CN118084621A - 一类链状多烯邻二醇类化合物及其制备方法和用途 - Google Patents
一类链状多烯邻二醇类化合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明提供了一类链状多烯邻二醇类化合物及其制备方法和用途。本发明人通过对南极曲霉Aspergillus sp.SCSIO 05702液体发酵提取物分离纯化,从中获得了化合物Aspertrienediols A和B。经结构分析,化合物1和2均为新化合物,具体结构如式(Ⅰ)所示。通过对化合物1和2的抗炎活性评价,发现化合物新化合物Aspertrienediol B(2)对脂多糖(LPS)诱导小鼠巨噬细胞株RAW264.7产生的一氧化氮具有显著的抑制作用,同时抑制MCP‑1、IL‑6和TNF‑α等促炎因子的mRNA表达,在相同浓度下,对RAW264.7细胞无细胞毒活性,可以做为抗炎药物开发的先导化合物。
Description
技术领域
本发明属于海洋天然产物化学领域,具体涉及链状多烯邻二醇类化合物及其制备方法和在制备抗炎药物中的应用。
背景技术
特殊海洋生态环境来源的微生物,特别是来自极地、深海、热液等极端环境胁迫,进化出了特殊的代谢途径,可产生显著药理活性的代谢产物,是新药研发的重要来源。目前,从极地等极端环境来源微生物中,获得骨架新颖的活性次生代谢产物已逐渐成为天然药物研究的重要方向之一。极地微生物所面临的独特环境和生态压力是次生代谢物产生和具有多种生物活性化合物出现的主要驱动因素。2018-2020年这三年期间报道了极地来源天然产物有201个,并且新化合物有94个,同样也具有丰富多样的生物活性。在对南极真菌来源的次生代谢产物的研究过程中,我们分离得到一类结构新颖的链状多烯邻二醇类化合物,对脂多糖(LPS)诱导小鼠巨噬细胞株RAW264.7产生的一氧化氮具有显著的抑制作用,且在有效剂量下,未发现有明显细胞毒性,同时抑制MCP-1、IL-6和TNF-α等促炎因子的mRNA表达,不仅为筛选结构新颖、高效低毒的抗炎药物提供了理想侯选化合物,也对开发利用极地等特境微生物资源具有重要意义。
发明内容
本发明的第一个目的是链状多烯邻二醇类化合物Aspertrienediols A和B(1和2)。
本发明的链状多烯邻二醇类化合物,其结构如式(Ⅰ)
本发明的第三个目的是提供如式(Ⅰ)所示的链状多烯邻二醇类化合物在制备抗炎药物中的应用。
优选,所述的链状多烯邻二醇类化合物是化合物2。
本发明的第三个目的是提供曲霉Aspergillussp.SCSIO 05702,保藏编号为:CGMCCNo.10279。
本发明的第四目的是提供上述南极曲霉Aspergillussp.SCSIO 05702在制备上述链状多烯邻二醇类化合物的应用。
本发明的第五个目的是提供一种制备链状多烯邻二醇类化合物的方法,包括以下步骤:
a)制备曲霉Aspergillus sp.SCSIO 05702的发酵培养物。
b)将发酵培养物用大号布氏漏斗将发酵液和菌丝体分离,发酵液用乙酸乙酯萃取,合并乙酸乙酯萃取液,浓缩后得到浸膏A;菌丝体先用丙酮浸提,合并浸提液,浸提液回收丙酮后剩余水混合液用乙酸乙酯萃取,乙酸乙酯萃取液浓缩后得到浸膏B,将浸膏A和浸膏B合并,得到粗提物;粗提物经中压正相硅胶柱层析,二氯甲烷/甲醇从100:0梯度洗脱至0:100,梯度洗脱顺序得5个组分(fr1-fr5),收集二氯甲烷/甲醇体积比为100:0洗脱的馏分fr1;将该馏分进行葡聚糖凝胶Sephadex LH-20层析纯化处理,以二氯甲烷/甲醇体积比1:1作为流动相洗脱,获得4个馏分(fr1-1-fr1-4);馏分fr1-3以220nm波长做检测、采用3mL/min的流速,以乙腈:水(25:75,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1(4.6mg,保留时间tR 10.7min)和化合物2(4.8mg,保留时间tR 16.1min)。
