十字孢碱产生菌优化及其衍生物合成研究
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摘要
吲哚咔唑类生物碱由于其独特的结构和良好的生物活性引起了许多有机化学家和药物学家浓厚的兴趣和热切的关注,其中以十字孢碱(staurosporine,ST)为代表的衍生物更是由于其强的蛋白激酶C(PKC)抑制活性吸引了众多研究者的目光。本文从十字孢碱的产生菌株出发,开展了一系列的研究工作。研究内容主要有:十字孢碱产生菌的优化——产生菌的筛选,高产菌株的选育,代谢调控研究,混合培养对次生代谢产物的影响以及突变高产株十字孢碱类似物的研究;另外,对高产菌株规模发酵,建立了十字孢碱的提取纯化方法,并对获得的十字孢碱进行了衍生物合成工作,寻找新的活性高、毒副作用小的蛋白激酶C抑制剂。
实验室保藏的放线菌株分别来自青岛胶州湾的海泥、青岛东风盐场的盐池底泥,从中进行广泛的筛选,获得了3株产生十字孢碱的链霉菌,分别是S. fradiae 007、S. arenae Z4007、S. rubrolavendulae THW-12。对这3株的十字孢碱的产量进行定量分析,发现产量较低,均在1μg/ml左右。因此开展了高产菌株的选育工作,采用常规的理化因子诱变,通过简便有效的紫外和亚硝基胍进行复合诱变,从菌株S. fradiae 007中得到3株高产突变株:S. fradiae M297、S. fradiae M301、S. fradiae M315,其中S. fradiae M315发酵效价由原来的1.02μg·mL-1提高到9.06μg·mL-1,提高了8倍,突变株经过稳定性试验考察,性能稳定。
为了提高菌株的发酵效价,我们还开展了代谢调控和混合培养研究。期望通过添加代谢前体、酶抑制剂以及竞争性生长因子等诱发新的次生代谢途径。初步研究了五种常见甲基酶抑制剂对十字孢碱产生菌的影响,包括D-甲硫氨酸、D,L-乙硫氨酸、S-腺苷-L-高半胱氨酸、西奈芬净;发现在培养时加入甲基化酶抑制西奈芬净,可使THW-12产生去甲基十字孢碱,但是产量较低。通过桐花树根部的内生真菌Penicillium citrinum WC29-5与链酶菌S. Fradiae 007的混合培养,考察了混合培养对次生代谢产物的影响,获得了10个化合物(1-10),首次确定了化合物6的绝对构型;细胞毒活性评价表明,化合物6对A549及HL-60细胞IC50值分别是0.9、0.8μM。混合培养的次级代谢产物与纯培养发生了很大的变化,虽然没有提高十字孢碱的产量,但是生成了不同于纯培养的活性次生代谢产物,为以后进一步研究混合培养积累了经验。
突变株M315经过发酵条件优化,进行大发酵(250L)。我们对其发酵产物进行追踪分离,建立了十字孢碱(19)的提取纯化方法,同时还获得了9个其它吲哚咔唑类生物碱,其中化合物(11-13)为新化合物,其结构特点是在十字孢碱的4'N上出现了取代基,化合物11出现了氰基,而12和13则分别在该位置出现了另一分子的色氨酸片段和杂原子基团。
我们以十字孢碱为原料,以得到PKC412和UCN-01(正在进行临床试验研究)的卤代产物为目标,对7-位亚甲基、4' N以及芳环进行结构修饰,研究卤代化合物对该类化合物的影响,期望得到“me-too”或者“me-better”药物分子。目前已经合成了50个化合物,其中新化合物45个,以A549及HL-60肿瘤细胞株为模型,用SRB法或MTT法对得到的进行了化合物抗肿瘤活性评价,其中化合物116, 117, 123, 194, 207, 222显示了良好的细胞毒活性,对A549肿瘤细胞株IC50值分别为0.8、0.5、5.1、1.0、0.6、0.4μM,对HL-60肿瘤细胞株IC50值分别为1.1、1.4、4.9、1.1、0.9、0.9μM;分子水平的活性评价表明,化合物123, 124, 126, 204对PKCβ2具有很强的抑制活性,其IC50值分别为22.3, 14.4, 37.0, 24.5 nM。
综上,我们对十字孢碱为研究对象,筛选获得了3株产生菌株;通过复合诱变获得了高产菌株,考察了代谢前体、甲基化酶抑制剂以及微生物种间竞争性生长对次生代谢产物的影响,得到了10个混合培养的次级代谢产物,其中一个具有良好的细胞毒活性;通过突变株的规模化发酵,获得了10个包括十字孢碱在内的吲哚咔唑生物碱,其中3个为新化合物。对十字孢碱进行衍生物的合成,获得了45个新化合物,其中部分衍生物显示了良好的细胞毒和PKCβ2抑制活性。
The unique structure and good biological activity of indolecarbazole alkaloids draw attention and rouse interest of organic chemists and pharmaceutical scientists, in which staurosporine (ST) is the representative for its strong protein kinase C (PKC) inhibition. In this dissertation, a series of research work were based on ST, including the optimization of ST producing strains, isolation and identification of ST, and the synthsis of halo-derivatives of ST. First work includes screening ST producing strains, breeding high-yielding strains, metabolic regulation, secondary metabolites of mixed culture and staurosporine analogs from the high-yield mutant strain; In addition, after the scale fermentation of producing strain, we established the methods for the extraction and purification of ST, and ST derivatives were also synthesized to find new protein kinase C inhibitors of good activity and low toxicity.
