊烯基的二苯并氧杂环庚酮类化合物”的产量较大,有望应用于新型抗副溶血弧菌的药物开发。
目前关于篮状菌属真菌(Talaromyces)的化学成分研究较少。中科院昆明植物所2011年从云南红豆杉内生真菌Talaromyces sp.TIBF中分离得到5α,6α-环氧-24(R)-甲基胆甾-7,22-二烯-3β-醇、醌茜素、苔色酸和间甲基苯酚,Bok(1999)等在活性跟踪下从Cordyceps sinensis分离得到的5α,6α-环氧-24(R)-甲基胆甾-7,22-二烯-3β-醇具有较好的抗肿瘤活性(李良群,杨艳光,曾英,邹澄,赵沛基,广西植物,云南红豆杉内生真菌Talaromyces sp.TIBF的化学成分研究,2011,31(5),pp 699-701)。
但是迄今还未查到有文献报道从篮状菌属真菌中分离得到抗病毒的化合物。
发明内容
本发明的目的在于从海洋篮状菌属真菌(Talaromyces)中提取获得具有药用价值的天然活性物质。
为实现上述目的,本发明提供了一种杂萜化合物,结构式如式(Ⅰ)所示:
本发明提供了一种篮状菌属真菌,命名为篮状菌属真菌CX11(Talaromycespurpureogenus CX11),保藏号为:CCTCC NO:M2018338。
所述的篮状菌属真菌CX11(Talaromyces sp.CX11)为海洋植物的附生真菌,该菌株于2018年6月4日保藏于中国典型培养物保藏中心。
本发明还提供了所述的杂萜化合物的制备方法,包括以下步骤:
(1)将所述的篮状菌属真菌CX11(Talaromyces purpureogenus CX11)经活化后接种于培养液中,进行发酵培养;
(2)发酵培养结束后,分离得到菌丝体和发酵液;
(3)将菌丝体加入有机溶剂中浸提,分离得到浸提液,浸提液浓缩后用蒸馏水混悬,得到水混悬液,然后用乙酸乙酯或氯仿对水混悬液进行萃取,萃取液经浓缩、分离纯化后,制得杂萜化合物;
所述的有机溶剂为甲醇、乙醇、乙酸乙酯和丙酮中的一种或两种。
或者,用乙酸乙酯或氯仿对发酵液进行萃取,萃取液经浓缩、分离纯化后,制得杂萜化合物。
步骤(1)中,对篮状菌属真菌CX11(Talaromyces sp.CX11)进行发酵培养。
篮状菌属真菌CX11(Talaromyces sp.CX11)为真菌,采用常规的PDA液体培养基或麦芽汁培养基即可用于发酵培养。为了更好地模拟海洋环境,给微生物生长代谢提供足够的营养成分,优选地,以体积1L计,所述的培养液包括以下原料:淀粉1-5g、麸皮10-20g、酵母膏3-15g、KH2PO41-8g,MgSO4·7H2O 0.1-0.8g,余量为海水;
或者,以体积1L计,所述的培养液包括以下原料:马铃薯200-600g、蛋白胨2-10g、酵母膏1-5g、葡萄糖5-20g、余量为海水;培养液初始pH值为6.0-7.0;
或者,以体积1L计,所述的培养液包括以下原料:蔗糖10-40g、玉米粉5-20g、NaNO31-4g、酵母膏1-4g、KH2PO4 0.2-0.8g、MgSO4·7H2O0.2-1g、KCl 0.2-1g、FeSO4 0.001-0.005g,余量为人工海水。
发酵培养的条件为20-30℃静态培养10-40天。所述静态培养方式即不进行摇瓶培养。
作为优选,发酵培养的温度为22-26℃。更优选为25℃培养20天,该条件下所述杂萜化合物的产量最高。
步骤(2)中,分离获得菌丝体和发酵液,所述的菌丝体和发酵液中均能提取分离得到所述杂萜化合物。
其中,利用菌丝体获取杂萜化合物时,将菌丝体置于有机溶剂中浸泡7-14天,菌丝体充分破壁,使胞内物质有效溶出。
