CN112707890A - Indole diketopiperazine derivative, preparation method thereof and application thereof in preparing anti-inflammatory drugs - Google Patents
Indole diketopiperazine derivative, preparation method thereof and application thereof in preparing anti-inflammatory drugs Download PDFInfo
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Abstract
The invention discloses an indole diketopiperazine derivative, a preparation method thereof and application thereof in preparing anti-inflammatory drugs. The structural formula of the indole diketopiperazine derivative or the pharmaceutical salt thereof is shown in any one of the formula (I). The invention provides indole diketopiperazine derivatives from deep sea fungi, which have the activity of inhibiting generation of Nitric Oxide (NO) in macrophage RAW264.7 induced by LSP and IC of the indole diketopiperazine derivatives50Respectively 89 mu M (1) and 20 mu M (2), can be used for preparing anti-inflammatory drugs, so that the indole diketopiperazine derivative from deep sea fungi provided by the invention has the function of treating inflammationClinical application potential of therapy.
Description
The technical field is as follows:
the invention relates to the field of pharmaceutical compounds, in particular to indole diketopiperazine derivatives derived from deep-sea fungi, a preparation method thereof and application thereof in preparing anti-inflammatory drugs.
Background art:
inflammatory response is a defensive physiological response produced by the immune system of the body under the harmful stimulation of tissue by trauma, infection, physical factors, and the like. Under normal conditions, the inflammatory reaction is beneficial to the body to identify and clear inflammatory factors, and can protect the body from being invaded by diseases; when the immune system is disordered, the body is easy to generate excessive inflammatory reaction, and a large number of inflammatory factors such as Nitric Oxide (NO), prostaglandin and the like are secreted, so that various diseases such as allergy, rheumatoid arthritis, even cardiovascular diseases and the like are further caused. Therefore, the development of anti-inflammatory drugs can provide new therapeutic targets and methods for diseases which are difficult to solve at present.
Macrophages are the primary reactive cells in nonspecific immunity, and have the functions of phagocytizing necrotic cells, recognizing antigens, secreting active cytokines and the like in immune regulation. Nitric Oxide (NO) is an important cytokine of an organism, is generated by Nitric Oxide Synthase (NOS) in a catalytic manner, and has the effects of maintaining vasodilatation, smooth muscle relaxation and the like; when inflammatory factors such as LPS stimulate macrophages, they cause cells to produce large amounts of NO, resulting in vasodilation and cell damage, further leading to an inflammatory response. Therefore, the excessive NO released by the macrophage is limited, so that the inflammatory reaction can be relieved to a certain extent, and the anti-inflammatory effect is achieved.
Compared with artificially synthesized compounds, natural products have more remarkable structural diversity and complexity, and have higher screening rate in the aspect of biological activity. The deep-sea fungi, as an important group in deep-sea microorganisms, is a main decomposer of deep-sea organic matters, has the characteristics of species diversity, wide distribution, complex and special metabolic pathway, renewability and the like, and simultaneously secondary metabolites of the deep-sea fungi also have the characteristics of high novelty and remarkable biological activity, such as antibiosis, tumor resistance, immunoregulation, inflammation resistance, enzyme inhibition and the like, and become important resources for researching and developing marine medicinal natural products at present.
The invention content is as follows:
the first purpose of the invention is to provide indole diketopiperazine derivatives or medicinal salts thereof from deep sea fungi.
The structural formula of the indole diketopiperazine derivative or the pharmaceutical salt thereof is shown in any one of the formula (I).
The second purpose of the invention is to provide a preparation method of the indole diketopiperazine derivative from the deep sea fungi, wherein the indole diketopiperazine derivative is separated from a fermentation culture of a marine fungus Aspergillus sp.FS445.
Specifically, the method comprises the following steps:
1) preparing a fermentation culture of the marine fungus Aspergillus sp.FS445;
2) extracting the fermentation culture with methanol, concentrating the extract to obtain an extract, extracting the extract with ethyl acetate to obtain an organic phase crude extract, separating the crude extract by silica gel normal phase chromatography, performing gradient elution with 10-70% v/v ethyl acetate/petroleum ether, and collecting Fr1 eluted with 30% v/v ethyl acetate/petroleum ether and Fr2 eluted with 40% v/v ethyl acetate/petroleum ether; purifying Fr2 by gel Sephdex-20 column chromatography, eluting with methanol as mobile phase to obtain mixture component containing compound 1, and further purifying by HPLC to obtain compound 1;
fr1 was purified by column chromatography on silica gel, again fractionally using 20% v/v ethyl acetate/petroleum ether, eluting 4 times in total, using equal amounts of eluent per column volume, to obtain 4 fractions Fr1.1 to Fr1.4 in sequence, and the third fraction Fr1.3 was eluted by Sephdex-20 gel column chromatography using 50% v/v methanol/dichloromethane as eluent to obtain Compound 2.
