CN111235042A - Butenolide dimer with COX-2 inhibition and antioxidation effects and application thereof - Google Patents

Butenolide dimer with COX-2 inhibition and antioxidation effects and application thereof Download PDF

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CN111235042A
CN111235042A CN202010219229.XA CN202010219229A CN111235042A CN 111235042 A CN111235042 A CN 111235042A CN 202010219229 A CN202010219229 A CN 202010219229A CN 111235042 A CN111235042 A CN 111235042A
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aspergillus
scau011
cox
fungus
aromatic
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张华�
鲍洁
贺菲
张玉颖
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University of Jinan
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Abstract

The invention discloses an aromatic butenolide dimer, a preparation method thereof and application thereof in COX-2 inhibitors and anti-oxidation drugs. The invention relates to an Aspergillus fungusAspergillus terreusSCAU011 CGMCC No:19270 to obtain the compound with COX-2 inhibitory activity and antioxidant activity (shown in figure 1), and has good application prospect in the aspect of preparing COX-2 inhibitors and antioxidant drugs.

Description

Butenolide dimer with COX-2 inhibition and antioxidation effects and application thereof
Technical Field
The invention belongs to the field of marine natural medicines, and particularly relates to an aromatic butenolide dimer and application thereof in preparation of COX-2 inhibitors and anti-oxidation medicines.
Background
Cyclooxygenase (COX) is a key enzyme that catalyzes the oxidative synthesis of prostaglandins from arachidonic acid. COX-1 is predominantly present in normal cells and catalyzes the production of prostaglandins that maintain normal physiological function; COX-2 is expressed in most tissues in an induction type, is an important induction enzyme in the inflammation process, is an action target of a non-steroidal anti-inflammatory drug, but the currently marketed non-steroidal anti-inflammatory drug can cause gastrointestinal and renal adverse reactions after being taken for a long time, and meanwhile, COX-2 is highly expressed in various tumor tissues, plays an important role in tumorigenesis and development, infiltration and metastasis and angiogenesis, and becomes one of new targets for tumor prevention and treatment. Therefore, the development of new COX-2 inhibitors is of great interest for the treatment of inflammation and cancer.
The oxidative damage is not only related to aging and tumors, but also has close relation with other diseases, such as coronary heart disease, heart failure, Alzheimer disease, chronic inflammation and the like, and the antioxidant can eliminate oxygen free radicals and improve the oxidative damage, and has important significance for treating diseases related to oxidative stress.
Disclosure of Invention
The invention provides an aromatic butenolide dimer compound with COX-2 inhibitory activity and antioxidant activity separated from Aspergillus fungi and a fermentation product thereof and a preparation method thereof.
In order to achieve the purpose, the invention adopts the following technical scheme.
Aspergillus fungusAspergillus terreusSCAU011, preserved in China general microbiological culture Collection center (CGMCC), with the address: west road No. 1, north west of the morning area, beijing, 3, institute for microbiology, china academy of sciences, accession number: CGMCC number 19270, preservation date: 12 month 27, 2019.
Aspergillus fungusAspergillus terreusSCAU011 and application of fermentation products thereof in producing COX-2 inhibitors and antioxidants. The Aspergillus fungusAspergillus terreusThe SCAU011 can produce fermentation product after being cultured, the fermentation product contains COX-2 inhibiting activity and antioxidant active substances, and the fermentation liquid can be used for producing drugs or additives with COX-2 inhibiting activity and antioxidant activity.
Aspergillus fungusAspergillus terreusThe aromatic butenolide dimer compound produced by SCAU011 has a structural formula shown in figure 1.
A preparation method of the aromatic butenolide dimer compound comprises the following steps:
(1) aspergillus fungiAspergillus terreusFermenting SCAU 011;
(2) extracting the fermented product obtained in the step (1) to obtain a fermented extract;
(3) and (3) separating the extract in the step (2) by a normal phase silica gel column, a rapid medium pressure chromatography column, a reverse phase C18 column high efficiency liquid phase and other methods.
The invention provides application of a compound containing the extract in the step (2) or shown in a figure 1 or salt thereof in preparing medicines and medicine intermediates of COX-2 inhibitors or antioxidants.
The invention provides a medicament containing a COX-2 inhibitor or an antioxidant comprising the extract of step (2), or a compound shown in figure 1 or a salt thereof. The COX-2 inhibitor and antioxidant agent further comprise medically acceptable adjuvants. The COX-2 inhibitor and antioxidant agent may also include other active ingredients to enhance COX-2 inhibition or antioxidant effects.
The invention has the following advantages:
the aromatic butenolide dimer of the present invention can be prepared byAspergillus terreusThe SCAU011 is obtained by fermentation, extraction and separation, has COX-2 inhibiting activity and oxygen free radical scavenging activity, and has application potential in preparation of COX-2 inhibitor and antioxidant.
Drawings
FIG. 1 is a structural formula of aromatic butenolide dimer compound.
FIG. 2 is a drawing of the culture of strain SCAU011 on a plate.
FIG. 3 is a graph of hydrogen (600 MHz) and carbon (150 MHz) spectra (CDCl) data for the compound of FIG. 13）。
FIG. 4 shows the main components of the compound shown in FIG. 11H-1H COSY, HMBC information.
FIG. 5 is an ECD spectrum of the compound shown in FIG. 1.
FIG. 6 shows the Mosher reagent derivative structure and delta of the compound shown in FIG. 1H(Δδ = δS−δR) The difference value.
Detailed Description
The present invention will be further described with reference to the following examples and drawings, but the present invention is not limited to 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.