利用发酵液获取杂萜化合物时,将发酵液与硅藻土搅拌后,采用乙酸乙酯回流进行萃取。
所述的分离纯化可以为:对萃取液进行正相硅胶柱层析分离,所得馏分再进行重结晶、反相硅胶柱层析或高效液相色谱分离。通过多步分离纯化,能获得纯度较高的杂萜化合物。
采用正相硅胶柱层析分离时,洗脱剂可采用石油醚、正己烷、乙酸乙酯、醇和水中的一种或多种混合物,对萃取液进行梯度洗脱。
作为优选,所述分离纯化包括:对萃取液进行正相硅胶柱层析分离,依次以体积比9:1、5:1、1:1、1:3、1:9的石油醚/乙酸乙酯混合液和乙酸乙酯进行梯度洗脱,收集体积比5:1的石油醚/乙酸乙酯混合液洗脱出的馏分。
对发酵液萃取的萃取液经上述的正相硅胶柱层析分离后,再进行反相硅胶柱层析/高效液相色谱分离。
本发明研究表明,利用上述方法从篮状菌属真菌CX11(Talaromyces sp.CX11)发酵培养物中分离得到的杂萜化合物具有较好的抗病毒活性,因此,本发明还提供了所述的杂萜化合物在制备抗病毒药物中的应用。
作为优选,所述病毒为伪狂犬病毒。
所述药物以本发明的杂萜化合物为主要活性成分,添加药剂学上可接受的辅料制成,可按照药剂学上记载的制剂制备方法制成制剂。所述的制剂可以为注射液、滴注液、粉针剂、颗粒剂、片剂、冲剂、散剂、口服液、糖衣片剂、薄膜衣片剂、肠溶衣片剂、口含剂、颗粒剂、丸剂、膏剂、丹剂、喷雾剂、滴丸剂、崩解剂、口崩片、微丸等。
本发明具备的有益效果:
(1)本发明利用杂萜的极性差异从海洋真菌的发酵培养物中提取、分离获得了一种具有新颖结构的杂萜化合物,该方法操作简便、提取得率高、产物纯度高,适合规模化生产。
(2)通过体外抗病毒试验,表明本发明提供的杂萜化合物具有较好的体外抗病毒活性,针对伪狂犬病毒(Pseudorabies virus,PRV)其CC50值为3.35μM,可用于制备抗病毒药物,具有良好的开发前景。
附图说明
图1为本发明杂萜化合物的结构式。
图2为本发明杂萜化合物的1H NMR图谱(in CDCl3)。
图3为本发明杂萜化合物的13C NMR图谱(in CDCl3)。
图4为本发明杂萜化合物的HSQC图谱(in CDCl3)。
图5为本发明杂萜化合物的HMBC图谱(in CDCl3)。
具体实施方式
下面结合具体实施例对本发明作进一步说明。
实施例1真菌分离
大型海洋植物采自浙江沿海,样品带回实验室后,首先用无菌海水冲洗3次,去掉非附着微生物;将植物置于离心管中,然后加入少量海水,用旋涡振荡器振荡10min,再将去除藻体后的悬液离心20min(5000r/min),倾去上清液;沉淀物用少量无菌海水悬浮,取0.1mL涂布于马丁氏培养基(含庆大霉素8U/L)平板;室温20℃下培养10d后,挑取单菌落经划线纯化后移于斜面4℃下保存备用。
实施例2篮状菌属真菌的鉴别
分离的真菌在PDA上培养,对菌株进行18S rDNA基因序列测定,该菌株的18S rDNA序列如SEQ ID No.1所示。
根据菌株的形态特征和18S rDNA序列分析结果,鉴定该菌株为篮状菌属真菌(Talaromyces sp.)。并将其命名为篮状菌属真菌CX11(Talaromyces purpureogenusCX11),于2018年6月4日保藏于中国典型培养物保藏中心,保藏地址:中国、武汉、武汉大学,保藏号为:CCTCC NO:M 2018338,于2018年6月18日鉴定存活。
实施例3篮状菌属真菌的发酵培养
将经活化的篮状菌属真菌制成孢子悬浮液,再接种到培养液中,于25℃静态发酵培养20天。
