CN116041305B - 青霉菌(Penicillium mali)的发酵化合物及其制备方法和抗肿瘤应用 - Google Patents
青霉菌(Penicillium mali)的发酵化合物及其制备方法和抗肿瘤应用 Download PDFInfo
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Abstract
本发明涉及一种青霉菌(Penicilliummali)的发酵化合物及其制备方法和应用,通过将青霉菌(Penicilliummali)菌丝在发酵培养基中于25℃静态培养30天获得到发酵物,经萃取、分离、纯化,得到发酵化合物。该方法具有环保、步骤简单、制备的产品纯度高的优点;所述发酵化合物为庚基环己烷类化合物,能够有效抑制前列腺癌细胞的迁移和浸润,具有良好的抵抗前列腺癌转移的活性,在制备抗前列腺癌药物方面具有良好的应用前景。
Description
技术领域
本发明涉及药物化合物技术领域,具体涉及一种菌(Penicillium mali)的发酵化合物及其制备方法和应用。
背景技术
前列腺癌是男性最常见的恶性肿瘤之一。癌症转移会大大增加前列腺癌患者的死亡率,骨是癌症转移的第二最常见部位,在我国超过80%的前列腺癌患者在确诊时已经发生骨转移,而骨转移是导致前列腺癌患者死亡的重要原因。早期患者的五年生存率高达95%以上,但晚期特别是发生骨转移的患者将降至30%以下。
目前临床上暂无针对前列腺癌骨转移的特效药物,根据不同的病情可以采用化学药物治疗、外放射治疗、放射性核素内放射治疗以及各种疗法的综合应用等。然而,放化疗药物不仅作用于肿瘤,还可以作用于肿瘤周围健康的组织,因而在杀伤肿瘤的同时,也给机体带来了很大的副作用,最终影响对肿瘤的治疗效果。因此,针对前列腺癌转移药物的开发是本领域的热点和难点。
海洋微生物能够产生结构新颖且活性显著的次级代谢产物,是开发抗癌药物重要的宝藏。
发明内容
本发明的目的在于提供一种分离自青霉菌(Penicillium mali)的发酵化合物及其制备方法和应用。所述青霉菌(Penicillium mali)的发酵产物为庚基环己烷类化合物,具有显著的抗肿瘤活性,可用于抗癌药物的制备和研发。
为此,本发明的第一方面提供一种青霉菌(Penicillium mali)的发酵化合物,所述发酵化合物为庚基环己烷类化合物,其包括式I~Ⅶ所示的化合物中的一种或多种:
本发明的第二方面,提供所述的青霉菌(Penicillium mali)发酵化合物的制备方法,包括以下步骤:
S1、将青霉菌(Penicillium mali)菌丝体接到含有PDB的培养液中培养获得种子液,将所述种子液接种到发酵培养基中于25℃静态培养30天,得到发酵物;
S2、将步骤S1得到的发酵物用乙酸乙酯进行萃取,所得萃取物经分离纯化,得到发酵化合物。
进一步的,上述步骤S2具体包括如下步骤:
S21、将步骤S1得到的发酵物进行萃取,发酵物用乙酸乙酯萃取,分别使用石油醚和甲醇对有机萃取物进行分液,浓缩甲醇层,得到粗提物;
S22、将步骤S21得到的粗提物用正相硅胶柱色谱进行分离,用石油醚-乙酸乙酯体系进行梯度洗脱,依次得到5个粗馏分:Fr.1~Fr.5;
