CN115960729A - Azotone compound with effect of promoting peripheral nerve injury repair and preparation method thereof - Google Patents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention discloses a diazoketone compound, a preparation method thereof and application thereof in a composition, a medicament and a health-care product for promoting the peripheral nerve injury repair effect. The invention relates to a strain of penicillium sclerotiorumPenicillium sclerotiorumThe compound capable of promoting peripheral nerve injury repair is separated from fermentation product of UJNMF0503 CGMCC No:40172An object:
has good application prospect in developing compositions, medicines and health products for promoting the peripheral nerve injury repair effect.
Description
Technical Field
The invention belongs to the field of marine natural medicines, and particularly relates to a diazoketone compound, a preparation method thereof, and application of the diazoketone compound in a composition, a medicine and a health-care product for promoting peripheral nerve injury repair.
Background
Peripheral nerve injury is one of the clinically common diseases in surgery. The repair of peripheral nerve injury is a very complex biological process, and because factors such as slow nerve regeneration, wallerian degeneration at nerve stumps, tissue adhesion, muscle atrophy, motor end plates and the like always restrict the functional recovery of damaged nerves, the disability rate is high, and heavy burden is brought to families and society of patients. The schwann cells are the most important glial cells in the peripheral nervous system, are distributed along the processes of neurons, can secrete various neurotrophic factors to promote the survival of damaged neurons, promote the growth, regeneration and myelination of axons, and play a key role in the neurodegeneration and regeneration processes related to peripheral nerve injury. Therefore, by promoting Schwann cell proliferation and secreting various neurotrophic factors to support the survival of damaged neurons, the repair of peripheral nerve injury can be accelerated, and the method has important value for treating and improving peripheral nerve injury and nervous system diseases.
Disclosure of Invention
The invention provides two azone compounds with the effect of promoting peripheral nerve injury repair, and the structural formula of the azone compounds is shown as the formula (I):
formula (I).
The invention also aims to provide a preparation method of the above-mentioned nitrilophile compound.
In order to achieve the purpose, the invention adopts the following technical scheme.
A fungus sclerotium (Penicillium notatum (B))Penicillium sclerotiorum) UJNMF0503, preserved in China general microbiological culture Collection center (CGMCC), with a preservation number: CGMCC No. 40172.
A fungus sclerotium (Penicillium notatum (B))Penicillium sclerotiorum) The UJNMF0503 and the application of the fermentation product thereof in the production of the medicine with the effect of promoting the peripheral nerve injury repair. The penicillium sclerotiorumPenicillium sclerotiorum The UJNMF0503 can produce fermentation products after being cultured, the fermentation products contain active substances with the effect of promoting the peripheral nerve injury repair, and the fermentation liquor can be used for producing compositions, medicines, health products or additives with the effect of repairing the peripheral nerve injury.
A fungus sclerotium (Penicillium notatum (B))Penicillium sclerotiorum) The structure of the azophilic ketone compound produced by UJNMF0503 is shown as formula (I).
A method for preparing a diazotrophone compound of formula (I), comprising the following steps:
(1) Penicillium sclerotiorum (A)Penicillium sclerotiorum) Fermentation of UJNMF 0503;
(2) Extracting the fermented product obtained in the step (1) to obtain a fermented extract;
(3) Separating the extract in the step (2) by normal phase silica gel column, rapid medium pressure chromatography column, reverse phase C18 column, high performance liquid chromatography and other methods.
The invention provides application of an extract in step (2) or a compound shown in formula (I) in preparation of health-care products, medicines or medicine intermediates for promoting peripheral nerve injury repair.
The invention provides a health-care product or a medicine containing the extract in the step (2) or the compound shown in the formula (I) and used for promoting the repair of peripheral nerve injury. The health care product or the medicine for promoting the repair of the peripheral nerve injury also comprises medically acceptable auxiliary materials. The health-care product or the medicine for promoting the repair of the peripheral nerve injury can also comprise other effective components so as to enhance the proliferation effect on Schwann cells or the repair effect on the peripheral nerve injury.
The invention has the following advantages:
the invention relates to a method for preparing the azone compoundPenicillium sclerotiorum The UJNMF0503 is obtained by fermentation, extraction and separation, has the effect of promoting the proliferation of Schwann cells, and has application potential in the aspects of preparing compositions, medicines, health products or additives for promoting the repair of peripheral nerve injury, and the like.
Biological preservation information
Penicillium sclerotiorum (A)Penicillium sclerotiorum) uJNMF0503 is deposited in China general microbiological culture Collection center (CGMCC) at 13.05.2022, the preservation address is China Beijing, beijing City, west Lu No. 1 Hospital No. 3, china academy of sciences, the preservation number is: CGMCC No. 40172.