The HPLC purification to obtain the compound 1 is carried out by preparing PFP-C18HPLC purification on a model carbon 18 column using 80% v/v acetonitrile-water as the mobile phase at a flow rate of 2mL/min, and collection of fractions with a retention time of 9.3min afforded monomeric compound 1.
The preparation of the fermentation culture of the marine fungus Aspergillus sp.FS445 comprises the steps of inoculating the marine fungus Aspergillus sp.FS445 into a seed culture medium, performing shake culture to obtain a seed culture solution, inoculating the seed culture solution into a rice solid culture medium, and performing standing culture to obtain the fermentation culture;
the formula of the seed culture medium is as follows: 200g/L of potato, 20g/L of glucose, 3g/L of monopotassium phosphate, 1.5g/L of magnesium sulfate heptahydrate and vitamin B110 mg/L, 30g/L sea salt and the balance of water; the formula of the rice solid culture medium is as follows: 250g of rice is added into every 400mL of seawater.
Preferably, the conditions of shaking table culture are that the rotation speed of the shaking table is 200rpm, and the culture is carried out for 5 days at the temperature of 28 ℃.
Preferably, the static culture condition is static culture at 28 ℃ for 25 days.
The third purpose of the invention is to provide an application of the indole diketopiperazine derivative or the pharmaceutical salt thereof derived from deep sea fungi in preparing anti-inflammatory drugs.
The fourth purpose of the invention is to provide an anti-inflammatory drug, which comprises the indole diketopiperazine derivative shown in the formula (I) or the pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.
A fifth object of the present invention is to provide the use of the marine fungus Aspergillus sp.fs445 as described above for the preparation of an indodiketopiperazine derivative according to any one of the formulae (I).
Compared with the prior art, the invention has the following beneficial effects:
the invention provides indole diketopiperazine derivatives from deep sea fungi, which have the activity of inhibiting generation of Nitric Oxide (NO) in macrophage RAW264.7 induced by LSP and IC of the indole diketopiperazine derivatives50Respectively 89 mu M (1) and 20 mu M (2), can be used for preparing anti-inflammatory drugs, so the indole diketopiperazine derivative derived from deep sea fungi provided by the invention has clinical application potential in inflammation treatment.
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Fig. 1 shows high resolution electrospray mass spectrometry (HRESIMS) and elemental composition information for compound 1.
Fig. 2 is a high resolution electrospray mass spectrum (HRESIMS) of compound 2 and its elemental composition information.
Detailed Description
The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
Example 1
A preparation method of indole diketopiperazine derivatives from deep sea fungi is disclosed, wherein the indole diketopiperazine derivatives are separated from an extracting solution of Aspergillus sp.FS445 from deep sea fungi. The deep sea fungus Aspergillus sp.FS445 is isolated from deep sea sediments of the Indian ocean.
The deep sea fungus Aspergillus sp.FS445 is preserved in the Guangdong province microbial culture Collection (GDMCC) at 23.12.2020, has the preservation number of GDMCC No.3.692, and is classified and named as Aspergillus sp.preservation unit, and the address of the Aspergillus sp.preservation unit is No. 59 building 5 of Mr. Dazhou 100, Jie furao, Guangzhou city, which is publicly preserved, and anyone can purchase the strain from the preservation center after the preservation date.
The specific preparation method of the indole diketopiperazine derivative comprises the following steps:
1) seed broth culture of the deep sea fungus Aspergillus sp.fs445: inoculating Aspergillus sp.FS445 into seed culture medium, and culturing at shaking table rotation speed of 200rpm and 28 deg.C for 5 days to obtain seed culture solution; the formula of the seed culture medium is as follows: 200g/L of potato, 20g/L of glucose, 3g/L of monopotassium phosphate, 1.5g/L of magnesium sulfate heptahydrate and vitamin B110 mg/L, 30g/L sea salt and the balance of water; the preparation method of the culture medium comprises the following steps: cleaning potato, peeling, weighing 200g of potato, cutting into small pieces, adding water, decocting, filtering with gauze, collecting filtrate, mixing with glucose, potassium dihydrogen phosphate, magnesium sulfate heptahydrate, and vitamin B1Mixing with sea salt, dissolving in water, stirring for dissolving, sterilizing at 115 deg.C for 30min, and cooling.
2) Solid fermentation culture of deep sea fungus Aspergillus sp.fs445: inoculating the seed culture solution obtained in the step 1) into a rice solid culture medium, and performing static culture at the room temperature of 28 ℃ for 25 days to obtain a rice culture medium (fermentation culture) combined with thalli. The formula of the rice solid culture medium is as follows: 250g of rice and 400mL of seawater, and the preparation method of the culture medium comprises the following steps: mixing rice and seawater, sterilizing at 115 deg.C for 30min, and cooling.
