WO2021098593A1 - 多硫代二酮哌嗪类化合物Secoemestrin C的制备方法及其用途 - Google Patents

多硫代二酮哌嗪类化合物Secoemestrin C的制备方法及其用途 Download PDF

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WO2021098593A1
WO2021098593A1 PCT/CN2020/128569 CN2020128569W WO2021098593A1 WO 2021098593 A1 WO2021098593 A1 WO 2021098593A1 CN 2020128569 W CN2020128569 W CN 2020128569W WO 2021098593 A1 WO2021098593 A1 WO 2021098593A1
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acid
compound
methanol
dichloromethane
pharmaceutically acceptable
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French (fr)
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司书毅
赵午莉
陈明华
常珊珊
张聪慧
王俊霞
邵荣光
余利岩
肖同美
李妍
甄心
姜威
许艳妮
张晶
刘超
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中国医学科学院医药生物技术研究所
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/14—Fungi; Culture media therefor
    • C12N1/145—Fungal isolates
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi

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  • the present invention belongs to the technical field of natural medicines. Specifically, the present invention relates to obtaining polythiodiketopiperazine compounds Secoemestrin C and its medicinal salts from microorganisms, especially from fungal fermentation products, in the preparation and treatment of cancer-related Diseases, such as lung cancer, stomach cancer, pancreatic cancer, colon cancer, breast cancer and liver cancer.
  • cancer-related Diseases such as lung cancer, stomach cancer, pancreatic cancer, colon cancer, breast cancer and liver cancer.
  • Malignant tumors are the second leading cause of death in the world, and nearly one-sixth of all deaths worldwide are caused by cancer. According to statistics, about 8.8 million people died of various cancers in 2015, including 1.69 million deaths from lung cancer, 788,000 deaths from liver cancer, 774,000 deaths from colorectal cancer, and 754,000 deaths from gastric cancer. Cancer has become a serious threat to human health. An important factor affecting family happiness has brought a huge burden to the family and society.
  • Cytotoxic anti-tumor drugs mainly include: paclitaxel, vinblastine, hydroxycamptothecin, docetaxel and other alkaloids; cyclophosphamide and ifosfamide and other bioalkylating agents; adriamycin, daunorin Antibacterial drugs such as mycin; platinum compounds such as cisplatin and carboplatin, gemcitabine, methotrexate, tegafur, etc.
  • the main monoclonal antibodies include trastuzumab, alemtuzumab, cetuximab, and rituximab.
  • Hormones mainly include tamoxifen, moxifen, exemestane, flutamid, anastrozole, formestane, norrad, goserelin, medroxyprogesterone, dehydromethestrone, etc.; biological response regulation
  • the main agents are interferon, interleukin-2, and thymosin.
  • Natural medicine resources are abundant, and microorganisms, medicinal plants and marine organisms have always been important sources of drug precursors and innovative drugs. Microbial secondary metabolites are more and more favored by scientific researchers due to their chemical structure diversity, wide biological activity, strong reproducibility, and easy access to large quantities of samples through fermentation and modern synthetic biology technology.
  • the present invention is separated and purified from the anti-tumor active components of a rice fermentation product of the genus Emericella sp.1454, and identified a polysulfide with anti-lung cancer, pancreatic cancer, colon cancer, breast cancer and liver cancer activities.
  • the second-generation diketopiperazine compound Secoemestrin C, activity test results show that for the first time it was found that the compound has strong toxicity to a variety of tumor cell lines, and also exhibits strong anti-tumor activity in animals. Therefore, the compound has good application prospects for anti-tumor activity.
  • the patent of the present invention relates to Secoemestrin C producing strain, preparation method, anti-tumor cell strain and anti-tumor activity in vivo. So far, there is no relevant report.
  • One of the objectives of the present invention is to provide a Gymnosporium fungus (Fungus 1454).
  • the strain of the present invention has an accession number: CGMCC No. 17765.
  • the strain was sent to the General Microbiology Center of the China Microbial Culture Collection Management Committee on May 30, 2019.
  • the strain of the present invention is used to prepare polythiodiketopiperazine compounds (Secoemestrin C).
  • the second objective of the present invention is to provide a polythiodiketopiperazine compound (Secoemestrin C) or a pharmaceutically acceptable salt thereof.
  • the molecular formula of the compound is: C 27 H 22 N 2 O 10 S 4 , and the molecular weight is: 662.
  • the medicinal salt of the polythiodiketopiperazine compound of the present invention includes the salt formed by the compound and inorganic acid, such as hydrochloric acid, sulfuric acid, and organic acid, such as acetic acid, trifluoroacetic acid, citric acid, and maleic acid.
  • the third object of the present invention is to provide a method for preparing the polythiodiketopiperazine compound or its pharmaceutically acceptable salt.
  • the present invention is the first to isolate and extract the compound represented by formula I from the strain (fungus 1454) with the deposit number: CGMCC No. 17765.
  • the preparation method of the polythiodiketopiperazine compound or its pharmaceutically acceptable salt according to the present invention includes the following steps:
  • the rice fermentation product is ultrasonically extracted 3 times with 10L 95% ethanol/water and 3 times with 10L 50% ethanol/water.
  • the extracts are combined and concentrated under reduced pressure to obtain an aqueous suspension.