The actinomycetes preserved in our laboratory were seperated from the mud of Jiaozhou Bay, Qingdao and from the salt pond sedimen of Qingdao Dongfeng salt. After an extensive screening, we got three streptomyces to produce ST, i.e S. fradiae 007, S. arenae Z4007, and S. rubrolavendulae THW-12. However, the ST output of is low, only about 1μg/ml. In order to improve the fermentation titer of ST producing strains, ultraviolet and nitrosoguanidine (NTG) were used as mutagens in treating S. fradiae 007, S. arenae Z4007 and S. rubrolavendulae THW-12. As a result, three mutant strains with high yield of ST, i.e. S. fradiae M297, S. fradiae M301 and S. fradiae M315, were obtained from S. fradiae 007, in which the titer of M315 was 9.06μg·mL-1, nine times as that of the original 007 (1.02μg·mL-1). The genetic stability of high-producing strains was confirmed by experiments.
In order to further improve the fermentation titer, we also carried out the work of metabolic regulation and mixed culture. We hoped that the new secondary metabolic pathways were induced by the addition of metabolic precursors, enzyme inhibitors, and competitive growth factors. Preliminary studies of five common methylation inhibitors (D-methionine, D, L-ethionine, S-adenosyl-L-homocysteine, sinefungin) showed that after the addition of sinefungin in the culture, THW-12 could produce demethylstaurosporine with the lower yield. Mixed culture was investigated on the influence of secondary metabolites by the use of Penicillium citrinum WC29-5, an epiphytic fungus with the mangrove plant, Aegiceras corniculata, and S. Fradiae 007. Ten compounds (1-10) were isolated and identified from the mix culture. The absolute configuration of compounds 6 was determined for the first time, and its cytotoxic activity was evaluated for the first time with IC50 values of 0.9 and 0.8μM on A549 and HL-60 cell lines, respectively. The results showed that secondary metabolites of mixed culture had great changes with that of the pure culture and the further research need to be carried out.
After optimization of fermentation conditions, M315 was cultured in a 250L- large scale. Ten indolocarbazole alkaloids (11-20) including ST were isolated and identified. Among them, compounds 11-13 were new compounds with different substituents at postion 4'N, in which compoud 11 is a nitrile group, compoud 12 is a tryptophan moiety, and compoud 13 is a carbonoamino group.
In order to obtain the halogenated derivatives of PKC412 and UCN-01, two anticancer drugs in clinical trial, we have designed and synthesized 45 new ST analogues belonged to three types substituted at the positions of C-7, N-4' and aromatic ring. And "me-too" or "me-better" drugs were also expected. The antitumor activities were evaluated in cellular and molecular level by the MTT or SRB assays. Compounds 116, 117, 123, 194, 207, 222 showed significant cytotoxic activity against A549 and HL-60 cell lines with IC50 values of 0.8、0.5、5.1、1.0、0.6、0.4 and 1.1、1.4、4.9、1.1、0.9、0.9μM, respectively. Compouds 123, 124, 126, 204, showed significant inhibitory effect on PKCβ2 with IC50 values of 22.3,14.4, 37.0, 24.5 nM, respectively.