3) Extracting the rice culture medium combined with the thalli obtained in the step 2) with methanol for three times, combining extracting solutions, concentrating the extracting solution to obtain an extract, and extracting the extract with ethyl acetate to obtain an organic phase crude extract; separating the crude extract by normal phase chromatography on silica gel, performing gradient elution by using 10-70% v/v ethyl acetate/petroleum ether, and collecting Fr1 eluted by 30% v/v ethyl acetate/petroleum ether and Fr2 eluted by 40% v/v ethyl acetate/petroleum ether; purifying 40% v/v ethyl acetate/petroleum ether eluate Fr2 by gel Sephdex-20 column chromatography, eluting with methanol as mobile phase to obtain mixture component containing compound 1, and further preparing PFP-C18HPLC purification of a model carbon 18 column, using 80% v/v acetonitrile-water as a mobile phase, the flow rate is 2mL/min, and collecting components with the retention time of 9.3min to obtain a monomer compound 1; purifying 30% v/v ethyl acetate/petroleum ether eluate fraction Fr1 by silica gel column chromatography, finely fractionating again using 20% v/v ethyl acetate/petroleum ether, eluting 4 times in total, using column volume equivalent eluents each time, to obtain 4 eluate fractions (Fr1.1-Fr1.4) in order, and eluting the third eluate fraction Fr1.3 by Sephdex-20 gel column chromatography, using 50% v/v methanol/dichloromethane as eluent, to obtain compound 2; performing TLC analysis by using a 10:1v/v dichloromethane/methanol developing agent, wherein Rf values of the compound 1 and the compound 2 are 0.33 and 0.47 respectively;the indole diketopiperazine derivative shown in the formula 1-2 can be obtained through the processes.
Example 2
The following experimental data were obtained by performing structural testing and analysis on compound 1-2:
1. compound 1: C29H33O3N3，HRESI-MS：472.2611[M+H]+(theoretical value 472.2595); the high resolution electrospray ionization mass spectrum (HRESIMS) and the element composition information thereof are shown in FIG. 1.
2. Compound 2: C24H27O3N3，HRESI-MS：406.2118[M+H]+(theoretical value 406.2125); the high resolution electrospray ionization mass spectrum (HRESIMS) and the element composition information thereof are shown in FIG. 2.
The NMR data of the compounds 1-2 are shown in Table 1.
TABLE 1 NMR data (600MHz/150MHz, ppm) for Compounds 1-2
aMeasured in chloroform-d；bMeasured in methanol-d4.
Based on the above data, the structural formula of compound 1-2 was confirmed as follows:
example 3
Screening experiment for Activity of Compound 1-2 in inhibiting the production of Nitric Oxide (NO) in LPS-induced mouse macrophage RAW 264.7.
Taking RAW264.7 cells in logarithmic growth phase according to the proportion of 1 × 105One well was seeded in 96-well plates at 100. mu.L/well. Placing into an incubator for 24h to allow cells to adhere to the wallEntering logarithmic growth phase, new complete medium (DMEM containing 10% fetal bovine serum) is replaced, LPS (final concentration 1. mu.g/mL) and inhibitors (samples) are added, repeating in 3 wells per concentration. The positive control group was added with only LPS without drug, the negative control group was added with only cells and complete medium, and the blank wells were added with only complete medium. After culturing in an incubator for 24h, 50 μ L of cell culture supernatant is taken and added into a new 96-well plate, and then 50 μ L of each of the nitric oxide detection reagent I and the nitric oxide detection reagent II is added. The absorbance (OD) at 540nm was measured with a microplate reader.
The enzyme activity was calculated using the following formula: inhibition ratio (%) - (A-A)0)/(A1–A0)]X 100% where A0The absorbance change value of the blank control, a of the sample, and a1 of the LPS group (positive control). 5 samples are measured, and a dose-inhibition rate curve is drawn to obtain the IC of the sample50The value is obtained. Each sample was assayed in triplicate and the results expressed as mean ± standard deviation.
As a result, it was found that Compound 1-2 had an inhibitory activity against the generation of Nitric Oxide (NO) in LSP-induced macrophage RAW264.7, IC thereof50Respectively 89. + -. 2.0. mu.M (Compound 1) and 20. + -. 0.28. mu.M (Compound 2).
The above is only a preferred embodiment of the present invention, and it should be noted that the above preferred embodiment should not be considered as limiting the present invention, and the protection scope of the present invention should be subject to the scope defined by the claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and these modifications and adaptations should be considered within the scope of the invention.
Claims (10)
1. The structure formula of the indole diketopiperazine derivative or the medicinal salt thereof is shown in any one of the formula (I):
2. a process for the preparation of an indole diketopiperazine derivative according to claim 1, wherein said indole diketopiperazine derivative is isolated from a fermentation culture of the marine fungus Aspergillus sp.fs445.