  • the extract was extracted with ethyl acetate to obtain the extract of ethyl acetate; the obtained extract was separated by normal phase silica gel chromatography, followed by gradient elution of dichloromethane, dichloromethane-methanol, and methanol, among which dichloromethane-methanol
  • the distillate is divided into the active component, and then the active component is purified by gel column chromatography and HPLC semi-preparative purification to obtain the compound represented by formula I.
  • the preparation method of the polythiodiketopiperazine compound or the pharmaceutically acceptable salt thereof of the present invention includes the following steps:
  • the rice fermentation product is ultrasonically extracted 3 times with 10L 95% ethanol and 3 times with 10L 50% ethanol.
  • the extracts are combined and concentrated under reduced pressure to obtain an aqueous suspension, which is extracted with ethyl acetate to obtain acetic acid Ethyl part extract; the obtained extract was separated by normal phase silica gel chromatography, followed by dichloromethane, dichloromethane-methanol (40:1), dichloromethane-methanol (30:1), dichloromethane- Methanol (20:1), dichloromethane-methanol (15:1), dichloromethane-methanol (10:1) and dichloromethane-methanol (5:1), methanol gradient elution, in which dichloromethane- The methanol (15:1) fraction J is the active component, and then the J component is eluted with methanol on a Sephadex LH-20 gel column, and the component JF is semi-preparatively purified (
  • the fungus 1454 which was sent to the General Microbiology Center of the China Microbial Culture Collection Management Committee on May 30, 2019, the address of the preservation unit: No. 3, No. 1, Beichen West Road, Chaoyang District, Beijing, and the preservation number: CGMCC No .17765.
  • the fourth object of the present invention is to provide a pharmaceutical application of the compound represented by formula I or its pharmaceutically acceptable salt.
  • polythiodiketopiperazine compound or its medicinal salt in the present invention in preparing and treating various tumor cell line toxicity and anti-tumor drugs.
  • the present invention uses a water-soluble tetrazolium salt-based cell proliferation and cytotoxicity detection method (Cell Counting Kit) to screen the fermented product, extracted fraction of fungus 1454 and the isolated polythiodiketopiperazine represented by formula I
  • Cell Counting Kit water-soluble tetrazolium salt-based cell proliferation and cytotoxicity detection method
  • the activity of the compound against various human tumor cell lines The experimental results showed that the compound represented by formula I showed resistance to A549 (lung cancer cells), HCT8 (colon cancer cells), MDA-MB-231 (breast cancer cells), MCF-7 (breast cancer cells), AsPC-1 (pancreatic cancer cells) Cancer cells), BxPC-3 (pancreatic cancer cells), MIA-paca-2 (pancreatic cancer cells), and SU86.86 (pancreatic cancer cells) all have strong cytotoxicity.
  • the polythiodiketopiperazine compound can be used as a medicine for preparing anti-tumor-related diseases; and the polythiodiketopiperazine compound is used as an active ingredient with one or more pharmaceutically acceptable compounds.
  • Compatibility of the various carriers, excipients or adjuvants can be made into an anti-tumor pharmaceutical composition.
  • the medicine and the pharmaceutical composition can be used for clinical treatment of anti-tumor.
  • the compound can also be combined with known drugs to form a compound preparation for the treatment of cancer diseases.
  • the fifth object of the present invention is to provide the use of a pharmaceutical composition containing the compound represented by formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition containing the compound represented by the formula I or its pharmaceutically acceptable salt is prepared to be toxic to various tumor cell lines and its application in anti-tumor drugs.
  • the applications of the present invention include anti-lung cancer, pancreatic cancer, colon cancer, gastric cancer, breast cancer and liver cancer.
  • the sixth object of the present invention is to provide a pharmaceutical composition containing the compound represented by formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present invention also contains a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention uses the compound represented by the formula (I) and the pharmaceutically acceptable salt thereof as the pharmaceutical active ingredient.
  • the weight ratio of the compound represented by formula (I) or its pharmaceutically acceptable salt contained in the pharmaceutical composition in the composition is 0.1-99.9%, and the weight ratio of the pharmaceutically acceptable carrier in the composition is 0.1-99.9%.
  • the pharmaceutical composition is in the form of a preparation suitable for medicinal use.
  • the medicinal preparations are tablets, capsules, granules, pills, powders, ointments, suspensions, injections, powder injections, suppositories, creams, drops or patches.
  • the tablet is a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet or a sustained-release tablet;
  • the capsule is a hard capsule, a soft capsule, or a sustained-release capsule;
  • the powder injection is Freeze-dried powder injection.
  • each dose refers to each preparation unit, such as each tablet or capsule , Can also refer to each dose, such as 100mg each time.
  • solid carriers When the pharmaceutical composition of the present invention is prepared into solid or semi-solid pharmaceutical preparations in the form of powders, tablets, dispersible powders, capsules, cachets, suppositories and ointments, solid carriers can be used.
  • the usable solid carrier is preferably one or more substances selected from diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, expanding agents, etc., or may be encapsulating substances. In powder formulations, 5 to 70% of the micronized active ingredient is contained in the carrier.
  • Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, methyl cellulose, sodium carboxymethyl cellulose, low boiling wax, cocoa butter and the like. Because of their ease of administration, tablets, powders, cachets and capsules represent the most advantageous oral solid preparations.
  • the liquid preparations of the present invention include solutions, suspensions and emulsions.
  • the injection preparation for parenteral administration may be in the form of water or water-propylene glycol solution, and its isotonicity, pH, etc. may be adjusted to suit the physiological conditions of the living body.