Drawings
FIG. 1 shows a fungusPenicillium sclerotiorum UJNMF0503 plates pictures.
FIG. 2 shows the principle of Compound 1 of formula (I) 1 H- 1 H COSY, HMBC information.
FIG. 3 is an ECD spectrum of the compound of formula (I).
FIG. 4 shows the effect of compounds 1 and 2 on the proliferation of Schwann cells.
Detailed Description
The present invention will be further described with reference to the following examples and the accompanying drawings, but the present invention is not limited by the following examples. The experimental procedures in the examples, unless otherwise specified, were carried out by conventional techniques in the art and the experimental reagents were all purchased commercially.
Example 1 preparation of the fermented product
The preparation method of the seed culture medium comprises the following steps: 200 mL of potato leachate, 20 g of glucose and 30 g of sea salt, and the volume is adjusted to 1L by water. The medium was charged into 20 Erlenmeyer flasks of 500 mL, about 150 mL per flask and autoclaved at 121 ℃ for 25 minutes for later use.
The PDB fermentation medium configuration method comprises the following steps: the potato leachate is 200 mL, the glucose is 20 g, the sea salt is 30 g, and the volume is 1L by using water. The medium was placed in a 1L triangular flask, 350mL liquid medium per flask, for a total of 150 flasks. Sterilizing with steam at 121 deg.C for 25 min.
Picking appropriate amount of fungus with sterile bamboo stickPenicillium sclerotiorum The strain UJNMF0503 is inoculated into a seed culture medium, the strain is cultured for 3 days in a shaking table (160 rpm) at the temperature of 28 ℃ to obtain a seed solution, then a liquid transfer gun is used for inoculating 10 mL seed solution into a triangular flask with 1L and PDB culture medium, the triangular flask is kept still for 30 days at the temperature of 28 ℃, and then the fermented product is collected.
Filtering the fermented product with gauze to obtain thallus and bacteria liquid, soaking thallus in 95% ethanol, recovering ethanol from the leaching liquid, extracting with ethyl acetate, concentrating under reduced pressure to obtain ethyl acetate extract A, extracting the bacteria liquid with equal amount of ethyl acetate for three times, concentrating under reduced pressure to obtain ethyl acetate extract B, and mixing A, B to obtain total extract.
EXAMPLE 2 preparation of Azophiles
The method of example 1 is used to obtain 70L liquid culture medium, the thalli are soaked in 95% ethanol, the residual water phase after ethanol is recovered from leaching solution is extracted by ethyl acetate, reduced pressure concentration is carried out to obtain ethyl acetate extract A, bacterial liquid is extracted by ethyl acetate with the same amount for three times, reduced pressure concentration is carried out to obtain ethyl acetate extract B, A, B is combined to obtain the total extract 200 g. Performing column chromatography on the ethyl acetate extract with macroporous resin adsorbent material, eluting with ethanol/water as eluent at volume ratio of 30%, 50%, 75%, and 90%, and recovering the eluting solvent to obtain 4 fractions (Fr.1-Fr.4).
Fr.3 through silica gel column chromatography (100-200 mesh), with dichloromethane/methanol (1:0-0:1) gradient elution, combined with thin layer chromatography silica gel plate detection, total 8 fractions (Fr.3.1-Fr.3.8). Fr.3.5 was subjected to silica gel column chromatography (200-300 mesh) with a gradient elution with methylene chloride/methanol (1:0-0:1), and 7 fractions (fr.3.5.1-fr.3.5.7) were combined, fr.3.5.4 was subjected to a gradient elution with Flash RP C-18 (methanol/water 40The column was YMC-Pack ODS-A10 mm X250 mm, the flow rate was 3.0 mL/min, the detection wavelengths were 280 nm and 320 nm, the mobile phase was 60:40 methanol-water) to give compound 2 (t) of the formula I R =20.4 min, 3.3 mg), fr.3.5.4.5 compound 1 of formula I (t.sub.3-Pack ODS-a 10 mm x 250 mm, flow rate 3.0 mL/min, detection wavelengths 280 nm and 320 nm, mobile phase is methanol-water in volume ratio 75 R =18.4 min, 3.7 mg)。
The compound shown in formula (I) is a light yellow jelly, is easily soluble in chloroform, methanol and DMSO, is hardly soluble in water, and has a value of [ alpha ] of the optical rotation degree of compound 1] 27 D –671.0（c 0.20，MeOH）。
Subjecting the separated compound to high resolution mass spectrometry (HR-ESIMS), 1 H NMR、 13 C NMR、2D 1 H- 1 H COSY, HSQC and HMBC analysis, a planar structure is determined, and relative configuration and absolute configuration of the compound are determined by combining NOESY signals and ECD spectrograms respectively. Process for preparing compounds 1 H and 13 c NMR data are shown in Table 1, for Compound 1 1 H- 1 The relevant information of H COSY and HMBC is shown in figure 2, and the ECD spectrogram is shown in figure 3.