The bacterial strain of the inventionAspergillus terreusSCAU011 is preserved in China general microbiological culture Collection center (CGMCC) with the address: west road No. 1, north west of the morning area, beijing, 3, institute for microbiology, china academy of sciences, accession number: CGMCC number 19270, preservation date: 12 month 27, 2019.
Example 1 isolation, purification and characterization of the species.
Separating and purifying the sediments in the mangrove forest protected area of Zhanjiang province to obtain strainsAspergillus terreusSCAU011, a typical culture picture of which is shown in FIG. 2: the colony is round, white hypha and earthy yellow spore. The product is identified by comparing with Gene Bank data through ITS rDNA detectionAspergillus terreusAnd (3) fungi.
Example 2 preparation of fermentates.
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 using water. PDB medium was charged into 20 500 mL Erlenmeyer flasks, about 150 mL per flask, and autoclaved at 121 ℃ for 25 minutes for future use.
The rice culture medium configuration method comprises the following steps: putting 80 g of rice sold in market, 0.4 g of yeast extract, 0.4 g of glucose, 120mL of sterile water and 3.6 g of sea salt into a 1L triangular flask, and putting 60 bottles in total. Sterilizing with high pressure steam at 121 deg.C for 25 min.
Picking appropriate amount of fungus with sterile bamboo stickAspergillus terreusInoculating SCAU011 strain into seed culture medium, culturing at 28 deg.C for 3 days in shaking table (180 rpm) to obtain seed solution, inoculating 10 mL seed solution into 1L triangular flask containing rice culture medium with liquid transfer gun, standing at 28 deg.C for 30 days, and collecting fermented culture medium.
Soaking fermented rice culture medium with 95% ethanol, recovering ethanol from the extractive solution, collecting the residual water phase, extracting with ethyl acetate, and concentrating under reduced pressure to obtain ethyl acetate extract as crude extract.
Example 3 preparation of aromatic butenolide dimer.
The method of example 2 was followed to obtain 4.0 kg of fermented rice medium, which was soaked in 95% ethanol, the ethanol was recovered from the extract, and the remaining aqueous phase was extracted with ethyl acetate, and concentrated under reduced pressure to obtain 60g of ethyl acetate extract. The ethyl acetate extract was subjected to column chromatography using normal phase silica gel (100-200 mesh), gradient elution was carried out from a volume ratio of 100:0 to 0:100 using methylene chloride-methanol as an eluent, and the respective fractions were combined according to the case of thin layer chromatography, and the elution solvent was recovered to obtain 7 fractions (Fr.1-Fr.7).
Fr.5 further subjected to normal phase silica gel (200-300 mesh) column chromatography using methylene chloride-acetone as an eluent, the fractions were combined according to the case of thin layer chromatography, and the elution solvent was recovered to obtain 6 fractions (Fr.5-1-Fr.5-6). The fraction Fr.5-4 was subjected to rapid medium pressure (reverse C-18) chromatography using methanol-water as an eluent, and the fractions were combined according to the case of thin layer chromatography, and the elution solvent was recovered to obtain 9 fractions (Fr.5-4-1-Fr.5-4-9). The component Fr.5-4-9 was isolated and purified by HPLC semi-preparative (column YMC-Pack ODS-A10 mm. times.250 mm, flow rate 3.0 mL/min, detection wavelength 254 nm, mobile phase methanol-water-acetic acid in volume ratio 76: 24: 0.05) at a peak-off time of 11.2 min to give the compound shown in FIG. 1 (6.3 mg).
The compound shown in FIG. 1 is pale yellow colloid, is easily soluble in chloroform, methanol and DMSO, is hardly soluble in water, and has specific optical rotation value [ α]29 D77.1（c0.36，MeOH）。
Subjecting the separated compound to high resolution mass spectrometry (HR-ESIMS),1H NMR、13C NMR、2D1H-1HCOSY, HSQC and HMBC analysis determines the planar structure, and determines the stereo structure of the compound by ECD and modified Mosher method.1H and13c NMR data are shown in FIG. 3, the main ones1H-1The related information of H COSY and HMBC is shown in figure 4, and the ECD spectrogram is shown in figure 5. The structure of the isolated compound is shown in FIG. 1.
Example 4 preparation of derivatives of the compounds shown in figure 1.
Weighing 1.0 mg of the compound shown in FIG. 1, dissolving in 0.5 mL of anhydrous pyridine, and adding 10. mu.L of Mosher reagent (Mosher reagent) ((Mosher reagent))R) 2-methoxy-2-trifluoromethylphenylacetyl chloride and 1.0 mg DMAP (as catalyst) at room temperature for 9 hours. Evaporating the solvent under reduced pressure, and semi-preparing the crude product with high performance liquid phase to obtain a compound a (figure 6); change Mosher reagent to (S) -2-methoxy-2-trifluoromethylphenylacetyl chloride, and the same procedure gave compound b (FIG. 6).
Example 5 COX-2 inhibitory activity of the compounds shown in figure 1.
COX-2 inhibitory activity of the compounds shown in FIG. 1 was tested using the cyclooxygenase (COX-2) inhibitor screening kit (Biyuntian), using celecoxib provided by the kit as a positive control.
The experimental result shows that the compound shown in the figure 1 has 76.47% of inhibition rate on COX-2 at the tested concentration of 20 nM, which is better than 56.7% of inhibition rate of the positive control celecoxib.
Example 6 antioxidant activity of the compound shown in figure 1.
The anti-oxygen radical activity of the compounds was determined by DPPH method: adding 100 μ L of 200 μ M DPPH ethanol solution and 100 μ L of ethanol solution of sample to be detected into 96-well plate, incubating at 25 deg.C for 30 min, and measuring absorbance A of reaction solution at 517 nmSA mixture of 100. mu.L of 200. mu.M ethanol DPPH solution and 100. mu.L ethanol solution was used as a negative control ACDPPH radical scavenging ratio (%）= [(AC- AS)/ AC]X 100%. Curcumin was used as a positive control.
The experimental results show that the compound shown in figure 1 has the activity of scavenging oxygen free radical, IC5016.6 μ M, comparable to the inhibitory activity of the positive control curcumin (IC)5016.2. mu.M).