  • Liquid preparations can also be made into solutions in polyethylene glycol or aqueous solutions.
  • the oral aqueous solution can be prepared by dissolving the active ingredient in water, and then adding appropriate amounts of coloring agents, flavoring agents, stabilizers and thickening agents.
  • the micronized active ingredients can be dispersed in viscous materials such as natural and synthetic gums, methyl cellulose, sodium carboxymethyl cellulose and other known suspending agents to prepare aqueous suspensions suitable for oral administration.
  • the dosage unit form of a formulation refers to physically separate units suitable as a single dose, each unit containing a calculated predetermined amount of active ingredient that produces the desired therapeutic effect.
  • Such dosage unit forms can be packaged forms such as tablets, capsules or powders in tubes or vials, or ointments, gels or creams in tubes or bottles.
  • the amount of the active ingredient contained in the dosage unit form can vary, it is generally adjusted within the range of 1 to 800 mg according to the potency of the selected active ingredient.
  • the initial treatment amount is lower than the optimal dosage of the active ingredient, and then the dosage is gradually increased until the optimal therapeutic effect is achieved.
  • the total daily dose can be administered at one time or several times.
  • the present invention separates and prepares a polythiodiketopiperazine compound as shown in formula I from the fermentation product of a fungus 1454, which has strong inhibitory activity on a variety of human tumor cell lines and tumors in the body, and is expected to be developed into a clinic New anti-tumor drugs on the market.
  • the compound represented by the formula (I) of the present invention has a superior therapeutic effect and is less toxic.
  • the source of the present invention is a microbial natural product, which is easy to obtain and has good reproducibility.
  • the preparation method has simple process and short time, greatly reduces the cost of medicine, and is suitable for large-scale production.
  • Figure 5 The inhibitory effect of compound 1 on the growth of human breast cancer MCF-7 transplanted tumor in nude mice
  • the embodiments of the present invention are applicable to the preparation of polythiodiketopiperazine compounds from any microorganisms, not limited to fungal fermentation products.
  • the following examples are to help those skilled in the art better understand the present invention, but do not limit the present invention in any way.
  • the activated fungus 1454 strain was inoculated on the PDA slope and cultured in a thermostat at 25°C for one week. The seeds were dug out on the slope, crushed and inoculated into 3 500mL Erlenmeyer flasks containing 100mL PDB medium. After shaking at 25°C for 5 days, it was used as seed solution. Put 100g rice and 100ml distilled water into each 500ml Erlenmeyer flask, seal it and sterilize it at 121°C for 15min. After cooling, add 10ml of the above seed solution (total 30 bottles) to each bottle, and cultivate at 25°C for 30 days. Fungus 1454 rice fermented product.
  • Example 1 Take the fermented rice in Example 1 and extract 3 times with 10L 95% ethanol/water ultrasonically and 3 times with 10L 50% ethanol/water. The extracts are combined and concentrated under reduced pressure to obtain an aqueous suspension, which is extracted with ethyl acetate. Obtain the ethyl acetate extract.
  • Example 2 The extract obtained in Example 2 was separated by normal phase silica gel chromatography, followed by dichloromethane, dichloromethane-methanol (40:1), dichloromethane-methanol (30:1), dichloromethane-methanol ( 20:1), dichloromethane-methanol (15:1), dichloromethane-methanol (10:1) and dichloromethane-methanol (5:1), methanol gradient elution, in which dichloromethane-methanol ( 15:1) The fraction is divided into active components, and then the components are eluted by Sephadex LH-20 gel column with methanol, and then semi-preparatively purified (Capcell-Pak C 18 5 ⁇ m, 10 ⁇ 250mm, 46% CH 3 CN/ H 2 O, 1.5 ml/min) to obtain the compound represented by formula I.
  • Compound 1 is a white powder, easily soluble in methanol solution.
  • High resolution electrospray mass spectrometry gave the quasi-molecular ion peak m/z 685.0053[M+H] + , suggesting that its molecular composition is C 27 H 22 N 2 O 10 S 4 (calcd for C 27 H 22 N 2 O 10 S 4 Na, 685.0054).
  • the 13 C NMR (Acetone-d 6 , 150MHz) of compound 1 is: 166.8(C-1), 32.3(C-NCH 3 -2), 68.7(C-3), 164.4(C-4), 60.2(C -5a), 72.7(C-6), 108.5(C-7), 140.1(C-8), 142.4(C-10), 113.2(C-10a), 78.5(C-11), 81.2(C- 11a), 123.8(C-1'), 122.9(C-2'), 145.5(C-3'), 156.3(C-4'), 56.6(C-4-OMe'), 113.2(C-5 '),129.0(C-6'),165.9(C-7'),146.5(C-1”),154.7(C-2”),117.7(C-3”),128.6(C-4”) ,130.8(C-5”),118.5(C-6”),191.0(C-7”).
  • Cell Counting Kit is a cell proliferation and cytotoxicity detection method based on water-soluble tetrazolium salt.
  • the electronic coupling reagent 1-Methoxy PMS it can be reduced to soluble orange-yellow formazan by dehydrogenase in the mitochondria.
  • the number of formazan is directly proportional to the number of living cells. The faster the cell proliferation, the lower the cytotoxicity, and the greater the number of cells, the darker the color, and the depth of the color has a good linear relationship with the number of cells.