TABLE 1 Compound 1 in CDCl 3 Neutralization of Compound 2 in DMSO-d 6 Is 1 H and 13 c NMR data
And (3) structural identification:
compound 1: yellow gel, high resolution mass spectrometry (HRESIMS) onm/zGiving an excimer ion peak 319.1905 ([ M + H ]] + Calculation 319.1904) in combination with NMR spectral data, the compound was presumed to have the formula C 19 H 26 O 4 The unsaturation degree was 8. 13 The C, HSQC and DEPT spectral data show that the compound contains 4 sp 2 Quaternary carbon, 5 sp 2 Methine, 1 sp 3 Quaternary carbon, 3 methines, 2 methylenes, 4 methyl groups. Nuclear magnetic number of the compoundSimilar to isochromophiles III reported in the literature (Norinko Arai et al 1995), the main difference is that the Cl atom at the C-5 position in isochromophiles III is replaced by an olefinic proton, and the nuclear magnetic data of the two compounds are greatly different at the C-9, C-10 and C-16 positions: isochromophilones IIIδ C 119.0 (C-9)，141.9 (C-10)，12.3 (C-16)；δ H 5.99 (H-9), 7.01 (H-10), 1.81 (H-16); in the compound 1δ C 121.5 (C-9)，132.4 (C-10)，20.3 (C-16)；δ H 5.98 (H-9), 7.31 (H-10), 1.88 (H-16), presumably due to steric effects caused by differences in the configuration of the double bond at position 5363 of C-11,12, and thus the C11/C12 double bond is presumed to becis。
J 8,8a (8.2 Hz) speculated that H-8 and H-8a are on either side of the plane; in NOE spectrum, H-8a and H 3 -18 uncorrelated speculation of H-8a with H 3 -18 on either side of the plane; the ECD spectrum of this compound was consistent with that of 1 (Weiyi Wang et al, 2018), and it was therefore presumed that the absolute configuration of this compound was 7R, 8R, 8aR,13S。
The structure of the compound is as follows:
example 3 Activity test for promoting proliferation of Schwann cell by Compound represented by formula (I)
The nerve injury repair activity of the compound represented by the formula (I) was measured using rat Schwann cells (RSC 96). The MTT method was used in the experiments to determine cell viability. Cells were aligned to 1.5X 10 5 Density of/mL (100. Mu.L wells) was inoculated into a 96-well plate, 37 ℃ C., 5% CO 2 Culturing for 24 hours at constant temperature; a blank control group (DMSO), a control group, and an experimental group (100 μ M compound) were set, compounds 1 and 2 were added to make the final concentration of the compound 100 μ M, respectively, and were incubated with the cells for 12 hours, 10 μ L of MTT was added and incubated in an incubator for 4 hours in the dark, and the absorbance (OD value) at 490nm was read to calculate the survival rate of RSC 96 cells.
Experimental results show that when the test concentration is 100 mu M, compared with a control group, the compounds 1 and 2 shown in the formula (I) promote the proliferation of RSC 96 cells, and the compounds 1 and 2 have the effect of promoting the proliferation of Schwann cells and have certain application potential in accelerating the repair of peripheral nerve injury, and treating and improving peripheral nerve injury and nervous system diseases.
Claims (5)
1. A fungus sclerotium (Penicillium notatum (B))Penicillium sclerotiorum) UJNMF0503, preserved in China general microbiological culture Collection center with the preservation number of CGMCC No. 40172.
2. A diazotrophone compound produced by penicillium sclerotiorum according to claim 1, having the general structural formula:
formula (I)
A Penicillium sclerotiorum (B) as defined in claim 1Penicillium sclerotiorum) Use of UJNMF0503 for preparing a compound of formula (I) according to claim 2, characterized in that it comprises the following steps:
(1) Penicillium sclerotiorum (B)Penicillium sclerotiorum) Fermentation of UJNMF 0503;
(2) Extracting the fermented product obtained in the step (1) to obtain a fermented extract;
(3) Separating the extract in the step (2) by normal phase silica gel column, rapid medium pressure chromatography column, reverse phase C18 column, high performance liquid chromatography and other methods.
3. Health products and drugs for promoting the repair of peripheral nerve injury, characterized by comprising an effective amount of the azophilic compound as claimed in claim 2 as an active ingredient, and a pharmaceutically acceptable carrier.
4. Use of the azone compound of claim 2 in the preparation of a health product, medicament or pharmaceutical intermediate for promoting repair of peripheral nerve injury.
5. The health product or medicine according to claim 4 or the use according to claim 5, further comprising medically acceptable auxiliary materials and other effective ingredients to enhance the repair effect of peripheral nerve injury.
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