其中,培养液配方为:淀粉3g,麸皮14g,酵母膏6g,KH2PO45g,MgSO4·7H2O 0.4g,海水1000mL。
实施例4篮状菌属真菌的发酵培养
将经活化的篮状菌属真菌制成孢子悬浮液,再接种到培养液中,于24℃静态发酵培养20天。
其中,培养液配方为:马铃薯400g,蛋白胨6g,酵母膏2g,葡萄糖10g,海水1000mL;培养液的初始pH值为6.5。
实施例5篮状菌属真菌的发酵培养
将经活化的篮状菌属真菌制成孢子悬浮液,再接种到培养液中,于25℃静态发酵培养20天。
其中,培养液配方为:蔗糖25g,玉米粉10g,NaNO3 2g,酵母膏2g,KH2PO4 0.5g,MgSO4·7H2O 0.5g,KCl 0.5g,FeSO4 0.001g,人工海水1000mL。
实施例6杂萜化合物的制备
篮状菌属真菌发酵培养后,取5L发酵培养液,离心取沉淀得到菌丝体;菌丝体用甲醇浸泡1周,浸泡液经浓缩后用1L蒸馏水混悬,水混悬液合并,用6L乙酸乙酯萃取,乙酸乙酯萃取液经浓缩得到浸膏10g;用硅胶(100目,100g)拌样,进行正相硅胶柱层析分离(200-300目,100g;硅胶柱尺寸L 50mm,),依次以体积比9:1、5:1、1:1、1:3、1:9的石油醚/乙酸乙酯混合液和乙酸乙酯进行梯度洗脱,每次300mL;TLC检测馏分;收集5:1馏分再用甲醇重结晶。
实施例7杂萜化合物的制备
篮状菌属真菌发酵培养后,取5L发酵培养液,离心取上清得到发酵液;发酵液浓缩,用10g硅藻土拌样,1L乙酸乙酯回流,进行正相硅胶柱层析分离(200-300目,1kg;硅胶柱尺寸L 50mm,),依次以体积比9:1、5:1、1:1、1:3、1:9的石油醚/乙酸乙酯混合液和乙酸乙酯进行梯度洗脱,收集5:1馏分;分段后用反相硅胶柱层析,洗脱剂为甲醇/水(1:9-9:1),依次以体积比1:9、2:8、3:7、4:6、5:5、6:4、7:3、8:2、9:1的甲醇/水混合液进行梯度洗脱,收集5:5馏分;继而用高效液相色谱分离,流动相为:甲醇/水(60:40),流速为10mL/min,高效液相色谱的检测波长为254nm,保留时间34分钟的峰用甲醇重结晶。
实施例8杂萜化合物的结构鉴定
采用HPLC对制得的化合物进行纯度鉴定,纯度大于98%的样品运用质谱和核磁共振技术进行结构鉴定,核磁共振用Bruker AVANCE DRX-500NMR Sectrometer测定,TMS作内标;高分辨质谱FTICRMS用Bruker Apex Spectrometer测定;电喷雾质谱ESI-MS用BrukerEsquire 3000plus Spectrometer测定。
根据化合物的一维NMR分析结果(见表1)和二维NMR分析结果(见图2-5),可知,该物质为杂萜化合物,分子式为C25H34O5,结构如图1所示:
表1杂萜化合物的NMR数据
实施例9杂萜化合物抗病毒活性分析
1 接种细胞
1.1 取Vero细胞一瓶,倾去旧培养液,在贴壁细胞对侧加入PBS清洗两次,每次4mL。加入含有EDTA的胰酶1mL,置于5%CO2恒温培养箱消化45S,弃去胰酶,加入6mL完全培养,反复吹打,转移至10mL离心管中,1000rpm离心5min),弃去上清,加入6mL完全培养悬。
1.2 蜗旋混匀后取10μl细胞悬液计数:131-221-366-464,以460计,细胞浓度为11.5×105个/mL,总细胞数69×105个。
1.3 取上述浓度为11.5×105个/mL的细胞悬液0.65mL,即7.5×105个进行传代。