  • HCT8 colon cancer cells
  • MDA-MB-231 breast cancer cells
  • MCF-7 breast cancer cells
  • AsPC-1 pancreatic cancer cells
  • BxPC-3 pancreatic cancer cells
  • MIA-paca-2 pancreatic cancer cells
  • PANC-1 pancreatic cancer cells
  • SU86.86 pancreatic cancer cells
  • SW1990 pancreatic cancer cells
  • Plating the plate adding the adjusted concentration of the cell culture solution to the wells of the 96-well plate, 200 ⁇ l per well, sealing the periphery with serum-free medium, and placing the cells in an incubator to grow to the logarithmic phase.
  • Test compound 1 gemcitabine (Gemcitabine), adriamycin (Dox), and oxaliplatin (1 mg), and mix them into a 10 mM DMSO stock solution for later use.
  • the compound to be tested was diluted with complete medium to make the final concentration of the drug 5 ⁇ M, 4 ⁇ M, 3 ⁇ M, 2 ⁇ M, 1 ⁇ M, 0.5 ⁇ M, respectively. Discard the original culture medium and add 200 ⁇ l of drug solution to each well.
  • Tumor cell survival rate% (fluorescence absorption value of dosing hole-fluorescence absorption value of blank hole)/(fluorescence absorption value of solvent control hole-fluorescence absorption value of blank hole) ⁇ 100%
  • the survival rate at each concentration was determined, and the IC 50 value of the sample to be tested was calculated using SigmaPlot software.
  • nude mice Take 25 female BALB/c nude mice weighing 18-22g, inoculate human breast cancer MCF-7 cells into the shoulders of nude mice, each inoculate 1 ⁇ 10 7 cells, when the tumor grows to 300mm 3 size, Take the tumor block for transfer.
  • the nude mice are grouped according to tumor size and weight, so that the average tumor size in each group is about 100 mm 3 , and the average weight of each group is close, with 5 nude mice in each group.
  • the compound of formula I and adriamycin were administered intraperitoneally, once every other day. Each nude mouse was injected with 200 ⁇ l, and the control group was given a blank solvent control.
  • the animals were sacrificed on the 24th day of the experiment, the tumors were isolated and weighed, and the tumor inhibition rate was calculated (Figure 2, Table 2).
