CN109134574A - Steroidal compounds and the preparation method and application thereof and anti-tumor drug - Google Patents

Steroidal compounds and the preparation method and application thereof and anti-tumor drug Download PDF

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CN109134574A
CN109134574A CN201811140308.0A CN201811140308A CN109134574A CN 109134574 A CN109134574 A CN 109134574A CN 201811140308 A CN201811140308 A CN 201811140308A CN 109134574 A CN109134574 A CN 109134574A
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steroidal compounds
compound
cancer
tumor drug
steroidal
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CN109134574B (en
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杨献文
谢春兰
夏金梅
李增鹏
邵宗泽
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Third Institute of Oceanography SOA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P33/00—Preparation of steroids

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  • Health & Medical Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
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Abstract

The invention discloses a kind of steroidal compounds, the structural formula of steroidal compounds is as follows；OrR in the structural formula of steroidal compounds1When for H, R2For H；R1When for OH, R2For H or OH.Steroidal compounds of the present invention are fermented generation by penicillium granulatum in specific culture medium, with anti-tumor activity, it can be used for preparing anti-tumor drug, the present invention provides new compound source for research and development anti-tumor drug, steroidal compounds are prepared as anti-tumor active substance using marine microorganism abundant as fermentation raw material fermentation, drug production cost is reduced, has apparent inhibiting effect to cancer cell, has a good application prospect.