S23、将步骤S22得到的粗馏分Fr.2先使用ODS柱色谱进行分离,使用水-甲醇体系进行梯度洗脱,依次得到15段粗馏分:Fr.2.1~Fr.2.15;
S24、将步骤S23得到的粗馏分Fr.2.8用葡聚糖凝胶柱和半制备液相色谱柱分离后得到式I化合物;
S25、将步骤S23得到的粗馏分Fr.2.6用葡聚糖凝胶柱色谱和半制备液相色谱手性柱分离后得到式Ⅱ化合物和式Ⅲ化合物;
S26、将步骤S22得到的粗馏分Fr.3用ODS柱色谱分离得到15段粗馏分:Fr.3.1~Fr.3.15;
S27、将步骤S26得到的粗馏分Fr.3.9用葡聚糖凝胶柱和半制备液相色谱柱分离得到式Ⅳ化合物;
S28、将步骤S22得到的粗馏分Fr.4用ODS柱色谱进行分离,浓缩得到18段粗馏分:Fr.4.1~Fr.4.18;
S29、将步骤S28得到的粗馏分Fr.4.15用葡聚糖凝胶柱和半制备液相色谱柱分离得到式Ⅴ化合物、式Ⅵ化合物和式Ⅶ化合物。
进一步的,上述步骤S22中所用正相硅胶柱色谱的洗脱溶剂为石油醚-乙酸乙酯体系,洗脱梯度为20:1→0:1。
进一步的,上述步骤S23中ODS色谱柱所用流动相为甲醇-水,梯度洗脱比例为:40%→100%。
进一步的,上述步骤S24中葡聚糖凝胶柱所用流动相为甲醇,半制备液相色谱柱所用流动相为甲醇-水,梯度洗脱比例为:60%→100%。
进一步的,上述步骤S25中葡聚糖凝胶柱所用流动相为甲醇半制备液相色谱柱所用流动相为甲醇-水,梯度洗脱比例为:50%→70%。
进一步的,上述步骤S26中ODS柱所用流动相为甲醇-水,梯度洗脱比例为:5%→40%→100%。
进一步的,上述步骤27中葡聚糖凝胶柱所用流动相为甲醇,半制备液相色谱柱所用流动相为甲醇-水,梯度洗脱比例为:70%→100%,。
进一步的,上述步骤28中ODS柱所用流动相为甲醇-水,梯度洗脱比例为:5%→40%→100%。
进一步的,上述步骤29中葡聚糖凝胶柱所用流动相为甲醇,半制备液相色谱柱所用流动相为甲醇-水,梯度洗脱比例为:90%→100%。
优选的,所述发酵培养基为大米。
进一步,上述步骤S1中的菌丝体通过以下步骤制备得到:将(Penicillium mali)在PDA平板上于28℃培养3~4天,获得所述菌丝体。
本发明的第三方面,提供青霉菌(Penicillium mali)的发酵化合物在制备肿瘤细胞抑制剂中的应用。
优选地,所述肿瘤细胞为前列腺癌细胞。
本发明的第四方面,提供青霉菌(Penicillium mali)的发酵化合物在预防和/或治疗肿瘤的药物中应用。
优选地,所述肿瘤为前列腺癌。
本发明的第五方面,提供一种抗肿瘤的组合物,所述组合物包含本发明的第一方面所述的发酵化合物。
与现有技术相比,本发明的有益效果为:
本发明提供了分离自深海青霉菌(Penicillium mali)的发酵化合物,其为庚基环己烷类化合物,结构如式I~Ⅶ所示。例式I化合物是庚基苯酚类新化合物。本发明提供的从深海青霉菌(Penicillium mali)发酵液中分离化合物I~Ⅶ的方法,具有环保、步骤简单、产品纯度高等优点。通过细胞毒活性实验以及细胞侵袭实验(transwell)证明了化合物能够有效抑制肿瘤细胞的迁移和浸润,具有良好的抵抗前列腺癌转移的活性。本发明提供的庚基环己烷类化合物在制备抗前列腺癌药物方面具有良好的应用前景。
附图说明