  • the experimental results show that the compound of formula I can significantly inhibit the growth of human breast cancer MCF-7 transplanted tumors in nude mice, and the tumor inhibition rates of the 2.5 mg/kg and 10.0 mg/kg dose groups are 69.6% ⁇ 8.8% and 73.8%, respectively ⁇ 11.2%, both showed stronger tumor growth inhibition than 3.0mg/kg (tolerable dose) of doxorubicin (tumor inhibition rate of 57.9% ⁇ 15.9%).

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Abstract

本发明属于天然药物技术领域，具体地，本发明涉及从微生物中，特别是从真菌发酵产物中获得多硫代二酮哌嗪类化合物Secoemestrin C及其药用盐类在制备和治疗与癌症相关的疾病，例如肺癌、胰腺癌、结肠癌、乳腺癌、胃癌和肝癌等。本发明所述的多硫代二酮哌嗪类化合物或其药用盐，其结构如（I）所示。

Description

多硫代二酮哌嗪类化合物Secoemestrin C的制备方法及其用途 技术领域
本发明属于天然药物技术领域，具体地，本发明涉及从微生物中，特别是从真菌发酵产物中获得多硫代二酮哌嗪类化合物Secoemestrin C及其药用盐类在制备和治疗与癌症相关的疾病，例如肺癌、胃癌、胰腺癌、结肠癌、乳腺癌和肝癌等。
背景技术
恶性肿瘤(癌症)是全球第二大死因，全球近六分之一的死亡是由癌症造成的。据统计，2015年约880万人死于各种癌症，其中肺癌死亡169万例、肝癌死亡78.8万例、结肠直肠癌死亡77.4万例、胃癌死亡75.4万例，癌症已成为严重威胁人类健康与影响家庭幸福的一个重要因素，为家庭和社会带来了巨大的负担。
目前，临床上抗肿瘤的药物根据其作用机制主要可以分为以下几类：细胞毒类、单抗类、激素类、生物反应调节剂等药物。细胞毒类抗肿瘤药物主要有：紫杉醇、长春花碱、羟基喜树碱、多西他赛等生物碱类；环磷酰胺和异环磷酰胺等生物烷化剂类；阿霉素、柔红霉素等抗菌药物；顺铂和卡铂等铂类化合物，吉西他宾、甲氨喋呤、替加氟等。单抗类主要有曲妥珠单抗、阿伦珠单抗西妥昔单抗和利妥昔单抗等。激素类主要有三苯氧胺、莫西芬、依西美坦、氟它米、阿那曲唑、福美司坦、诺雷得、戈舍瑞林、甲孕酮、去氢甲孕酮等；生物反应调节剂主要有干扰素、细胞介素-2、胸腺肽类。
这些药物的应用虽在一定程度上为癌症患者带来了很大的福音，但是随着药物的长期应用，其中有些药物在临床上发生了继发性耐药的情况，其中有治疗肺癌的抗肿瘤药吉非替尼、培美曲塞；治疗胃肠道间质瘤的伊马替尼；治疗乳腺癌的抗肿瘤药氟维司群；治疗胶质瘤的抗肿瘤药替尼泊苷等。另外，传统的抗肿瘤药物因选择性差、不良反应大等问题也一直是世界科学家们寻找新的抗肿瘤药物的动力。
天然药物资源丰富，微生物、药用植物及海洋生物一直是药物先导物及创新药物的重要来源。微生物次级代谢产物由于其化学结构多样性、广泛的生物活性、可重复性强，并可通过发酵及利用现代合成生物学技术容易大量获得样品等优点，越发受到科研工作者的青睐。
本发明从一株裸胞壳属真菌Emericella sp.1454大米发酵产物的抗肿瘤活性组分中分离纯化，并鉴定了一个具有抗肺癌、胰腺癌、结肠癌、乳腺癌和肝癌等活性的多硫代二酮哌嗪类化合物Secoemestrin C，活性测试结果表明，首次发现该化合物对多种肿瘤细胞株具有较强的毒性，在动物体内也体现出较强的抗肿瘤活性。因此，该化合物具有较好的抗肿瘤活性应用前景。本发明专利涉及Secoemestrin C的产生菌株、制备方法及抗肿瘤细胞株和体内抗肿瘤活性，迄今为止，尚未见有相关报道。
发明内容
本发明目的之一是，提供一株裸胞壳菌真菌(真菌1454)。
本发明所述的菌株，保藏编号：CGMCC No.17765。
该菌株于2019年05月30日送交中国微生物菌种保藏管理委员会普通微生物中心保藏，保藏单位地址：北京市朝阳区北辰西路1号院3号，保藏编号：CGMCC No.17765，分类命名：裸胞壳菌Emericella sp.。
本发明所述的菌株用于制备多硫代二酮哌嗪类化合物(Secoemestrin C)。
本发明目的之二是，提供一种多硫代二酮哌嗪类化合物(Secoemestrin C)或其药用盐。
本发明所述的多硫代二酮哌嗪类化合物或其药用盐，该化合物的结构如式I所示：
Figure PCTCN2020128569-appb-000001
该化合物的分子式为：C 27H 22N 2O 10S 4，分子量为：662。
本发明所述的多硫代二酮哌嗪类化合物的药用盐，包括该化合物与无机酸，如盐酸、硫酸形成的盐，与有机酸，如乙酸、三氟乙酸、柠檬酸、马来酸、草酸、琥珀酸、苯甲酸、酒石酸、富马酸、扁桃酸、抗坏血酸或苹果酸形成的盐，以及氨基酸，如丙氨酸、天冬氨酸、赖氨酸形成的盐或与磺酸，如甲磺酸、对甲苯磺酸形成的盐。
本发明目的之三是，提供所述多硫代二酮哌嗪类化合物或其药用盐的制备方法。
本发明首次从保藏编号：CGMCC No.17765的菌株(真菌1454)中分离提取出式Ⅰ所示的化合物。
本发明所述的多硫代二酮哌嗪类化合物或其药用盐的制备方法，包括以下步骤：
