CN107224432B - Application of compound Stemphol in preparation of antitumor drugs - Google Patents
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- NBGSKXDSPVJDSI-UHFFFAOYSA-N stemphol Natural products CCCCCC1=C(O)C=C(CCCC)C=C1O NBGSKXDSPVJDSI-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 17
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 title abstract description 31
- CZZVTNRWOQFMEU-UHFFFAOYSA-N Stemphol Chemical compound CCCCCC1=CC(O)=C(CCCC)C(O)=C1 CZZVTNRWOQFMEU-UHFFFAOYSA-N 0.000 title abstract description 29
- 238000002360 preparation method Methods 0.000 title abstract description 9
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- IRMPFYJSHJGOPE-UHFFFAOYSA-N olivetol Chemical compound CCCCCC1=CC(O)=CC(O)=C1 IRMPFYJSHJGOPE-UHFFFAOYSA-N 0.000 description 2
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 241000471262 Ardisia japonica Species 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
The invention discloses a new application of a compound Stemphol in preparation of an antitumor drug, and belongs to the technical field of preparation of antitumor drugs. In vitro experiments show that the compound Stemphol has strong cytotoxic effect on human lung adenocarcinoma cell strain A549 and human breast cancer cell strain MCF-7 at microgram concentration (microgram/mL), effectively inhibits the proliferation of tumor cells, and has potential application as an antitumor drug. The invention discovers in the mechanism research that the compound Stemphol can inhibit the transcription activity of the retinoic acid X receptor when acting alone or when being combined with ligand 9-cis, and shows that the compound has the application in the aspect of preparing the retinoic acid X receptor inhibitor. The invention also provides a pharmaceutical composition with the compound Stemphol as an effective ingredient.
Description
Technical Field
The invention relates to the technical field of preparation of antitumor drugs, in particular to a new application of a compound Stemphol in preparation of antitumor drugs.
Background
The diversity of marine environments creates a diversity of marine microorganisms that in turn have a diverse metabolic role, and marine symbiotic fungi are a large group of special microorganisms that live with hosts for a long time, and thus, marine symbiotic fungi can provide bioactive products of diverse structural types.
Currently, cancer is one of the leading causes of death in humans. According to the statistics of the world health organization, the number of cancer cases will increase to 3000 ten thousand in 2020, and the new cancer patients are mainly concentrated in developing countries.
Among various therapeutic approaches for cancer, drug therapy is important. Therefore, anticancer drugs are still the focus of research of most drug enterprises and scientific research institutions. The particularity of marine environment and the diversity of marine microorganisms enable the marine microorganisms to have greater potential to help human to discover novel natural drug lead compounds with anti-tumor activity.
The literature [ Shingo Marumo, Hiroyuki Hattori, Masato Katayama.Stempholfromopara herbarum as a Self-inhibitor. agric.Bio.chem., 1985,49(5),1521-1522] discloses a method for preparing the compound Stempholm from P.subtillis and its Self-inhibiting function.
Publication No. CN 102372630A discloses that resorcinol derivatives with anti-tumor activity are obtained by separating from rhizome of Ardisia japonica with short stem, and the structural formula is shown in general formula I, wherein R is saturated or unsaturated long-chain substituent with carbon atom number of ten to fifteen. In-vitro anti-tumor experiments show that the resorcinol derivative has obvious inhibition effects on various tumor cell strains such as human prostate cancer PC-3, human lung cancer A549, human gastric cancer SGC7901, human breast cancer MCF-7, human pancreatic cancer PANC-1, human liver cancer SMMC-7721, human glioma U251 and the like, and can be prepared into anti-tumor drugs.
Although the application of the resorcinol compound with the publication number of CN1954805A in preparing the antitumor drug also discloses that the resorcinol compound has the antitumor activity, the application does not have any test method and data to prove that the dialkyl resorcinol compound Stemphol has the antitumor activity, and any substituent group does not have the same pharmacological activity due to the influence of factors such as chemical structure, polarity and the like.