通过阅读下文优选实施方式的详细描述,各种其他的优点和益处对于本领域普通技术人员将变得清楚明了。附图仅用于示出优选实施方式的目的,而并不认为是对本发明的限制。
图1为本发明化合物I~VII的结构式。
图2为本发明的化合物I~VII对PC3-KLF5/K369Q、PC3-KLF5/K369R、DU145-KLF5/K369Q、DU145-KLF5/K369R细胞毒活性结果。
图3为本发明的化合物I~VII(单一浓度)对PC3-KLF5/K369Q细胞迁移结果。
图4为本发明的化合物I(梯度浓度)抑制PC3-KLF5/K369Q细胞迁移、浸润结果。
图5为本发明的化合物I(梯度浓度)抑制DU145-KLF5/K369Q细胞迁移、浸润结果。
具体实施方式
为了便于理解本发明,下面将参照实施例对本发明进行更全面的描述,以下给出了本发明的较佳实施例。但是,本发明可以以许多不同的形式来实现,并不限于本文所描述的实施例。提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
SP/KLF(Kruppel-like factor)转录因子的遗传畸变参与了包括癌症在内的多种人类疾病的发生发展,其中KLF5作为KLFs超家族中的重要成员,在包括前列腺癌在内的多种实体瘤中表达异常,同时在多种癌症相关信号通路的调控中发挥重要作用。TGFβ通常产生于肿瘤微环境中,晚期肿瘤也具有TGFβ的自分泌能力,TGFβ能够促进晚期肿瘤的上皮-间质转化(EMT)进而诱导肿瘤转移,并受到KLF5的调控。在前列腺癌中,激活的TGFβ信号通路可招募乙酰转移酶p300,介导KLF5在369位赖氨酸位点乙酰化,通过乙酰化KLF5(Ac-KLF5)和Smads复合物对下游靶点进行调控,进而诱导前列腺癌骨转移。因此在前列腺癌细胞PC3和DU145中敲除KLF5,再稳定过表达模拟KLF5乙酰化形式的突变体KLF5/K369Q,得到的稳转细胞系PC3-KLF5/K369Q和DU145-KLF5/K369Q,是模拟前列腺癌骨转移的重要体外细胞模型,可用于评价药物抗前列腺癌转移的活性。
实施例1发酵化合物的制备
(1)将青霉菌(Penicillium mali)(购自于中国海洋微生物菌种保藏管理中心,保藏编号MCCC 3A00140)在PDA平板上于28℃培养3天;然后将新鲜的菌丝体接到含有400mlPDB的培养液中,48h后,将20ml种子液接种到1L的三角烧瓶中(100瓶),每瓶中有100g大米和120ml盐度1.5%的海水,在25℃下静态培养30天,得到发酵物。
(2)将步骤(1)得到的发酵物用乙酸乙酯萃取三次,减压蒸发掉有机溶剂,得到有机萃取物(50g);将这些萃取物进行分液萃取,分别使用石油醚和甲醇进行分层萃取;浓缩甲醇层,得到粗提物(25.0g);
(3)将步骤(2)得到的粗提物使用正相硅胶柱色谱进行分离,用石油醚-乙酸乙酯体系进行梯度洗脱,得到5个粗馏分(Fr.1~Fr.5);
(4)将步骤(3)中的粗馏分Fr.2(2.3g)先使用ODS柱色谱进行分离,使用水-甲醇体系进行梯度洗脱得到15段粗馏分(Fr.2.1-Fr.2.15)。Fr.2.8(53.6mg)使用葡聚糖凝胶柱(纯甲醇)和半制备液相色谱柱(甲醇-水,60%→100%)分离后得到化合物I(5mg)。Fr.2.6(56.3mg)使用葡聚糖凝胶色谱柱(纯甲醇),半制备液相色谱柱(甲醇-水,50%→70%)分离后得到化合物Ⅱ(0.5mg)和化合物Ⅲ(2.5mg)。