先取真菌1454经大米发酵得到大米发酵产物，将大米发酵产物经10L 95％乙醇/水超声提取3次、10L 50％乙醇/水提取3次，合并提取液，减压浓缩后得到水混悬液，用乙酸乙酯萃取，得到乙酸乙酯部位浸膏；所得浸膏利用正相硅胶色谱柱色谱分离，依次用二氯甲烷、二氯甲烷-甲醇、甲醇梯度洗脱，其中二氯甲烷-甲醇馏分为活性组分，然后该活性组分经凝胶柱色谱以及HPLC半制备纯化，得到式I所示化合物。
优选的，本发明所述的多硫代二酮哌嗪类化合物或其药用盐的制备方法，包括以下步骤：
真菌1454经大米发酵后，大米发酵产物经10L 95％乙醇超声提取3次、10L 50％乙醇提取3次，合并提取液，减压浓缩后得到水混悬液，用乙酸乙酯萃取，得到乙酸乙酯部位浸膏；所得浸膏利用正相硅胶色谱柱色谱分离，依次用二氯甲烷、二氯甲烷-甲醇(40:1)、二氯甲烷-甲醇(30:1)、二氯甲烷-甲醇(20:1)、二氯甲烷-甲醇(15:1)、二氯甲烷-甲醇(10:1)和二氯甲烷-甲醇(5:1)、甲醇梯度洗脱，其中二氯甲烷-甲醇(15:1)馏分J为活性组分，然后将 J组分经Sephadex LH-20凝胶柱甲醇洗脱，其中组分J-F经半制备纯化(Capcell-Pak C 185μm,10×250mm,46％CH 3CN/H 2O,1.5ml/min)得到式I所示化合物。
其中，真菌1454，该菌株于2019年05月30日送交中国微生物菌种保藏管理委员会普通微生物中心保藏，保藏单位地址：北京市朝阳区北辰西路1号院3号，保藏编号：CGMCC No.17765。
本发明的目的之四是，提供式I所示化合物或其药用盐的药物应用。
本发明所述的多硫代二酮哌嗪类化合物或其药用盐在制备治疗各种肿瘤细胞株毒性及抗肿瘤药物上的应用。本发明所述的化合物或其药用盐在制备抗肺癌、胰腺癌、结肠癌、乳腺癌和肝癌药物中的应用。
本发明采用一种基于水溶性四唑盐的细胞增殖和细胞毒性检测方法(Cell Counting Kit)筛选真菌1454的发酵物、提取馏分及所分离获得的式I所示的多硫代二酮哌嗪类化合物的抗各种人肿瘤细胞株的活性。实验结果表明，式I所示的化合物显示对A549(肺癌细胞)、HCT8(结肠癌细胞)、MDA-MB-231(乳腺癌细胞)、MCF-7(乳腺癌细胞)、AsPC-1(胰腺癌细胞)、BxPC-3(胰腺癌细胞)、MIA-paca-2(胰腺癌细胞)、SU86.86(胰腺癌细胞)均有较强的细胞毒性。表明所述多硫代二酮哌嗪类化合物可用作制备抗肿瘤相关疾病的药物；而以所述多硫代二酮哌嗪类化合物作为活性成分，与药学上可接受的一种或多种载体、赋形剂或辅料配伍，可制成抗肿瘤药物组合物。所述药物及药物组合物可用于抗肿瘤的临床治疗。所述化合物也可与已知药物组成复方制剂用于癌症疾病的治疗。
本发明的目的之五是，提供含有式I所示化合物或其药用盐的药物组合物的应用。
含有式I所示化合物或其药用盐的药物组合物在制备对各种肿瘤细胞株上毒性及其在抗肿瘤药物中的应用。
本发明所述应用包括，抗肺癌、胰腺癌、结肠癌、胃癌、乳腺癌和肝癌。
本发明的目的之六是，提供一种含有式I所示化合物或其药用盐的药物组合物。
本发明所述的药物组合物，还含有药物上可接受的载体。
本发明所述的药物组合物，以式(I)所示化合物及其药用盐作为药物活性成分。
药物组合物含有的式(I)所示化合物或其药用盐在组合物中的重量比为0.1～99.9％，药物可接受的载体在组合物中的重量比为0.1～99.9％。
药物组合物以适合药用的制剂形式存在。
药用的制剂为片剂、胶囊剂、颗粒剂、丸剂、散剂、膏剂、混悬剂、注射剂、粉针剂、栓剂、霜剂、滴剂或贴剂。其中，所述片剂为糖衣片剂、薄膜衣片剂、肠溶衣片剂或缓释片剂；所述胶囊剂为硬胶囊剂、软胶囊剂、缓释胶囊剂；所述粉针剂为冻干粉针剂。
本发明的药物组合物，作为制剂形式，每剂中含有的发明化合物的有效量为0.1～1000mg，所述每剂指的是，每一制剂单位，如片剂的每片，胶囊的每粒，也可指每次服用剂量，如每次服用100mg。
本发明的药物组合物在制备成粉剂、片剂、可分散粉剂、胶囊、扁囊剂、栓剂和软膏形式的固体或半固体药物制剂时，可使用固体载体。可使用的固体载体优选为选自稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、膨胀剂等中的一种或多种物质，或可为包封物质。在粉状制剂中，在载体中含有5～70％的微粒化活性成分。适宜的固体载体包括碳酸镁、硬脂酸镁、滑石粉、蔗糖、乳糖、果胶、糊精、淀粉、明胶、甲基纤维素、羧甲基纤维素钠、低沸点 蜡、可可脂等。由于它们易于给药，片剂，粉剂、扁囊剂和胶囊等代表最有利的口服固体制剂。
本发明的液体制剂包括溶液、悬液和乳液。例如，非胃肠道给药的注射制剂可为水或水-丙二醇溶液形式，调节其等渗度，pH等使适于活体的生理条件。液体制剂还可制成在聚乙二醇、水溶液中的溶液形式。可通过将活性成分溶解在水中，再加入适量的着色剂、调味剂、稳定剂和增稠剂，来制备口服水溶液。可将微粒化的活性成分分散在粘性物质如天然和合成胶、甲基纤维素、羧甲基纤维素钠和其它已知悬浮剂中制备适于口服的水悬液。
为了易于给药及剂量均一，将上述药物制剂配制成剂量单位形式是特别有利的。制剂的剂量单位形式指适于作为单一剂量的物理分离单位，每个单位含有产生所期望的治疗效果的计算好的预定量的活性成分。这种剂量单位形式可为包装形式，如片剂、胶囊或装在小管或小瓶中的粉剂，或装在管或瓶中的软膏、凝胶或霜剂。