Description

Steroidal compounds and the preparation method and application thereof and anti-tumor drug
Technical field
The invention belongs to the application fields of marine microorganism drugs, and in particular to steroidal compounds and preparation method thereof with answer With and anti-tumor drug.
Background technique
Tumour is grave danger of human health and life, and the key for the treatment of is to find accurately contain tumour cell The measure of growth.Proliferation, survival and the differentiation of tumour cell are influenced by a variety of heredity and molecular changes.The growth of tumour There is intersect and compensatory between the relied on many A signal pathways of surviving.This complexity to act only on a target spot Tumour cell cannot be killed completely.This special survival mechanism of tumour cell also results in existing anti-tumor drug drug resistance Frequently occur.Therefore, it is important to influence multiple tumour growths clinically to need to act on a variety of receptors or signal path The drug of link.This demand also promotes people to turn to new source searching mechanism novelty, the unique anti-tumor activity object of activity Matter.
Ocean has the characteristics that with high salt, high pressure, oligotrophic, therefore marine microorganism has unique metabolic pathway, makes it Generate some secondary metabolites different from land microorganism.In recent years, the technologies such as marine microorganism acquisition, culture is prominent It is broken, marine active substance R&D work has been extended to broader far-reaching sea from nearly shallow sea.It is deep relative to nearly shallow sea microorganism The more complicated multiplicity of structure of extra large microbial secondary metabolite, activity are also more significant.Therefore, it is found from Deep-Sea Microorganisms low Malicious efficient anti-cancer agent purpose is strong, and success rate is high.
Summary of the invention
It is an object of the invention to: Deep-Sea Microorganisms resources advantage is made full use of, a kind of steroidal compounds are provided.
The structural formula of a kind of steroidal compounds, steroidal compounds is as follows；
R in the structural formula of steroidal compounds1When for H, R2For H；R1When for OH, R2For H or OH.
The present invention also provides a kind of preparation methods of steroidal compounds, comprising the following steps:
S1, penicillium granulatum is subjected to fermented and cultured in the medium, obtain tunning；
S2, tunning extracted, obtain extract liquor；Extract liquor obtains steroidal compounds after isolating and purifying.
Preferably, mannitol 20ml/L, yeast extract powder 3g/L, KH in culture medium2PO40.5g/L, sodium glutamate: 10g/ L, glucose 10g/L, MgSO4·7H2O 0.3g/L, maltose 20g/L, corn pulp 1mL/L.
The salt of steroidal compounds and steroidal compounds provided by the invention is used to prepare anti-tumor drug.
Preferably, anti-tumor drug is for treating bladder cancer, lung cancer, the cancer of the esophagus, cancer of pancreas, liver cancer, bladder cancer, colloid Tumor, cervical carcinoma.
The present invention also provides a kind of anti-tumor drug, in the salt including steroidal compounds and steroidal compounds at least one Kind and pharmaceutically acceptable carrier.
In terms of existing technologies, the invention has the following advantages:
Steroidal compounds of the present invention ferments generation by penicillium granulatum in specific culture medium, with antitumor work Property, it can be used for preparing anti-tumor drug, the present invention provides new compound source for research and development anti-tumor drug, and utilization is abundant Marine microorganism prepares steroidal compounds as anti-tumor active substance as fermentation raw material fermentation, reduces drug production cost, There is apparent inhibiting effect to cancer cell, has a good application prospect.
Specific embodiment
Invention is further described in detail With reference to embodiment.
The preparation of steroidal compounds
(1) by penicillium granulatum (can be commercially available from Chinese marine microorganism culture presevation administrative center, deposit number: MCCC 3A00475), it is added to fermented and cultured in the triangular flask containing culture medium, finally obtains tunning, it is sweet in culture medium Reveal alcohol: 20ml/L, yeast extract powder: 3g/L, KH2PO4: 0.5g/L, sodium glutamate: 10g/L, glucose: 10g/L, MgSO4· 7H2O:0.3g/L, maltose: 20g/L, corn pulp 1mL/L.Tunning is centrifuged, bacterium solution and thallus are collected；Toward thallus Middle addition methanol is extracted, and into extract liquor again through petroleum ether and methylene chloride grease removal, last low pressure concentration obtains thallus hair Ferment crude extract；
(2) thallus fermentation crude extract in step (1) is subjected to silica gel post separation, uses dichloro methane-methanol to wash De- agent is eluted；Gradient obtains eight fractions (Fr.1-Fr.8)；
(3) by second fraction Fr.2 in step (2), through gel Sephadex LH-20 chromatographic column (2 × 160cm) pure first Alcohol elution, using normal phase column chromatography (49 × 460mm, petroleum ether-ethyl acetate, 10:1) isolated compound 3；
(4) by the 5th fraction Fr.5 in step (2), through gel Sephadex LH-20 chromatographic column (2 × 160cm) pure first Alcohol elution separation, obtains compound 2；
(5) by the 6th fraction Fr.6 in step (2), through gel Sephadex LH-20 chromatographic column (2 × 180cm) pure first After alcohol elution separation, is separated using half preparation HPLC, chemical combination is obtained using methanol-water solution (20:80 → 80:20) gradient elution Object 1；
(6) by the 7th fraction Fr.7 in step (2), through gel Sephadex LH-20 chromatographic column (2 × 160cm) pure first After alcohol elution, half preparation HPLC separation is carried out, compound 6 is obtained using methanol-water solution (30:70 → 70:30) gradient elution；
