CN109020991A - 一类美达霉素类化合物及其制备方法和应用 - Google Patents
一类美达霉素类化合物及其制备方法和应用 Download PDFInfo
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- CN109020991A CN109020991A CN201811080510.9A CN201811080510A CN109020991A CN 109020991 A CN109020991 A CN 109020991A CN 201811080510 A CN201811080510 A CN 201811080510A CN 109020991 A CN109020991 A CN 109020991A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/14—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/181—Heterocyclic compounds containing oxygen atoms as the only ring heteroatoms in the condensed system, e.g. Salinomycin, Septamycin
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Oncology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
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Abstract
本发明公开了一类美达霉素类化合物,结构式分别如下式(I)~下式(Ⅳ)所示:这一类结构新颖的美达霉素类化合物,均为由放线菌通过发酵培养及提纯后得到的天然产物,大大增加了美达霉素类似物的种类。
Description
技术领域
本发明涉及放线菌次级代谢产物制备活性化合物领域,具体涉及一类美达霉素类化合物及其制备方法和应用。
背景技术
美达霉素(medermycin,结构式如下式(1))属于吡喃萘醌类家族的一种芳香聚酮类抗生素,最早于1976年,由日本研究人员从链霉菌K73中分离得到。研究表明,美达霉素对于某些癌细胞中过量表达的AKT激酶具有很好的活性抑制作用,AKT激酶作为肿瘤细胞信号通路中的关键组分己经成为抗癌药物筛选的重要靶标;美达霉素还能够作用于包括葡萄球菌在内的许多革兰氏阳性细菌。因此,美达霉素具有潜在抗癌、抗菌功效。
美达霉素自发现至今已有40多年,但研究发现美达霉素没有特异性,在对肿瘤细胞发挥作用的同时也影响正常细胞的增殖分裂,作为临床开发应用毒性太大,导致其一直无法成药。因此,基于该类化合物的作用机制,不断开发结构和功能与美达霉素相似的化合物一直是研究人员的主要方向。然而,截止目前只有约7个美达霉素类似物被发现。结构式分别如下式(2)~(8)。
其中,化合物Medermycin A和Medermycin B为从链霉菌KB10中分离得到的两个美达霉素类似物,活性研究显示,这两个化合物对KB人上皮癌细胞和N18-RE-105神经细胞具有一定的细胞毒活性;化合物lactoquinomycin B从链霉菌IM8442T中分离得到,活性研究表明,该化合物具有抗菌和抗肿瘤活性;化合物G15-F和G-15G是中国研究人员从硫藤黄链轮丝菌G15中分离得到,活性研究显示,这两种化合物具有抗革兰氏阳性菌和人口腔上皮癌细胞KB细胞的活性;化合物MDN-0171从链霉菌CA-186053中分离得到,没有相关活性报道;最后一种化合物3'-N-methyl-medermycin是从链霉菌ZS-A45中分离得到,活性研究显示具有对前列腺癌细胞具有明显的抑制作用其IC50值为0.81±0.42μM。