虽然剂量单位形式中所含活性成分的量可以变化，但一般根据所选择活性成分的效力，调节在1～800mg范围内。
本领域技术人员可按常规方法确定适于某种情况的优选剂量。一般，开始治疗的量低于活性成分的最佳剂量，然后逐渐增加给药剂量，直到达到最佳治疗效果。为治疗需要，总的日剂量可一次给药或分数次给药。
本发明从一株真菌1454的发酵产物中分离制备获得如式Ι所示多硫代二酮哌嗪类化合物，对多种人肿瘤细胞株以及体内肿瘤具有很强的抑制活性，有望开发成为临床上抗肿瘤的新型药物。
本发明式(I)所示化合物，与现有的同类抗肿瘤药物相比，具有更加优越的治疗效果，毒性更小。同时，本发明的来源为微生物天然产物，容易获得以及重复性好，制备方法工艺简单，用时短，大大降低药品的成本，适合大规模生产。
附图说明
图1：化合物1的高分辨质谱
图2：化合物1的 1H NMR谱
图3：化合物1的 13C NMR谱
图4：化合物1杀伤8株肿瘤细胞的浓度-生存率曲线
图5：化合物1对人乳腺癌MCF-7裸鼠移植瘤的生长抑制作用
实施方案：
本发明实施方案适用于从任何微生物，而不限于从真菌发酵物制备多硫代二酮哌嗪类化合物。以下所列实施例是为帮助本领域技术人员更好地理解本发明，但不以任何方式限制本发明。
<实施例1>用于真菌1454的发酵：
取活化的真菌1454菌种接种于PDA斜面，25℃恒温箱培养一周。将种子斜面挖块，碾碎接种于3个装有100mL PDB培养基的500mL锥形瓶中，25℃振摇培养5天后，作为种子液。每个500ml的三角瓶中放入100g大米及100ml蒸馏水，封口后在121℃，灭菌15min，冷却后向每瓶加入10ml上述种子液(共30瓶)，并在25℃培养30天，得到真菌1454大米发酵物。
<实施例2>真菌1454发酵物的提取与浸膏的获得：
取实施例1中大米发酵物经10L 95％乙醇/水超声提取3次、10L 50％乙醇/水提取3次，合并提取液，减压浓缩后得到水混悬液，用乙酸乙酯萃取，得到乙酸乙酯部位浸膏。
<实施例3>化合物1的分离、制备及结构鉴定：
取实施例2所得浸膏利用正相硅胶色谱柱色谱分离，依次用二氯甲烷、二氯甲烷-甲醇(40:1)、二氯甲烷-甲醇(30:1)、二氯甲烷-甲醇(20:1)、二氯甲烷-甲醇(15:1)、二氯甲烷-甲醇(10:1)和二氯甲烷-甲醇(5:1)、甲醇梯度洗脱，其中二氯甲烷-甲醇(15:1)馏分为活性组分，然后将该组分经Sephadex LH-20凝胶柱甲醇洗脱，再经半制备纯化(Capcell-Pak C 185μm,10×250mm,46％CH 3CN/H 2O,1.5ml/min)得到式I所示化合物。
式I所示化合物1的结构鉴定
(1)化合物1为白色粉末，易溶于甲醇溶液。高分辨电喷雾质谱(HRESIMS)给出准分子离子峰m/z 685.0053[M+H] +，提示其分子组成为C 27H 22N 2O 10S 4(calcd for C 27H 22N 2O 10S 4Na,685.0054)。化合物1的 13C NMR(Acetone-d 6,150MHz)为：166.8(C-1),32.3(C-NCH 3-2),68.7(C-3),164.4(C-4),60.2(C-5a),72.7(C-6),108.5(C-7),140.1(C-8),142.4(C-10),113.2(C-10a),78.5(C-11),81.2(C-11a),123.8(C-1'),122.9(C-2'),145.5(C-3'),156.3(C-4'),56.6(C-4-OMe'),113.2(C-5'),129.0(C-6'),165.9(C-7'),146.5(C-1”),154.7(C-2”),117.7(C-3”),128.6(C-4”),130.8(C-5”),118.5(C-6”),191.0(C-7”)。该化合物的氢谱和碳谱数据与Secoemestrin C[Ooike M,Nozawa K,Kawai K I.An epitetrathiodioxopiperazine related to emestrin from Emericella foveolate.Phytochemistry,1997,46(1):123-126.]文献报道的数据基本一致，因此鉴定化合物1为secoemestrin C。
本发明化合物的结构式为：
Figure PCTCN2020128569-appb-000002
<实施例4>式Ⅰ化合物杀伤肿瘤细胞能力测试
Cell Counting Kit,是一种基于水溶性四唑盐的细胞增殖和细胞毒性检测方法。它在电子耦合试剂1-Methoxy PMS存在的情况下，可以被线粒体内的脱氢酶还原为可溶性的橙黄色甲臜(formazan)。甲臜的数量与活细胞的数量成正比。细胞增殖越快、细胞毒性越小、细胞数量越多，则颜色越深，颜色的深浅与细胞数量呈现良好的线性关系。
操作步骤