Disclosure of Invention
The invention aims to provide a new application of a compound Stemphol (2-butyl, 5-pentylresorcinol), which is applied to preparation of antitumor drugs.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention separates and extracts an active compound Stempholl from marine arthropod symbiotic fungi PO4, and the structural formula is as follows:
in addition to being obtained from the above-mentioned route, Stemphol can also be obtained by chemical synthesis or prepared from P.cumulans as mentioned in the background.
In vitro experiments show that the compound Stemphol has strong cytotoxic effect on human lung adenocarcinoma cell strain A549 and human breast cancer cell strain MCF-7 at microgram concentration (microgram/mL), and effectively inhibits the proliferation of tumor cells. The compound Stemphol has potential application as an antitumor drug.
The invention provides application of a compound Stemphol in preparation of antitumor drugs. The tumor is lung adenocarcinoma or breast cancer.
The invention discovers in a mechanism study that the compound Stemphol can inhibit the transcriptional activity of a retinoic acid X receptor (RXR) when acting alone or in combination with a ligand 9-cis, and the compound Stemphol is possibly a small molecule interacting with the RXR.
The invention provides application of a compound Stemphol in preparation of a retinoic acid X receptor inhibitor.
The invention also provides an anti-tumor pharmaceutical composition which comprises the compound Stemphol as an effective component.
The anti-tumor medicine composition takes an effective dose of a compound Stemphol as an active ingredient, and pharmaceutically acceptable auxiliary materials are added.
The pharmaceutically acceptable adjuvants include fillers such as starch, sucrose and microcrystalline cellulose, binders such as starch slurry, hydroxypropyl cellulose, gelatin and polyethylene glycol, humectants such as magnesium stearate, silica gel micropowder and polyethylene glycol, absorption enhancers such as polysorbate and lecithin, surfactants such as poloxamer, sorbitan fatty acid and polysorbate, and other adjuvants such as flavoring agent and sweetener can be added.
The medicament can be prepared into tablets, pills, powder, dispersible tablets, sachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, capsules, injections, liniments, suppositories and the like. The above-mentioned various dosage forms can be prepared by conventional method.
The administration route is enteral administration or parenteral administration, and includes oral administration, intramuscular injection, subcutaneous injection, intravenous injection, etc.
The invention has the following beneficial effects:
the invention provides a new application of a compound Stemphol (2-butyl, 5-pentylresorcinol) in the aspects of inhibiting tumor cell proliferation and inhibiting tretinoin X receptor transcriptional activity, and provides a lead compound for researching and developing novel antitumor drugs.
Detailed Description
The present invention will be described in detail with reference to examples, but the practice of the present invention is not limited thereto.
Materials used in the examples: marine arthropod symbiotic fungi PO 4.
A human lung adenocarcinoma cell strain A549 and a human breast cancer cell strain MCF-7.
Example 1
1. Collection, separation and identification of strains
Live sea cockroaches (Ligia ocean) are collected from the east sand sea area (E122 degrees 22 '54', N29 degrees 56 '28') of the Toshima town of Zhujiajiajia, Zhoshan, Zhejiang, 5 months in 2013, living bodies of the live sea cockroaches are soaked in sterile seawater and then dissected, the sections of intestinal tracts are inoculated to 1/2PDA culture medium plates, after fungi grow, the fungus community plates are picked and streaked, the culture plates are placed at 28 ℃ for 5-7 days, and preliminary screening and purification are carried out according to culture morphological differences of colony sizes, shapes, colors and the like. Inoculating the strain after multiple purification to nutrient agar slant, inoculating to 20% glycerol, and storing at-80 deg.C at oceanic institute of Zhejiang university. The fungus PO4 was selected as a subject and identified as Geospora (Pleospora sp.) by 26s rDNA.