(7) by the 8th fraction Fr.8 in step (2), through gel Sephadex LH-20 chromatographic column (3 × 180cm) pure first Alcohol elution separation carries out half preparation HPLC separation, using methanol-water solution (60:40 → 100:0) gradient elution, respectively obtains Compound 4 and 5.
Compound 1-6 obtained in above-mentioned steps is subjected to Structural Identification with NMR and high resolution mass spectrum etc..
Compound 1 determines that its molecular formula is C by high resolution mass spectrum HRESIMS30H48O5.Contain in 1H-NMR prompt compound 1 There are 7 methyl (δH0.83,0.83,0.87,1.09,1.15,1.33,1.98), 3 sp2Methine hydrogen (δH 5.14,5.19, And 5.19), the methine hydrogen signal (δ of 4 company's oxygenH3.41,3.76,4.27,5.01).Wherein δ c 0.86 (d), 0.87 (d), 0.92 (d), 0.91 (s), 1.38 (s) this 5 methyl hydrogen signals imply that this compound is a steroid backbone.13C NMR shows 30 carbon signals, including 7 methyl, 5 methylene, 14 methines and 4 quaternary carbons (Tables 1 and 2) altogether, The position C-5, C-6 of compound 1 is a double bond (δC146.0,125.5) it, is parsed through HSQC, COSY, HMBC, NOESY, determines that 1 is 16β-acetoxy-3β,7β,11β-trihydroxyergost-5,22E-diene。
The molecular formula of compound 2 is determined as C by HRESIMS30H48O4, NMR data is extremely similar with compound 1, only One the difference is that the C-7 of compound 2 is methylene rather than methine.According to HMBC correlation, determine that compound 2 is 16 β- acetoxy-3β,7β-dihydroxyergost-5,22E-diene。
1 compound 1-6 of table1H NMR data (400MHz, CD3OD)
2 compound 1~6 of table13C NMR data (100MHz, CD3OD)
The molecular formula of compound 3 is determined as C by HRESIMS30H48O3, NMR data and compound 2 are closely similar, poor It is not only that the C-11 for compound 2 is methylene rather than methine.It is parsed through the 2D such as HMBC NMR, determines that compound 3 is 16 β-acetoxy-3β-hydroxyergost-5,22E-diene。
The molecular formula of compound 4 is determined as C by HRESIMS30H50O7, NMR data and compound 1 are closely similar, poor It is not that the C-5 of compound 4 is methine, a hydroxyl more than C-5, C-6 is methylene, and acetyl group is connected in C-7, and It is C-16 non-.It is parsed through detailed 2D NMR, the structure of compound 4 is ultimately determined to 7 β-acetoxy-3 β, 5 α, 6 β, 11 β, 16 β-pentahydroxyergost-22E-ene。
The molecular formula of compound 5 is determined as C by HRESIMS30H50O6,1H and13C-NMR nuclear magnetic data and compound 4 Closely similar, difference is only that the position C-11 of compound 5 is methylene, rather than connects the methine of oxygen in 4, passes through detailed 2D NMR parsing, it is final to determine that compound 5 is 7 β-acetoxy-3 β, 5 α, 6 β, 16 β-tetrahydroxyergost-22E-ene.
Compound 6 determines that molecular formula is C by HRESIMS30H50O5,1H and13C-NMR nuclear magnetic data and compound 5 are non- Often similar, unique difference is that the position C-5 of compound 6 is methine, rather than connects the methine of oxygen in compound 5.Through detailed The parsing such as HSQC, COSY, HMBC, NOESY determines that compound 6 is 7 β-acetoxy-3 β, 6 β, 16 β- trihydroxyergost-22E-ene。
The anti-tumor activity of steroidal compounds is investigated
The present embodiment selects 8 plants of tumour cells, including SHG-44 cell (people's glioma), HepG2 cell (liver cancer), 7402 Cell (liver cancer), A549 cell (lung cancer), BIU-87 cell (bladder cancer), ECA-109 cell (cancer of the esophagus), Hela cell (palace Neck cancer) and PANC-1 cell (cancer of pancreas).
The present embodiment is divided into following 3 groups:
(1) negative control group of corresponding steroidal compounds is not added in cell culture fluid；
(2) cell is free of, but has the blank control group of equivalent culture solution；
(3) steroidal compounds experimental group: 6 compounds obtained in specific embodiment；
The present embodiment is using following operation:
(1) after cell dissociation, it is resuspended and is blown and beaten into single cell suspension, is then arrived with 2000~5000, every hole cell inoculation 96 orifice plates, every 200 μ L of pore volume.
(2) 37 DEG C, 5%CO2Incubator in cultivate for 24 hours, then be added various concentration compound handle cell.
(3) continue after cultivating 72h, every hole adds 10 μ L 5mg/mL MTT, and 37 DEG C are protected from light 3h.Careful inhale abandons supernatant Afterwards, the DMSO of 150 μ L is added in every hole, vibrates 10min, melts crystal sufficiently.
(4) microplate reader measures 570nm absorbance value, calculates antitumor inhibiting rate using following formula.
The results show that 1~6 pair eight kinds of compound different tumour cells all show significant inhibiting effect (table 3), and select Selecting property is preferable, shows that these compounds have extraordinary development and application prospect.
Inhibiting effect (the IC of 1~6 pair eight kinds of 3 compound of table different tumour cells50, μM)
Compound 1~6 and its esters can be used for preparing anti-tumor drug, specifically, compound 1~6 and its esters can match It closes pharmaceutically acceptable carrier and prepares anti-tumor drug.
Each technical characteristic of above embodiments can be combined arbitrarily, for simplicity of description, not to above-described embodiment In each technical characteristic it is all possible combination be all described, as long as however, the combination of these technical characteristics be not present lance Shield all should be considered as described in this specification.
Only several embodiments of the present invention are expressed for above embodiments, and the description thereof is more specific and detailed, but can not Therefore it is construed as limiting the scope of the patent.It should be pointed out that for those of ordinary skill in the art, Under the premise of not departing from present inventive concept, various modifications and improvements can be made, and these are all within the scope of protection of the present invention. Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.