将对数生长期的HCT8(结肠癌细胞)、MDA-MB-231(乳腺癌细胞)、MCF-7(乳腺癌细胞)、AsPC-1(胰腺癌细胞)、BxPC-3(胰腺癌细胞)、MIA-paca-2(胰腺癌细胞)、PANC-1(胰腺癌细胞)、SU86.86(胰腺癌细胞)和SW1990(胰腺癌细胞)用0.25％胰酶消化，调整细胞浓度 为2.5×10 4个/mL。铺板，将调整浓度后的细胞培养液加入96孔板的孔中，每孔200μl，周边以无血清的培养基封闭，将细胞置于培养箱中培养至对数期。分别取待测化合物1、吉西他滨(Gemcitabine)、阿霉素(Adriamycin,Dox)、奥沙利铂(Oxaliplatin)1mg，配成10mM的DMSO储液备用。将待测化合物以完全培养基稀释，使药物终浓度分别为5μM、4μM、3μM、2μM、1μM、0.5μM。弃原培养液，每孔加入200μl药物溶液。每个浓度设立3个复孔，设立空白对照组和溶剂对照组。在细胞培养箱中继续培养48h。取出96孔板，弃上清液，每孔加入100μl含有10％的CCK Solution的完全培养基，在细胞培养箱中继续培养1-4小时，用酶标仪测定450nm处的吸光值。
肿瘤细胞生存率％＝(给药孔荧光吸收值-空白孔的荧光吸收值)/(溶剂对照孔的荧光吸收值-空白孔的荧光吸收值)×100％
测定每个浓度下的生存率，使用SigmaPlot软件计算得到待测样品的IC 50值。
实验结果：式Ⅰ化合物杀伤8株肿瘤细胞的IC 50值如表1所示，浓度-生存率曲线如图1所示。
表1.式Ⅰ化合物以及阳性对照药对9株肿瘤细胞株的毒性
Figure PCTCN2020128569-appb-000003
<实施例5>式Ⅰ化合物对人乳腺癌MCF-7裸鼠移植瘤的生长抑制作用
取体重为18-22g的雌性BALB/c裸鼠25只，将人乳腺癌MCF-7细胞接种于裸鼠肩部，每只接种1×10 7个细胞，待瘤子长至300mm 3大小时，取瘤块进行转接。待瘤子长至100mm 3大小时将裸鼠按照瘤子大小和体重进行分组，使每组瘤子大小平均值约为100mm 3，且各组体重平均值接近，每组5只裸鼠。分别腹腔给药式Ⅰ化合物和阿霉素，隔天一次。每只裸鼠注射200μl，对照组给予空白溶剂对照。实验期间每2天测量一次肿瘤直径和体重，根据公式V＝ab 2/2计算肿瘤体积(a：肿瘤长径，b：肿瘤短径)，绘制肿瘤生长曲线，观察体重变化。实验第24天处死动物，分离肿瘤并称重，计算抑瘤率(图2，表2)。
表2.化合物IMB-122对人乳腺癌MCF-7裸鼠移植瘤的生长抑制作用
组别 裸鼠数量 瘤重(g)Mean±SD 抑瘤率％(瘤重)ean±SD
对照组 5 0.99±0.38 -
式Ⅰ化合物2.5mg/kg 5 0.30±0.09 69.6±8.8**
式Ⅰ化合物5.0mg/kg 5 0.37±0.01 63.2±10.7
式Ⅰ化合物10.0mg/kg 5 0.26±0.11 73.8±11.2**
阿霉素3.0mg/kg 5 0.42±0.16 57.9±15.9
**与对照组相比，P<0.01
实验结果表明，式Ⅰ化合物可显著的抑制人乳腺癌MCF-7裸鼠移植瘤的生长，其中2.5mg/kg和10.0mg/kg剂量组的抑瘤率分别为69.6％±8.8％和73.8％±11.2％，均表现出比3.0mg/kg(耐受剂量)的阿霉素(抑瘤率为57.9％±15.9％)更强的肿瘤生长抑制。

Claims (9)

  1. 一种多硫代二酮哌嗪类化合物Secoemestrin C或其药用盐，其特征在于，该化合物的结构如式I所示：
    Figure PCTCN2020128569-appb-100001
  2. 根据权利要求1所述的多硫代二酮哌嗪类化合物或其药用盐，其特征在于，该化合物的药用盐，包括与无机酸，如盐酸、硫酸形成的盐，与有机酸，如乙酸、三氟乙酸、柠檬酸、马来酸、草酸、琥珀酸、苯甲酸、酒石酸、富马酸、扁桃酸、抗坏血酸或苹果酸形成的盐，以及氨基酸，如丙氨酸、天冬氨酸、赖氨酸形成的盐或与磺酸，如甲磺酸、对甲苯磺酸形成的盐。
  3. 根据权利要求1所述的多硫代二酮哌嗪类化合物或其药用盐，其特征在于，式Ⅰ所示的化合物是从真菌1454大米发酵产物中分离提取出的。
  4. 权利要求1所述的多硫代二酮哌嗪类化合物或其药用盐的制备方法，其特征在于，包括以下步骤：
    真菌1454经大米发酵后，大米发酵产物经10L 95％乙醇超声提取3次、10L 50％乙醇提取3次，合并提取液，减压浓缩后得到水混悬液，用乙酸乙酯萃取，得到乙酸乙酯部位浸膏；所得浸膏利用正相硅胶色谱柱色谱分离，依次用二氯甲烷、二氯甲烷-甲醇(40:1)、二氯甲烷-甲醇(30:1)、二氯甲烷-甲醇(20:1)、二氯甲烷-甲醇(15:1)、二氯甲烷-甲醇(10:1)和二氯甲烷-甲醇(5:1)、甲醇梯度洗脱，其中二氯甲烷-甲醇(15:1)馏分J为活性组分，然后将J组分经Sephadex LH-20凝胶柱甲醇洗脱，其中组分J-F经半制备纯化(Capcell-Pak C 18 5μm,10×250mm,46％CH 3CN/H 2O,1.5ml/min)得到式I所示化合物。
  5. 权利要求1所述的多硫代二酮哌嗪类化合物或其药用盐在制备治疗各种肿瘤细胞株毒性及抗肿瘤药物上的应用。
  6. 含有权利要求1所述的多硫代二酮哌嗪类化合物或其药用盐的药物组合物在制备治疗肿瘤细胞株毒性及抗肿瘤药物上的应用。
  7. 权利要求6的化合物或者权利要求7的药物组合物在制备抗肺癌、胃癌、胰腺癌、结肠癌、乳腺癌和肝癌药物中的应用。
  8. 含有权利要求1所述的多硫代二酮哌嗪类化合物或其药用盐的药物组合物。
  9. 一株裸胞壳菌真菌，保藏编号为：CGMCC No.17765。
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