2. Fermentation culture of marine arthropod symbiotic fungus PO4
Fermenting with PDB culture medium, charging 200ml culture solution into per 500ml conical flask, taking appropriate amount of thallus from PDA culture medium cultured at 28 deg.C, inoculating into 2 bottles of PDB liquid culture medium, standing and culturing at 28 deg.C for 7 days to obtain seed solution, shaking up to obtain 4ml bacterial solution, inoculating into 50 bottles of PDB culture solution, and standing and culturing at 28 deg.C for 30 days.
3. Isolation and extraction of active compounds
Filtering the bacteria and bacteria mixture after fermentation culture with eight layers of medical cotton-removed gauze to obtain bacteria solution and bacteria, extracting the bacteria solution with ethyl acetate, extracting the bacteria solution with methanol, analyzing the extract by TLC and HPLC to show that the components are approximately the same, and mixing to obtain 7.8g crude extract. Mixing the crude extract with 10g of column chromatography silica gel, loading the mixture to 550g of silica gel column by a dry method, performing gradient elution in the order of cyclohexane/ethyl acetate 100:1-1:1, then performing dichloromethane/methanol 90:10-1:1, eluting with 4L of solvent in each ratio, and combining by TLC analysis to finally obtain 14 components. Stemphol (7.09mg) was isolated as the target compound from fraction 3.
Analyzing the structure of a target compound by using methods such as spectrum, nuclear magnetism and the like, and determining that the compound is Stemphol through examining documents, wherein the structure is as follows:
EXAMPLE 2 determination of antitumor Activity of Compound Stemphol
The MTT method is adopted to carry out in vitro anti-tumor activity determination.
Cell lines: lung adenocarcinoma cell strain A549 and breast cancer cell strain MCF-7.
The inhibitory effect of the compound Stemphol on lung adenocarcinoma cell strain A549 and breast cancer cell strain MCF-7 is shown in Table 1.
Table 1: inhibition effect of Stemphol on lung adenocarcinoma cell strain A549 and breast cancer cell strain MCF-7
As can be seen from Table 1, the IC of compound Stemphol on MCF-7 and A549 tumor cells50The values are respectively 5.46 and 15.8 mu g/mL, so that the compound Stemphol has good inhibition effect on the proliferation of MCF-7 and A549 tumor cells.
EXAMPLE 3 determination of the inhibitory Activity of Stemphol on RXR transcription
The inhibitory effect of the compound Stemphol on RXRa transcriptional activity is shown in table 2.
Table 2: inhibition effect of compound Stemphol on RXR transcriptional activity
As shown in Table 2, Stemphol compound can inhibit the transcription activity of RXR when acting alone and combining with 9-cis, and is a potential small molecule capable of interacting with RXR.
Claims (3)
1. The application of Stemphol compound with a structural formula shown as a formula (I) in preparing antitumor drugs is characterized in that tumors are lung adenocarcinoma or breast cancer,
2. the use of claim 1, wherein said antineoplastic drug further comprises a pharmaceutically acceptable excipient.
3. The use of claim 1, wherein the anti-neoplastic agent is a tablet, pill, powder, sachet, elixir, suspension, emulsion, solution, syrup, aerosol, capsule, injection, liniment, or suppository.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710321870.2A CN107224432B (en) | 2017-05-09 | 2017-05-09 | Application of compound Stemphol in preparation of antitumor drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710321870.2A CN107224432B (en) | 2017-05-09 | 2017-05-09 | Application of compound Stemphol in preparation of antitumor drugs |
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| Publication Number | Publication Date |
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| CN107224432B true CN107224432B (en) | 2020-03-03 |
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| CN114469908B (en) * | 2021-12-21 | 2023-09-26 | 中国科学院南海海洋研究所 | Preparation method and application of acinetobacter baumanii-resistant compound stephol |
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- 2017-05-09 CN CN201710321870.2A patent/CN107224432B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| Two new stemphol sulfates from the mangrove endophytic fungus Stemphylium sp. 33231;Xue Ming Zhou等;《The Journal of Antibiotics》;20150225;1-3 * |
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