所述的曲霉Aspergillussp.SCSIO 05702的发酵培养物是通过以下方法制备的:将活化的曲霉SCSIO 05702接入种子培养基中,24℃,180rpm,培养3天制得种子液,将种子液以体积百分比5%的接种量接入到发酵培养基中,24℃,静置培养70天,而制得发酵培养物,所述的种子培养基和发酵培养基的配方为每升培养基液体中含有:可溶性淀粉10g、蛋白胨1g。
本发明人通过对南极曲霉Aspergillussp.SCSIO 05702液体发酵提取物分离纯化,从中获得了化合物Aspertrienediols A和B(1和2)。经结构分析,化合物1和2均为新化合物,具体结构如式(Ⅰ)所示。通过对化合物1和2的抗炎活性评价,发现化合物新化合物Aspertrienediol B(2)对脂多糖(LPS)诱导小鼠巨噬细胞株RAW264.7产生的一氧化氮具有显著的抑制作用,同时抑制MCP-1、IL-6和TNF-α等促炎因子的mRNA表达,在相同浓度下,对RAW264.7细胞无细胞毒活性,可以做为抗炎药物开发的先导化合物。
本发明的曲霉Aspergillussp.SCSIO 05702于2015年1月6日保藏于中国普通微生物菌种保藏管理中心(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.10279。
附图说明:
图1:链状多烯邻二醇类化合物1和2主要的1H-1H COSY,HMBC信息;
图2:链状多烯邻二醇类化合物1和2的ECD计算谱图
图3:链状多烯邻二醇类化合物2的抗炎活性(b中每组柱子中由左至右分别为Ctrl、LPS、LPS+化合物2)
具体实施方式
以下结合实施例来进一步解释本发明,但实施例并不对本发明做任何形式的限定。
实施例1:化合物1和2的制备及结构鉴定
1、制备南极曲霉Aspergillus sp.SCSIO 05702的发酵培养物。
每1000mL培养基(种子培养基和发酵培养基)是这样配制的:可溶性淀粉10g、蛋白胨1g,然后溶于适量的水中,用水定容至1000mL,121℃高温灭菌20min,备用。将南极曲霉Aspergillus sp.SCSIO 05702接种到上述培养基中,24℃,180rpm,培养3天制得种子液,将种子液以体积百分比5%的接种量接入到发酵培养基中,24℃,静置培养70天,得到南极曲霉Aspergillus sp.SCSIO 05702的静置培养发酵产物。
2、化合物1和2的分离纯化
上述发酵培养物,用大号布氏漏斗将发酵液和菌丝体分离,发酵液用乙酸乙酯萃取,合并乙酸乙酯萃取液,浓缩后得到浸膏A;菌丝体先用丙酮浸提,合并浸提液,浸提液回收丙酮后剩余水混合液用乙酸乙酯萃取,乙酸乙酯萃取液浓缩后得到浸膏B,将浸膏A和浸膏B合并,得到粗提物;粗提物经中压正相硅胶柱层析,二氯甲烷/甲醇从100:0梯度洗脱至0:100,梯度洗脱顺序得5个组分(fr1-fr5),收集二氯甲烷/甲醇体积比为100:0洗脱的馏分fr1;将该馏分进行葡聚糖凝胶Sephadex LH-20层析纯化处理,以二氯甲烷/甲醇体积比1:1作为流动相洗脱,获得4个馏分(fr1-1-fr1-4);馏分fr1-3(TLC薄层色谱Rf值为0.7,展开剂是二氯甲烷/甲醇=10/1,体积比)以220nm波长做检测、采用3mL/min的流速,以乙腈:水(25:75,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1(4.6mg,保留时间tR 10.7min)和化合物2(4.8mg,保留时间tR16.1min)。
表1. 500MHz 1H and 125MHz 13C NMR spectral data of1 and2 in CD3OD
3、化合物1和2的结构鉴定