(5)将步骤(3)中的粗馏分Fr.3(2.4g)先使用ODS柱色谱进行分离,使用水-甲醇体系进行梯度洗脱得到15段粗馏分(Fr.3.1-Fr.3.15)。Fr.3.9(34.0mg)使用葡聚糖凝胶柱(纯甲醇)和半制备液相色谱柱(甲醇-水,70%→100%)分离后得到化合物Ⅳ(3.5mg)。
(6)将步骤(3)中的粗馏分Fr.4(4.0g)先使用ODS柱色谱进行分离,使用水-甲醇体系进行梯度洗脱得到18段粗馏分(Fr.4.1-Fr.4.18)。Fr.4.15(34.0mg)使用葡聚糖凝胶柱(纯甲醇)和半制备液相色谱柱(甲醇-水,90%→100%)分离后得到化合物Ⅴ(1.5mg)、化合物Ⅵ(9mg)、化合物Ⅶ(2.0mg)。
实施例2化合物I~化合物Ⅶ的结构鉴定
将实施例1制备得到的化合物I~化合物Ⅶ分别用1D、2D NMR图谱以及高分辨质谱分析确定化合物的平面结构,然后利用NOESY确定其相对构型,用ECD计算等确定其绝对构型,详述如下:
化合物I为棕色固体。根据高分辨质谱确定其分子式为C13H16O2。1H、13C NMR数据(表1)显示13个碳信号,包括1个甲基,2个亚甲基,7个次甲基和3个季碳,经过详细的二维数据分析,确定了化合物I的平面结构,最后利用NOESY相关和ECD计算确定了化合物I的相对及绝对构型如图1中式I所示。
化合物Ⅱ的分子式为C13H16O3。其1H、13C NMR数据(表3)显示有13个碳,包括1个甲基,2个亚甲基,7个次甲基和3个季碳。经过详细的二维数据确定了化合物的平面结构,最后利用NOE图谱和ECD和1H NMR计算确定了式Ⅱ化合物的相对及绝对构型如图1中式Ⅱ所示。
化合物Ⅲ的分子式为C13H16O3。其1H、13C NMR数据(表3)显示碳谱数据与化合物Ⅱ非常相似(表3)。利用NOE图谱和ECD计算确定了化合物Ⅲ的相对及绝对构型如图1中式Ⅲ所示。
化合物Ⅳ的分子式为C14H22O3。其1H、13C NMR数据(表2)显示有14个碳,包括1个甲基,5个亚甲基,7个次甲基和1个季碳。通过详细的波谱解析,确定其结构如图1中式Ⅳ所示。
化合物Ⅴ的分子式为C14H24O3。其1H、13C NMR数据(表2)显示有14个碳,包括1个甲基,5个亚甲基,8个次甲基。通过详细的波谱解析,确定其结构如图1中式Ⅴ所示。
化合物Ⅵ的分子式为C13H22O3,1H、13C NMR数据(表1)显示有13个碳,包括1个甲基,4个亚甲基,8个次甲基。通过详细的1D、2D NMR解析,确定式化合物Ⅵ结构如图1中式Ⅵ所示。
化合物Ⅶ的分子式为C14H24O3。其1H、13C NMR数据(表1)显示有14个碳,包括1个甲基,5个亚甲基,8个次甲基。通过详细的波谱解析,确定其结构如图1中式Ⅶ所示。
表1.化合物I、VI及VII的1H和13C NMR数据
a MeOD;b DMSO-d6.
表2.化合物Ⅳ和Ⅴ的1H和13C NMR数据
a MeOD;b DMSO-d6.
表3.化合物II和III的1H和13C NMR数据
a MeOD;b DMSO-d6.