发明内容
本发明提供了一类共四种结构新颖的美达霉素类化合物,均为由放线菌通过发酵培养及提纯后得到的天然产物,大大增加了美达霉素类似物的种类。
具体技术方案如下:
一类美达霉素类化合物,结构式分别如下式(I)~下式(Ⅳ)所示:
式(I)和式(Ⅱ)对应的两个化合物为首次将美达霉素母核中的5位的酮羰基氧化成酯羰基形成5,10-oxepindione环骨架的美达霉素类似物。因此,这两个化合物的母核结构相较于美达霉素的母核结构已经发生了显著变化。
式(Ⅲ)对应的化合物,相对于已知的美达霉素类似物G15-G类似,其结构上的区别在于4a位置的双键被还原成邻二醇。
式(Ⅳ)对应的化合物,相对于已知的美达霉素类似物medermycin B,其结构上的区别在于吡喃环上增加了一个双键。
本发明还公开了上述的美达霉素类化合物的制备方法,包括以下步骤:
1)将放线菌活化后接种于高氏一号液体培养基中,摇床培养,获得发酵液;
所述放线菌,采用中国工业微生物菌种保藏管理中心出售的链霉菌Streptomycessp.CICC 11028;
2)将所述发酵液经有机溶剂萃取后获得萃取液;
3)将所述萃取液浓缩后,经分离纯化,分别获得如式(I)~式(Ⅳ)结构的美达霉素类化合物。
步骤1)中,所述放线菌活化的过程包括:
将所述放线菌接种到高氏一号平板固体培养基上,于26~30℃培养箱中静置,活化培养若干天。
步骤1)中:
所述高氏一号液体培养基的配制包括:
将可溶性淀粉20g、KNO3 1g、K2HPO4 0.5g、MgSO4·7H2O 0.5g、NaCl 0.5g、FeSO4·7H2O 0.01g、海盐25g混合后加水至1L,再调节pH值至7.2~7.4;
所述摇床培养的条件为:26~30℃下,150~250rpm摇床中培养5~10天。
步骤2)中,所述有机溶剂选自乙酸乙酯。
步骤3)中:
所述浓缩,具体为:
所述萃取液经真空干燥除去溶剂;
所述分离纯化,具体为:
(a)浓缩后萃取液采用硅胶柱层析分离,用体积比为100:1至0:1的二氯甲烷-甲醇体系进行梯度洗脱,收集含有目标化合物的馏分并合并;
(b)将步骤(a)所得馏分采用凝胶柱色谱分离,并以纯甲醇作为洗脱液,收集含有目标化合物的馏分并合并;
(c)将步骤(b)所得馏分采用反相高效液相色谱分离,依次分离得到如式(I)~式(Ⅳ)所示的美达霉素类化合物。
优选地,步骤(b)中,所述凝胶柱色谱分离采用的填料为羟丙基葡聚糖凝胶。
优选地,步骤(c)中,采用的填料为十八烷基键合硅胶;
检测波长为230nm,采用甲醇体积百分数为10%~100%的甲醇-0.05%三氟乙酸-水体系,以20mL/min进行梯度洗脱40min,收集13~15min的洗脱液得到如式(I)结构的美达霉素类化合物;
检测波长为230nm,采用甲醇体积百分数为10%~100%的甲醇-0.05%三氟乙酸-水体系,以20mL/min进行梯度洗脱40min,收集10~12min的洗脱液得到如式(Ⅱ)结构的美达霉素类化合物;
检测波长为254nm,采用甲醇体积百分数为10%~100%的甲醇-0.05%三氟乙酸-水体系,以20mL/min进行梯度洗脱40min,收集15~17min的洗脱液得到如式(Ⅲ)结构的美达霉素类化合物;
检测波长为254nm,采用甲醇体积百分数为10%~100%的甲醇-0.05%三氟乙酸-水体系,以20mL/min进行梯度洗脱40min,收集23~25min的洗脱液得到如式(Ⅳ)结构的美达霉素类化合物。
采用上述的制备工艺可以高产率、高纯度的分别获得如式(I)~式(Ⅳ)所示的化合物。