Claims (6)

1. a kind of steroidal compounds, which is characterized in that the structural formula of the steroidal compounds is as follows；
R in the structural formula of the steroidal compounds1When for H, R2For H；R1When for OH, R2For H or OH.
2. a kind of preparation method of steroidal compounds as described in claim 1, which comprises the following steps:
S1, penicillium granulatum is subjected to fermented and cultured in the medium, obtain tunning；
S2, tunning extracted, obtain extract liquor；Extract liquor obtains steroidal compounds after isolating and purifying.
3. the preparation method of steroidal compounds according to claim 2, which is characterized in that mannitol in the culture medium 20ml/L, yeast extract powder 3g/L, KH2PO40.5g/L, sodium glutamate: 10g/L, glucose 10g/L, MgSO4·7H2O 0.3g/L, maltose 20g/L, corn pulp 1mL/L.
4. a kind of application of steroidal compounds as described in claim 1, which is characterized in that the steroidal compounds and the steroid The salt of body compound is used to prepare anti-tumor drug.
5. the application of steroidal compounds according to claim 4, which is characterized in that the anti-tumor drug is for treating wing Guang cancer, lung cancer, the cancer of the esophagus, cancer of pancreas, liver cancer, glioma, cervical carcinoma.
6. a kind of anti-tumor drug, which is characterized in that including steroidal compounds as described in claim 1 and the steroidal Close at least one of salt of object and pharmaceutically acceptable carrier.
CN201811140308.0A 2018-09-28 2018-09-28 Steroid compound, preparation method and application thereof, and anti-tumor drug Active CN109134574B (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109942658A (en) * 2019-04-29 2019-06-28 自然资源部第三海洋研究所 A kind of miscellaneous terpene compound and the preparation method and application thereof and anti-tumor drug
CN112194578A (en) * 2019-07-08 2021-01-08 自然资源部第三海洋研究所 Compound with anti-tumor activity and application thereof, anti-tumor medicine and application thereof
CN112521398A (en) * 2020-07-30 2021-03-19 上海交通大学医学院附属仁济医院 Sponge epiphyte-derived open-loop rearrangement steroid compound and preparation method and application thereof

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JPH0748397A (en) * 1993-08-05 1995-02-21 Taisho Pharmaceut Co Ltd Steroidal compound
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CN101880302A (en) * 2010-06-11 2010-11-10 中国科学院海洋研究所 Polyhydroxylated sterol derivative as well as preparation and application thereof

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109942658A (en) * 2019-04-29 2019-06-28 自然资源部第三海洋研究所 A kind of miscellaneous terpene compound and the preparation method and application thereof and anti-tumor drug
CN112194578A (en) * 2019-07-08 2021-01-08 自然资源部第三海洋研究所 Compound with anti-tumor activity and application thereof, anti-tumor medicine and application thereof
CN112521398A (en) * 2020-07-30 2021-03-19 上海交通大学医学院附属仁济医院 Sponge epiphyte-derived open-loop rearrangement steroid compound and preparation method and application thereof

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