实施例3化合物I~VII的细胞毒活性检测
本实施例选择两对稳转的前列腺癌细胞:PC3-KLF5/K369Q(模拟乙酰化KLF5)、PC3-KLF5/K369R(模拟去乙酰化KLF5)、DU145-KLF5/K369Q(模拟乙酰化KLF5)、DU145-KLF5/K369R(模拟去乙酰化KLF5)。通过检测受试样品对这些肿瘤细胞的抑制率,确定式I~式Ⅶ化合物的细胞毒性。
本实施例设置以下3组:
阴性对照组:等量培养液,0.1%DMSO,含细胞,不加入式I~式Ⅶ化合物;
空白对照组:等量培养液,不含细胞,且不加入式I~式Ⅶ化合物;
实验组:向细胞培养液分别加入式I~式Ⅶ化合物;
具体步骤包括:
(1)细胞经常规消化后,于培养基中重悬并吹打成单细胞悬液,然后以每孔2000个细胞接种到96孔板,每孔体积100μl;
(2)37℃,5%CO2的培养箱中培养24h,然后分别加入20μM化合物处理细胞;
(3)继续培养48h后,每孔加10μl的5mg/ml MTT,37℃避光反应3h;小心吸弃上清液后,每孔加入100μLDMSO,振荡10min,使结晶物充分融解;
(4)酶标仪测定490nm光吸收值,计算细胞增殖率和抑制率。
结果如图2所示,式I化合物显示出较弱的细胞毒性(20μM条件下的细胞增殖抑制率小于50%,预估IC50>20μM),而式II~式Ⅶ化合物则对细胞增殖基本没有影响。
实施例4式I~式Ⅶ化合物的细胞迁移活性测试
本实施例选择具有高迁移活性的的稳转前列腺癌细胞株PC3-KLF5/K369Q,通过细胞侵袭实验(transwell)检测化合物样品对肿瘤细胞迁移的影响。
本实施例设置以下2组:
阴性对照组:等量培养液,0.1%DMSO,含细胞,不加入式I~式Ⅶ化合物;
实验组:向细胞培养液分别加入式I~式Ⅶ化合物;
具体步骤包括:
(1)细胞经常规消化后,于培养基中重悬并吹打成单细胞悬液,然后以每孔20000个细胞接种到6孔板,每孔体积1ml;
(2)37℃,5%CO2的培养箱中培养24h,然后分别加入10μM化合物处理细胞24h;
(3)将transwell小室放置在24孔板中,小室外加入正常含血清的培养基600μL;
(4)将步骤2中处理后的细胞消化并用无血清培养基重悬,然后以每组40000个细胞接种到小室内,每室体积200μL,将同等数量的细胞直接接种在无小室的24孔板中作为对照增殖组,再次培养24h;
(5)小心吸弃上清液后,PBS清洗三次后每孔加入500μL多聚甲醛(4%),室温固定10min,PBS清洗三次后加入500μl结晶紫染色液,室温染色10min,PBS清洗三次后使用棉签擦除小室内侧细胞,最终在阴凉处晾干;
(6)使用体视镜进行拍照(4.5X物镜),再每孔/室加入500μL醋酸溶液(33.3%),振荡10min,使结晶物充分融解,酶标仪测定570nm光吸收值,计算细胞迁移率;
结果如图3所述,式I化合物能够抑制PC3-KLF5/K369Q细胞的迁移。
实施例5式I化合物的细胞迁移、浸润活性测试
本实施例选择具有高迁移活性的的两株稳转前列腺癌细胞PC3-KLF5/K369Q和DU145-KLF5/K369Q,通过细胞侵袭实验(transwell)检测化合物I对肿瘤细胞迁移活性的影响。
本实施例设置以下2组:
阴性对照组:等量培养液,0.1%DMSO,含细胞,不加入式I化合物;
实验组:向细胞培养液分别加入化合物I。
具体步骤包括:
(1)细胞经常规消化后,于培养基中重悬并吹打成单细胞悬液,然后以每孔20000个细胞接种到6孔板,每孔体积1ml;
(2)37℃,5%CO2的培养箱中培养24h,然后分别加入2.5、5、10、20μM式I化合物处理细胞48h;
(3)将transwell小室放置在24孔板中,同时用无血清培养基稀释基质胶(5:1),将稀释后的基质胶溶液均匀铺在小室内侧底部,每室50μL,并放置在培养箱中固定1h,铺胶的小室用于检测细胞浸润,等数量的空白小室用于检测细胞迁移;
(4)小室外加入正常含血清的培养基600μL,将步骤2中处理后的细胞消化并用无血清培养基重悬,然后以每组40000个细胞接种到小室内,每室体积200μL,将同等数量的细胞直接接种在无小室的24孔板中作为对照增殖组,再次培养24h;