为进一步测试本发明分离得到的多种美达霉素类化合物的活性,本发明采用大肠杆菌、金黄色葡萄球菌和白色念珠菌进行抗微生物活性评价试验。研究表明,本发明分离得到的如式(I)~式(Ⅳ)的四种化合物均能抑制以上微生物的生长,因此可用于制备抗生素类药物。特别适合用于抑制大肠杆菌、金黄色葡萄球菌和白色念珠菌。
本发明还采用人前列腺癌细胞株(PC3)和结肠癌细胞(HCT116)分别进行抗肿瘤活性评价试验。研究表明,式(Ⅲ)、式(Ⅳ)两种化合物均具有抗肿瘤活性,尤其是对于结肠癌细胞(HCT116)具有更为显著的增殖抑制作用,因此可用于制备抗肿瘤药物,特别适合用于制备抗前列腺癌药和抗结肠癌药物。
本发明还进一步进行了激酶抑制试验,研究发现,具有式(Ⅳ)的化合物对ROCK 2蛋白激酶表现出较好的激酶抑制作用,可应用于制备激酶抑制剂类药物。进而用于治疗与激酶抑制有关的急、慢性白血病、淋巴癌、乳腺癌、肺癌、肉瘤等癌症,艾滋病,老年痴呆症等疾病。
与现有技术相比,本发明具有如下优点:
本发明公开了多种结构新颖的美达霉素类化合物,均为由放线菌通过发酵培养及提纯后得到,其结构为天然产物中首次发现。其中,具有式(I)、式(Ⅱ)结构的两种化合物具有不同于美达霉素的母核结构,活性测试发现可抑制微生物的生长,因此可用于制备抗生素类药物。具有式(Ⅲ)、式(Ⅳ)结构的两种化合物不仅可抑制微生物的生长,且具有抗肿瘤活性,特别适合用于制备抗前列腺癌药和抗结肠癌药物。特别的是,具有式(Ⅳ)结构的化合物还对ROCK 2蛋白激酶表现出较好的激酶抑制作用,可用于制备激酶抑制剂类药物。
具体实施方式
菌种来源
本发明放线菌采用中国工业微生物菌种保藏管理中心出售的链霉菌Streptomyces sp.CICC 11028。
培养基
高氏一号平板固体培养基:以培养基1L计,将可溶性淀粉20g、KNO3 1g、K2HPO40.5g、MgSO4·7H2O 0.5g、NaCl 0.5g、FeSO4·7H2O 0.01g、琼脂20g、海盐25g混合后加水至1L,再调节pH值至7.2~7.4。
高氏一号液体培养基:以发酵培养基1L计,将可溶性淀粉20g、KNO3 1g、K2HPO40.5g、MgSO4·7H2O 0.5g、NaCl 0.5g、FeSO4·7H2O 0.01g、海盐25g混合后加水至1L,再调节pH值至7.2~7.4。
实施例1
一、化合物的发酵
1)从原保存斜面或甘油管取放线菌适量,接种到高氏一号平板固体培养基上,于28℃培养箱中静置,活化培养4天。
2)将步骤1)中己经活化的放线菌的单菌落接种于含有250mL液体培养基的500mL锥形瓶中,每瓶含250mL高氏一号液体培养基,在摇床中28℃下以180rpm振荡培养8天,获得发酵液。
二、化合物的制备
(a)将发酵液用等体积的乙酸乙酯萃取3次,所得萃取液经真空干燥除去乙酸乙酯溶剂。将所得乙酸乙酯部位进行硅胶柱层析,用体积比为100:1至0:1的二氯甲烷-甲醇体系梯度洗脱,薄层检识含有新化合物的馏分,合并。
(b)所得馏分用Sephadex LH-20凝胶柱色谱分离,洗脱剂为纯甲醇溶液,合并含有新化合物的馏分。
(c)所得含有新化合物的馏分用反相高效液相色谱分离(Agilent Pursuit C-18(10μm,21.2×250mm)色谱柱,检测波长230nm,采用的流动相为甲醇体积比为10~100%含0.05%三氟乙酸的甲醇-水体系,以20mL/min梯度洗脱40分钟,收集13~15min的洗脱液。将分离纯化得到的化合物进行结构鉴定,分子式根据高分辨质谱HR-ESI-MS计算为C24H28NO9([M+H]+474.1762),进一步依据核磁共振数据(表1),其具体结构如下所示,记为strepoxepinmycin A:
该化合物的核磁共振数据列于下表1中,核磁共振参数1H 600MHz,13C 150MHz,溶剂DMSO-d6。
表1
实施例2