In summary, we have got three staurosporine producing strains, and the fermentation titers were improved by the compound mutation method; effects on secondary metabolites were also investigated by adding metabolic precursor, methyltransferase in the culture, and growth competition between microbial species. Ten compounds were isolated and identified from the mixed culture broth, one of which displayed obvious cytotoxic activity. Besides, ten indole carbazole alkaloids including ST were obtained from the scale fermentation of mutant strain, 3 of which were new compounds. Forty-five new ST analogues belonge to three types also had been synthesized, some of which showed significant cytotoxicity on HL-60 and A549 cells and PKCβ2 inhibition.
实验室保藏的放线菌株分别来自青岛胶州湾的海泥、青岛东风盐场的盐池底泥,从中进行广泛的筛选,获得了3株产生十字孢碱的链霉菌,分别是S. fradiae 007、S. arenae Z4007、S. rubrolavendulae THW-12。对这3株的十字孢碱的产量进行定量分析,发现产量较低,均在1μg/ml左右。因此开展了高产菌株的选育工作,采用常规的理化因子诱变,通过简便有效的紫外和亚硝基胍进行复合诱变,从菌株S. fradiae 007中得到3株高产突变株:S. fradiae M297、S. fradiae M301、S. fradiae M315,其中S. fradiae M315发酵效价由原来的1.02μg·mL-1提高到9.06μg·mL-1,提高了8倍,突变株经过稳定性试验考察,性能稳定。
为了提高菌株的发酵效价,我们还开展了代谢调控和混合培养研究。期望通过添加代谢前体、酶抑制剂以及竞争性生长因子等诱发新的次生代谢途径。初步研究了五种常见甲基酶抑制剂对十字孢碱产生菌的影响,包括D-甲硫氨酸、D,L-乙硫氨酸、S-腺苷-L-高半胱氨酸、西奈芬净;发现在培养时加入甲基化酶抑制西奈芬净,可使THW-12产生去甲基十字孢碱,但是产量较低。通过桐花树根部的内生真菌Penicillium citrinum WC29-5与链酶菌S. Fradiae 007的混合培养,考察了混合培养对次生代谢产物的影响,获得了10个化合物(1-10),首次确定了化合物6的绝对构型;细胞毒活性评价表明,化合物6对A549及HL-60细胞IC50值分别是0.9、0.8μM。混合培养的次级代谢产物与纯培养发生了很大的变化,虽然没有提高十字孢碱的产量,但是生成了不同于纯培养的活性次生代谢产物,为以后进一步研究混合培养积累了经验。
突变株M315经过发酵条件优化,进行大发酵(250L)。我们对其发酵产物进行追踪分离,建立了十字孢碱(19)的提取纯化方法,同时还获得了9个其它吲哚咔唑类生物碱,其中化合物(11-13)为新化合物,其结构特点是在十字孢碱的4'N上出现了取代基,化合物11出现了氰基,而12和13则分别在该位置出现了另一分子的色氨酸片段和杂原子基团。
我们以十字孢碱为原料,以得到PKC412和UCN-01(正在进行临床试验研究)的卤代产物为目标,对7-位亚甲基、4' N以及芳环进行结构修饰,研究卤代化合物对该类化合物的影响,期望得到“me-too”或者“me-better”药物分子。目前已经合成了50个化合物,其中新化合物45个,以A549及HL-60肿瘤细胞株为模型,用SRB法或MTT法对得到的进行了化合物抗肿瘤活性评价,其中化合物116, 117, 123, 194, 207, 222显示了良好的细胞毒活性,对A549肿瘤细胞株IC50值分别为0.8、0.5、5.1、1.0、0.6、0.4μM,对HL-60肿瘤细胞株IC50值分别为1.1、1.4、4.9、1.1、0.9、0.9μM;分子水平的活性评价表明,化合物123, 124, 126, 204对PKCβ2具有很强的抑制活性,其IC50值分别为22.3, 14.4, 37.0, 24.5 nM。
综上,我们对十字孢碱为研究对象,筛选获得了3株产生菌株;通过复合诱变获得了高产菌株,考察了代谢前体、甲基化酶抑制剂以及微生物种间竞争性生长对次生代谢产物的影响,得到了10个混合培养的次级代谢产物,其中一个具有良好的细胞毒活性;通过突变株的规模化发酵,获得了10个包括十字孢碱在内的吲哚咔唑生物碱,其中3个为新化合物。对十字孢碱进行衍生物的合成,获得了45个新化合物,其中部分衍生物显示了良好的细胞毒和PKCβ2抑制活性。
The unique structure and good biological activity of indolecarbazole alkaloids draw attention and rouse interest of organic chemists and pharmaceutical scientists, in which staurosporine (ST) is the representative for its strong protein kinase C (PKC) inhibition. In this dissertation, a series of research work were based on ST, including the optimization of ST producing strains, isolation and identification of ST, and the synthsis of halo-derivatives of ST. First work includes screening ST producing strains, breeding high-yielding strains, metabolic regulation, secondary metabolites of mixed culture and staurosporine analogs from the high-yield mutant strain; In addition, after the scale fermentation of producing strain, we established the methods for the extraction and purification of ST, and ST derivatives were also synthesized to find new protein kinase C inhibitors of good activity and low toxicity.