(5)小心吸弃上清液后,PBS清洗三次后每孔加入500μL多聚甲醛(4%),室温固定10min,PBS清洗三次后加入500μl结晶紫染色液,室温染色10min,PBS清洗三次后使用棉签擦除小室内侧细胞,最终在阴凉处晾干;
(6)使用体视镜进行拍照(4.5X物镜),再每孔/室加入500μL醋酸溶液(33.3%),振荡10min,使结晶物充分融解,酶标仪测定570nm光吸收值,计算细胞迁移率;
结果显示,式I化合物能够浓度依赖地抑制PC3-KLF5/K369Q(图4)和DU145-KLF5/K369Q(图5)细胞的迁移、浸润,是具有应用前景的抗前列腺癌药物。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (9)
1.一种青霉菌Penicillium mali的发酵化合物,其特征在于,所述发酵化合物为庚基环己烷类化合物,如式I所示:
2.如权利要求1所述的发酵化合物的制备方法,其特征在于,包括以下步骤:
S1、将青霉菌Penicillium mali菌丝体接到含有PDB的培养液中培养获得种子液,将所述种子液接种到发酵培养基中于25℃静态培养30天,得到发酵物;所述青霉菌Penicilliummali的保藏编号为MCCC 3A00140,保藏地址为中国海洋微生物菌种保藏管理中心;
S2、将步骤S1得到的发酵物进行萃取,发酵物用乙酸乙酯萃取,分别使用石油醚和甲醇对有机萃取物进行分液,浓缩甲醇层,得到粗提物;
S3、将步骤S2得到的粗提物用正相硅胶柱色谱进行分离,用石油醚-乙酸乙酯体系进行梯度洗脱,依次得到5个粗馏分:Fr.1~Fr.5;
S4、将步骤S3得到的粗馏分Fr.2先使用ODS柱色谱进行分离,使用水-甲醇体系进行梯度洗脱,依次得到15段粗馏分:Fr.2.1~Fr.2.15;
S5、将步骤S4得到的粗馏分Fr.2.8用葡聚糖凝胶柱和半制备液相色谱柱分离后得到式I化合物。
3.如权利要求2所述的发酵化合物的制备方法,其特征在于,所述步骤S1中的所述发酵培养基为大米。
4.如权利要求2所述的发酵化合物的制备方法,其特征在于,所述步骤S1中的菌丝体通过以下步骤制备得到:将青霉菌Penicillium mali在PDA平板上于28℃培养3~4天,获得所述菌丝体。
5.如权利要求1所述的发酵化合物在制备肿瘤细胞抑制剂中应用。
6.如权利要求5所述的应用,所述肿瘤细胞为前列腺癌细胞。
7.如权利要求1所述的发酵化合物在制备预防和/或治疗肿瘤的药物中应用。
8.如权利要求7所述的应用,其特征在于,所述肿瘤为前列腺癌。
9.一种抗肿瘤的组合物,其特征在于,所述组合物包含权利要求1所述的发酵化合物。
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CN112047901A (zh) * | 2020-09-21 | 2020-12-08 | 自然资源部第三海洋研究所 | 苯并噻唑杂萜类化合物及其衍生物以及制备方法与应用 |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN112047901A (zh) * | 2020-09-21 | 2020-12-08 | 自然资源部第三海洋研究所 | 苯并噻唑杂萜类化合物及其衍生物以及制备方法与应用 |
Non-Patent Citations (3)
Title |
---|
南海海洋真菌Penicillium sp. FS60的次级代谢产物研究;张玲;李冬利;陈玉婵;陶美华;章卫民;;中药材(07);1091-1094 * |
海泥青霉Penicillium sp.WF-06的抗肿瘤活性代谢产物;任虹;于洋;;国外医药(抗生素分册)(02);86-90 * |
深海苹果青霉和肉座菌的抗肿瘤活性成分研究;徐琳;自然资源部第三海洋研究所硕士学位论文;全文 * |
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