1.4 Vero细胞浓度调整:取11.5×105个/mL的Vero细胞悬液2mL,加含10%小牛血清的DMEM培养液28mL,制成浓度为0.75×105个/mL的细胞稀释液30mL。
1.5 将上述制备的细胞稀释液接种于2块96孔细胞板上,每孔100μL,于37℃,5%CO2的细胞培养箱中孵育24h至形成单层。
2 实验病毒的稀释
2.1 病毒母液制备:疫苗稀释液(5头份/mL):25头份疫苗粉末加入4mL的PBS,涡旋溶解,分装于200μL EP管中,-80℃保存备用。
2.2_10-2PrV稀释液:从-80℃取出一管分装的PrV母液,吸取50μL置于10mL离心管中,加入DMEM 4.95mL,混匀,制得10-2的病毒稀释液5mL。
2.3 100TCID50PrV稀释液:取10-2的PrV稀释液0.6mL置于50mL离心管中,加入DMEM培养液31.8mL,制成100TCID50 PrV稀释液33mL。
3 细胞攻毒
取出96孔板甩弃原来板中培养液,第1列加入DMEM。其余每孔加入100TCID50 PrV稀释液100μL,于37℃,5%CO2的细胞培养箱中孵育2h。
4 药物稀释液的制备
于离心管中,根据前期确定的药物稀释浓度,先加药物储备液,再加DMEM培养液,制备最高浓度的药物稀释液。然后,倍比稀释制成5个不同浓度的稀释液。
5 细胞给药
取出步骤3中经细胞攻毒后的96孔板甩弃原来板中培养液,孔加入不同浓度药物100μL,第1、12列加入DMEM。于37℃,5%CO2的细胞培养箱中孵育2h。
6 加维持液
取含10%FCS的DMEM完全培养液6mL置于加样槽中,加入DMEM培养液24mL,用1mL移液枪吹打混匀,制成含2%FCS的维持液30mL。
取出96孔板,弃去板内原液(甩的时候要小心,甩完直接倒扣在纸巾上,尽量使孔中原液流干净),采用按100μL/孔加入含2%FCS的维持液100μL。37℃,5%CO2的细胞培养箱培养。
7 CPE观察与MTT检测
取出96孔板,对细胞状态进行显微镜拍照。
取出细胞培养板,各孔加入50μL的MTT溶液,置于培养箱中孵育4h。
将96孔细胞培养板从培养箱中取出,2000r/min离心5min,甩去上清,用纸吸干残留液体,加含4%1N盐酸的DMSO 150μl/孔,避光震荡使结晶溶解,于酶标仪492nm处测定OD值。
表2杂萜化合物I的CC50
实施例10含杂萜化合物滴丸制剂的制备
取0.5g杂萜化合物与10.5g聚乙二醇-6000混合均匀,加热熔融,化料后移至滴丸滴灌中,药液滴至6~8℃液体石蜡中,除油,制得滴丸300粒。
实施例11含杂萜化合物冻干粉针剂的制备
取杂萜化合物0.5g、葡萄糖4.5g、硫代硫酸钠0.9g和蒸馏水1000ml,上述组分混合均匀后,冷冻干燥,分装400支,即得。
序列表
<110> 浙江大学
<120> 一种杂萜化合物及其制备方法和应用
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 558
<212> DNA
<213> 篮状菌属真菌CX11(Talaromyces purpureogenus CX11)
<400> 1
ggccccggga tacgggtcct cgtggacgac ctcccaccct tgtctcttgt ataccctgtt 60
gctttggcgg gcccactggg aatccccagt cgccgagggg cactgtgccc ctgggcccgt 120