The actinomycetes preserved in our laboratory were seperated from the mud of Jiaozhou Bay, Qingdao and from the salt pond sedimen of Qingdao Dongfeng salt. After an extensive screening, we got three streptomyces to produce ST, i.e S. fradiae 007, S. arenae Z4007, and S. rubrolavendulae THW-12. However, the ST output of is low, only about 1μg/ml. In order to improve the fermentation titer of ST producing strains, ultraviolet and nitrosoguanidine (NTG) were used as mutagens in treating S. fradiae 007, S. arenae Z4007 and S. rubrolavendulae THW-12. As a result, three mutant strains with high yield of ST, i.e. S. fradiae M297, S. fradiae M301 and S. fradiae M315, were obtained from S. fradiae 007, in which the titer of M315 was 9.06μg·mL-1, nine times as that of the original 007 (1.02μg·mL-1). The genetic stability of high-producing strains was confirmed by experiments.
In order to further improve the fermentation titer, we also carried out the work of metabolic regulation and mixed culture. We hoped that the new secondary metabolic pathways were induced by the addition of metabolic precursors, enzyme inhibitors, and competitive growth factors. Preliminary studies of five common methylation inhibitors (D-methionine, D, L-ethionine, S-adenosyl-L-homocysteine, sinefungin) showed that after the addition of sinefungin in the culture, THW-12 could produce demethylstaurosporine with the lower yield. Mixed culture was investigated on the influence of secondary metabolites by the use of Penicillium citrinum WC29-5, an epiphytic fungus with the mangrove plant, Aegiceras corniculata, and S. Fradiae 007. Ten compounds (1-10) were isolated and identified from the mix culture. The absolute configuration of compounds 6 was determined for the first time, and its cytotoxic activity was evaluated for the first time with IC50 values of 0.9 and 0.8μM on A549 and HL-60 cell lines, respectively. The results showed that secondary metabolites of mixed culture had great changes with that of the pure culture and the further research need to be carried out.
After optimization of fermentation conditions, M315 was cultured in a 250L- large scale. Ten indolocarbazole alkaloids (11-20) including ST were isolated and identified. Among them, compounds 11-13 were new compounds with different substituents at postion 4'N, in which compoud 11 is a nitrile group, compoud 12 is a tryptophan moiety, and compoud 13 is a carbonoamino group.
In order to obtain the halogenated derivatives of PKC412 and UCN-01, two anticancer drugs in clinical trial, we have designed and synthesized 45 new ST analogues belonged to three types substituted at the positions of C-7, N-4' and aromatic ring. And "me-too" or "me-better" drugs were also expected. The antitumor activities were evaluated in cellular and molecular level by the MTT or SRB assays. Compounds 116, 117, 123, 194, 207, 222 showed significant cytotoxic activity against A549 and HL-60 cell lines with IC50 values of 0.8、0.5、5.1、1.0、0.6、0.4 and 1.1、1.4、4.9、1.1、0.9、0.9μM, respectively. Compouds 123, 124, 126, 204, showed significant inhibitory effect on PKCβ2 with IC50 values of 22.3,14.4, 37.0, 24.5 nM, respectively.
In summary, we have got three staurosporine producing strains, and the fermentation titers were improved by the compound mutation method; effects on secondary metabolites were also investigated by adding metabolic precursor, methyltransferase in the culture, and growth competition between microbial species. Ten compounds were isolated and identified from the mixed culture broth, one of which displayed obvious cytotoxic activity. Besides, ten indole carbazole alkaloids including ST were obtained from the scale fermentation of mutant strain, 3 of which were new compounds. Forty-five new ST analogues belonge to three types also had been synthesized, some of which showed significant cytotoxicity on HL-60 and A549 cells and PKCβ2 inhibition.
引文
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