发酵液的获得与实施例1中相同,区别仅在于,化合物的制备步骤(c)中,所得含有新化合物的馏分用反相高效液相色谱分离(Agilent Pursuit C-18(10μm,21.2×250mm)色谱柱,检测波长230nm,采用的流动相为甲醇体积比为10~100%含0.05%三氟乙酸的甲醇-水体系,以20mL/min梯度洗脱40分钟,收集10~12min的洗脱液。将分离纯化得到的化合物进行结构鉴定,分子式根据高分辨质谱HR-ESI-MS计算为C25H32NO10([M+H]+m/z 506.2020),进一步依据核磁共振数据,其具体结构如下所示,记为strepoxepinmycin B:
该化合物的核磁共振数据列于下表2中。
表2
实施例3
发酵液的获得与实施例1中相同,区别仅在于,化合物的制备步骤(c)中,所得含有新化合物的馏分用反相高效液相色谱分离(Agilent Pursuit C-18(10μm,21.2×250mm)色谱柱,检测波长254nm,采用的流动相为甲醇体积比为10~100%含0.05%三氟乙酸的甲醇-水体系,以20mL/min梯度洗脱40分钟,收集15~17min的洗脱液。将分离纯化得到的化合物进行结构鉴定,分子式根据高分辨质谱HR-ESI-MS计算为C25H34NO10([M+H]+m/z 508.2179),进一步依据核磁共振数据,其具体结构如下所示,记为strepoxepinmycin C:
该化合物的核磁共振数据列于下表3中。
表3
实施例4
发酵液的获得与实施例1中相同,区别仅在于,化合物的制备步骤(c)中,所得含有新化合物的馏分用反相高效液相色谱分离(Agilent Pursuit C-18(10μm,21.2×250mm)色谱柱,检测波长254nm,采用的流动相为甲醇体积比为10~100%含0.05%三氟乙酸的甲醇-水体系,以20mL/min梯度洗脱40分钟,收集23~25min的洗脱液。将分离纯化得到的化合物进行结构鉴定,分子式根据高分辨质谱HR-ESI-MS计算为C25H30NO9([M+H]+m/z 488.1915),进一步依据核磁共振数据,其具体结构如下所示,记为strepoxepinmycin D:
该化合物的核磁共振数据列于下表4中。
表4
活性测试:
一、抗微生物实验
抗微生物活性检测采用96孔板法,将在MH培养基生长的待测大肠杆菌Escherichia coli ATCC 25922、金黄色葡萄球菌Staphylococcus aureus ATCC43300菌液和白色念珠菌Candida albicans分别取190μL接种于96孔板中,加入不同浓度的实施例1~4分别纯化得到的化合物的DMSO溶液,37℃培养12h,测算抑制微生物的最低浓度(MIC),数据列于下表5中。分别以多粘菌素B、万古霉素、两性霉素B为阳性药对照。
表5
二、抗肿瘤活性实验
人前列腺癌细胞PC3和结肠癌细胞HCT116抑制率实验。测定不同浓度实施例1~4分别纯化得到的化合物的抑制活性。以美达霉素作为阳性药对照。取正常培养的处于对数期的细胞,3×104个/mL铺96孔板,加入药物培养24h后CCK8检测细胞活力。细胞存活率(%)=实验组OD值/不加药组OD值×100%。最终根据各浓度抑制率计算半数抑制浓度IC50如表6所示:
表6
三、激酶抑制实验
采用KinEASETM-TK assay kit(Cisbio),以美达霉素为阳性药,测定不同浓度化合物strepoxepinmycin D对ROCK 2蛋白激酶的抑制活性。HRFT值通过测定蛋白激酶在经340nm紫外光激发后665nm和620nm的荧光比值获得,即HTRF值T=[F665nm/F620nm]×104。蛋白激酶抑制%=((T待测)-(Tmin))/((Tmax)-(Tmin))×100,Tmax为反应液的HTRF值,Tmin为没有蛋白激酶的空白反应液HTRF值。最终根据各浓度抑制率计算半数抑制浓度IC50如表7所示:
表7
IC50(μM) | |
化合物 | ROCK2 |
Strepoxepinmycin D | 19 |
美达霉素 | 0.015 |
Claims (10)
1.一类美达霉素类化合物,其特征在于,结构式分别如下式(I)~下式(Ⅳ)所示:
2.一种根据权利要求1所述的美达霉素类化合物的制备方法,其特征在于,包括以下步骤:
1)将放线菌活化后接种于高氏一号液体培养基中,摇床培养,获得发酵液;
所述放线菌,采用中国工业微生物菌种保藏管理中心出售的链霉菌Streptomycessp.CICC 11028;
2)将所述发酵液经有机溶剂萃取后获得萃取液;
3)将所述萃取液浓缩后,经分离纯化,分别获得如式(I)~式(Ⅳ)结构的美达霉素类化合物。
3.根据权利要求2所述的美达霉素类化合物的制备方法,其特征在于,步骤1)中,所述放线菌活化的过程包括:
将所述放线菌接种到高氏一号平板固体培养基上,于26~30℃培养箱中静置,活化培养若干天。
4.根据权利要求2所述的美达霉素类化合物的制备方法,其特征在于,步骤1)中:
所述高氏一号液体培养基的配制包括:
将可溶性淀粉20g、KNO3 1g、K2HPO4 0.5g、MgSO4·7H2O 0.5g、NaCl 0.5g、FeSO4·7H2O0.01g、海盐25g混合后加水至1L,再调节pH值至7.2~7.4;
所述摇床培养的条件为:26~30℃下,150~250rpm摇床中培养5~10天。
5.根据权利要求2所述的美达霉素类化合物的制备方法,其特征在于,步骤2)中,所述有机溶剂选自乙酸乙酯。
6.根据权利要求2所述的美达霉素类化合物的制备方法,其特征在于,步骤3)中:
所述浓缩,具体为:
所述萃取液经真空干燥除去溶剂;
所述分离纯化,具体为:
(a)浓缩后萃取液采用硅胶柱层析分离,用体积比为100:1至0:1的二氯甲烷-甲醇体系进行梯度洗脱,收集含有目标化合物的馏分并合并;
(b)将步骤(a)所得馏分采用凝胶柱色谱分离,并以纯甲醇作为洗脱液,收集含有目标化合物的馏分并合并;
(c)将步骤(b)所得馏分采用反相高效液相色谱分离,依次分离得到如式(I)~式(Ⅳ)所示的美达霉素类化合物。
7.根据权利要求6所述的美达霉素类化合物的制备方法,其特征在于,步骤(c)中:
检测波长为230nm,采用甲醇体积百分数为10%~100%的甲醇-0.05%三氟乙酸-水体系,以20mL/min进行梯度洗脱40min,收集13~15min的洗脱液得到如式(I)结构的美达霉素类化合物;
检测波长为230nm,采用甲醇体积百分数为10%~100%的甲醇-0.05%三氟乙酸-水体系,以20mL/min进行梯度洗脱40min,收集10~12min的洗脱液得到如式(Ⅱ)结构的美达霉素类化合物;
检测波长为254nm,采用甲醇体积百分数为10%~100%的甲醇-0.05%三氟乙酸-水体系,以20mL/min进行梯度洗脱40min,收集15~17min的洗脱液得到如式(Ⅲ)结构的美达霉素类化合物;
检测波长为254nm,采用甲醇体积百分数为10%~100%的甲醇-0.05%三氟乙酸-水体系,以20mL/min进行梯度洗脱40min,收集23~25min的洗脱液得到如式(Ⅳ)结构的美达霉素类化合物。
8.一种根据权利要求1所述的如式(I)~式(Ⅳ)所示的美达霉素类化合物在制备抗生素药物中的应用。
9.一种根据权利要求1所述的如式(Ⅲ))~式(Ⅳ)所示的美达霉素类化合物在制备抗肿瘤药物中的应用。
10.一种根据权利要求1所述的如式(Ⅳ)所示的美达霉素类化合物在制备激酶抑制剂类药物中的应用。
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