3. The method of claim 2, comprising the steps of:
1) preparing a fermentation culture of the marine fungus Aspergillus sp.FS445;
2) extracting the fermentation culture with methanol, concentrating the extract to obtain an extract, extracting the extract with ethyl acetate to obtain an organic phase crude extract, separating the crude extract by silica gel normal phase chromatography, performing gradient elution with 10-70% v/v ethyl acetate/petroleum ether, and collecting Fr1 eluted with 30% v/v ethyl acetate/petroleum ether and Fr2 eluted with 40% v/v ethyl acetate/petroleum ether; purifying Fr2 by gel Sephdex-20 column chromatography, eluting with methanol as mobile phase to obtain mixture component containing compound 1, and further purifying by HPLC to obtain compound 1;
fr1 was purified by column chromatography on silica gel, again fractionally using 20% v/v ethyl acetate/petroleum ether, eluting 4 times in total, using equal amounts of eluent per column volume, to obtain 4 fractions Fr1.1 to Fr1.4 in sequence, and the third fraction Fr1.3 was eluted by Sephdex-20 gel column chromatography using 50% v/v methanol/dichloromethane as eluent to obtain Compound 2.
4. The process of claim 3, wherein the HPLC purification to obtain Compound 1 is performed by means of PFP-C preparation18HPLC purification on a model carbon 18 column using 80% v/v acetonitrile-water as the mobile phase at a flow rate of 2mL/min, and collection of fractions with a retention time of 9.3min afforded monomeric compound 1.
5. The preparation method of claim 3, wherein the preparation of the fermentation culture of the marine fungus Aspergillus sp.FS445 comprises inoculating the marine fungus Aspergillus sp.FS445 into a seed culture medium, performing shake culture to obtain a seed culture solution, inoculating the seed culture solution into a rice solid culture medium, and performing standing culture to obtain the fermentation culture;
the formula of the seed culture medium is as follows: 200g/L of potato, 20g/L of glucose, 3g/L of monopotassium phosphate, 1.5g/L of magnesium sulfate heptahydrate and vitamin B110 mg/L, 30g/L sea salt and the balance of water; the formula of the rice solid culture medium is as follows: 250g of rice is added into every 400mL of seawater.
6. The method according to claim 5, wherein the conditions of shaking table culture are shaking table rotation speed of 200rpm and shaking table rotation speed of 28 ℃ for 5 days.
7. The method according to claim 5, wherein the static culture condition is a static culture at 28 ℃ for 25 days.
8. Use of the indole diketopiperazine derivative according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of an anti-inflammatory agent.
9. An anti-inflammatory agent comprising the indole diketopiperazine derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.
10. Use of the marine fungus Aspergillus sp.fs445 for the preparation of an indole diketopiperazine derivative according to claim 1.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0368577A (en) * | 1989-08-08 | 1991-03-25 | Tsumura & Co | Novel dioxopiperazine compound and anti-allergic agent containing the dioxopiperazine compound as active component |
| CN102584852A (en) * | 2011-12-30 | 2012-07-18 | 厦门大学 | Qiaonan mycin serving as fungus metabolism product and preparation method and application thereof |
| CN106497797A (en) * | 2016-11-01 | 2017-03-15 | 深圳大学 | A kind of extract of fungal cultures and its preparation method and application |
| CN107721990A (en) * | 2017-08-25 | 2018-02-23 | 中山大学 | The iso-indole ketone compounds in a kind of marine fungi source and preparation method thereof and the application in anti-inflammatory drug is prepared |
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- 2020-12-29 CN CN202011590611.8A patent/CN112707890B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0368577A (en) * | 1989-08-08 | 1991-03-25 | Tsumura & Co | Novel dioxopiperazine compound and anti-allergic agent containing the dioxopiperazine compound as active component |
| CN102584852A (en) * | 2011-12-30 | 2012-07-18 | 厦门大学 | Qiaonan mycin serving as fungus metabolism product and preparation method and application thereof |
| CN106497797A (en) * | 2016-11-01 | 2017-03-15 | 深圳大学 | A kind of extract of fungal cultures and its preparation method and application |
| CN107721990A (en) * | 2017-08-25 | 2018-02-23 | 中山大学 | The iso-indole ketone compounds in a kind of marine fungi source and preparation method thereof and the application in anti-inflammatory drug is prepared |
Non-Patent Citations (2)
| Title |
|---|
| AHIAKI AOKI 等: "Total Synthesis of (–)-Neoechinulin A", 《SYNLETT》 * |
| KOUJI KURAMOCHI 等: "Synthesis of Neoechinulin A and Derivatives", 《SYNTHESIS》 * |
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