gcccgccaga gcgcccttga accctaatga agatggactg tctgagcatg attgataata 180
atcaaaactt tcaacaatgg atctcttggt tccggcatcg atgaagaacg cagcgaaatg 240
cgataagtaa tgtgaattgc agaattccgt gaatcatcga atctttgaac gcacattgcg 300
ccccctggca ttccgggggg catgcctgtc cgagcgtcat ttctgccctc aagcacggct 360
tgtgtgttgg gtgtggtccc cctggggacc tgcctgaaag gcagtggcga cgcccgccta 420
ggtcctcgag cgtatggggc tttgtcaccc gctcgggaag gatctacggg cgttggtctt 480
ccatattttt ttccacggtt gacctcggat caggtaggag ttacccgctg aacttaagca 540
tatcaataag cggaggaa 558
Claims (6)
2.一种篮状菌属真菌,其特征在于,命名为篮状菌属真菌CX11(Talaromycespurpureogenus CX11),保藏号为:CCTCC NO:M 2018338。
3.如权利要求1所述的杂萜化合物的制备方法,其特征在于,包括以下步骤:
(1)将权利要求2所述的篮状菌属真菌CX11(Talaromyces purpureogenus CX11)经活化后接种于培养液中,进行发酵培养;
(2)发酵培养结束后,分离得到菌丝体和发酵液;
(3)将菌丝体加入有机溶剂中浸提,分离得到浸提液,浸提液浓缩后用蒸馏水混悬,得到水混悬液,然后用乙酸乙酯或氯仿对水混悬液进行萃取,萃取液经浓缩、分离纯化后,制得杂萜化合物;
所述的有机溶剂为甲醇、乙醇、乙酸乙酯和丙酮中的一种或两种;
或者,用乙酸乙酯或氯仿对发酵液进行萃取,萃取液经浓缩、分离纯化后,制得杂萜化合物;
步骤(1)中,以体积1L计,所述的培养液包括以下原料:淀粉1-5g、麸皮10-20g、酵母膏3-15g、KH2PO4 1-8g,MgSO4·7H2O 0.1-0.8g,余量为海水;
或者,以体积1L计,所述的培养液包括以下原料:马铃薯200-600g、蛋白胨2-10g、酵母膏1-5g、葡萄糖5-20g、余量为海水;培养液初始pH值为6.0-7.0;
或者,以体积1L计,所述的培养液包括以下原料:蔗糖10-40g、玉米粉5-20g、NaNO3 1-4g、酵母膏1-4g、KH2PO4 0.2-0.8g、MgSO4·7H2O 0.2-1g、KCl 0.2-1g、FeSO4 0.001-0.005g,余量为人工海水;
发酵培养的条件为20-30℃静态培养10-40天;
步骤(3)中,所述分离纯化包括:对萃取液进行正相硅胶柱层析分离,依次以体积比9:1、5:1、1:1、1:3、1:9的石油醚/乙酸乙酯混合液和乙酸乙酯进行梯度洗脱,收集体积比5:1的石油醚/乙酸乙酯混合液洗脱出的馏分。
4.如权利要求3所述的制备方法,其特征在于,对发酵液萃取的萃取液经正相硅胶柱层析分离后,再进行反相硅胶柱层析/高效液相色谱分离。
5.如权利要求1所述的杂萜化合物在制备抗病毒药物中的应用。
6.如权利要求5所述的应用,其特征在于,所述病毒为伪狂犬病毒。
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