对获得的链状多烯邻二醇类化合物1和2进行核磁共振(NMR)、质谱(MS)、圆二色谱(CD)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:淡黄色油状物,高分辨质谱m/z 177.0890[M+Na]+(calcdfor177.0886)建议其分子式为C9H14O2含有3个不饱和度,1H和13C NMR数据见表1,13C NMR结合DEPT-135谱提示其9个碳原子信号包括:1个甲基,2个sp3杂化连氧次甲基,6个sp2杂化的双键次甲基。二维核磁谱图1H-1H COSY(图1)确认了出CH2-1/CH-2/CH-3/CH-4/CH-5/CH-6/CH-7/CH-8/CH3-9一个独立的自选耦合体系。HMBC的关键相关信息(图1)(H-5与C-3,C-7相关;H-6与C-4,C-8相关),进一步确定了连氧邻二醇片段位移长链烷烃的5位和6位。通过CH3-9和C-7跟C-8的BC相关信号,证明9位甲基位于末端,与烯碳C-8直接相连。进一步通过ECD量子化学计算,确定化合物1的构型为5S,6R。经Scifinder检索,化合物1为崭新的结构,命名为Aspertrienediol A。
新化合物2结构鉴定:淡黄色油状物,高分辨质谱数据显示化合物2跟化合物1分子式完全一致,1D NMR数据也几乎完全一致,考虑到分子结构中仅有邻二醇两个手性碳,推测化合物2和1是差向异构体。进一步二维核磁数据COSY,HSQC,和HMBC谱也证实了它们是差向异构体的推论。通过ECD量子化学计算,确定了化合物2的构型为5S,6S。经Scifinder检索,化合物2为崭新的结构,命名为Aspertrienediol B。
实施例2:链状多烯邻二醇类化合物1和2的抗炎活性实验数据
采用Griess法检测链状多烯邻二醇类化合物对RAW264.7细胞NO的影响,ELISA试剂盒检测戊酮噻吩类化合物对RAW264.7细胞促炎因子水平的影响,RT-PCR检测巨噬细胞极化状态相关因子的基因表达水平。
实验结果(图3)表明链状多烯邻二醇类化合物Aspertrienediol B(2)能够有效抑制LPS诱导的促炎细胞因子(MCP-1、IL-6和TNF-α)水平的趋势,同时也能有效抑制MCP-1、IL-6和TNF-α等促炎因子的mRNA表达。这与链状多烯邻二醇类化合物Aspertrienediol B(2)对NO释放的抑制作用是一致的。在相同浓度下,对RAW264.7细胞无细胞毒活性,可以做为抗炎药物开发的候选先导化合物。
Claims (7)
1.链状多烯邻二醇类化合物,其结构如式(Ⅰ)
2.权利要求1所述的链状多烯邻二醇类化合物在制备抗炎药物中的应用。
3.根据权利要求2所述的应用,其特征在于,所述的链状多烯邻二醇类化合物是化合物2。
4.曲霉Aspergillus sp.SCSIO 05702,保藏编号为:CGMCC No.10279。
5.权利要求4所述的南极曲霉Aspergillus sp.SCSIO 05702在制备权利要求1所述的链状多烯邻二醇类化合物的应用。
6.一种制备权利要求1所述的链状多烯邻二醇类化合物的方法,其特征在于,包括以下步骤:
a)制备曲霉Aspergillus sp.SCSIO 05702的发酵培养物;
b)将发酵培养物用大号布氏漏斗将发酵液和菌丝体分离,发酵液用乙酸乙酯萃取,合并乙酸乙酯萃取液,浓缩后得到浸膏A;菌丝体先用丙酮浸提,合并浸提液,浸提液回收丙酮后剩余水混合液用乙酸乙酯萃取,乙酸乙酯萃取液浓缩后得到浸膏B,将浸膏A和浸膏B合并,得到粗提物;粗提物经中压正相硅胶柱层析,二氯甲烷/甲醇从100:0梯度洗脱至0:100,梯度洗脱顺序得5个组分,收集二氯甲烷/甲醇体积比为100:0洗脱的馏分fr1;将该馏分进行葡聚糖凝胶Sephadex LH-20层析纯化处理,以二氯甲烷/甲醇体积比1:1作为流动相洗脱,获得4个馏分fr1-1-fr1-4;馏分fr1-3以220nm波长做检测、采用3mL/min的流速,以乙腈:水(25:75,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1和化合物2。
7.根据权利要求6所述的方法,其特征在于,所述的曲霉Aspergillus sp.SCSIO 05702的发酵培养物是通过以下方法制备的:将活化的曲霉SCSIO 05702接入种子培养基中,24℃,180rpm,培养3天制得种子液,将种子液以体积百分比5%的接种量接入到发酵培养基中,24℃,静置培养70天,而制得发酵培养物,所述的种子培养基和发酵培养基的配方为每升培养基液体中含有:可溶性淀粉10g、蛋白胨1g。
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