Claims (6)

1. Aspergillus fungusAspergillus terreusSCAU011 preserved in China general microbiological culture collection center with the preservation number of CGMCC No. 19270.
2. An aromatic butenolide dimer produced by the Aspergillus fungus of claim 1, having a structural formula shown in FIG. 1.
3. An Aspergillus fungus as claimed in claim 1Aspergillus terreusUse of SCAU011 for preparing a compound according to claim 2 and represented in FIG. 1, comprising the steps of:
(1) aspergillus fungiAspergillus terreusFermenting SCAU 011;
(2) extracting the fermented product obtained in the step (1) to obtain a fermented extract;
(3) and (3) separating the extract in the step (2) by a normal phase silica gel column, a rapid medium pressure chromatography column, a reverse phase C18 column high efficiency liquid phase and other methods.
A COX-2 inhibitor drug comprising an effective amount of the Aspergillus fungus of the above-mentioned step (2) as an active ingredientAspergillus terreusSCAU011 fermentation extract, or aromatic butyrolactone dimer compound of claim 2, or a salt thereof, and a pharmaceutically acceptable carrier.
5. An antioxidant agent comprising an effective amount of the fungus of the genus Aspergillus of the above step (2) as an active ingredientAspergillus terreusThe SCAU011 fermented extract is prepared by fermenting SCAU011 fermented extract,or the aromatic butyrolactone dimer compound or salt thereof according to claim 2, and a pharmaceutically acceptable carrier.
6. The Aspergillus fungus of the step (2)Aspergillus terreusUse of a SCAU011 fermentation extract, or an aromatic butyrolactone dimer compound of claim 2, or a salt thereof, in the preparation of COX-2 inhibitors and antioxidant drugs or pharmaceutical intermediates.
CN202010219229.XA 2020-03-25 2020-03-25 Butenolide dimer with COX-2 inhibition and antioxidation effects and application thereof Pending CN111235042A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111334438A (en) * 2020-03-25 2020-06-26 济南大学 Preparation method of aromatic butenolide dimer and application of aromatic butenolide dimer in preparation of antibacterial drugs

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CN107586721A (en) * 2016-07-07 2018-01-16 中国科学院海洋研究所 A kind of benzophenone compound with antioxidation activity and its preparation method and application
CN111321095A (en) * 2020-03-25 2020-06-23 济南大学 Butenolide dimer with α -glucosidase inhibition effect and application thereof
CN111334438A (en) * 2020-03-25 2020-06-26 济南大学 Preparation method of aromatic butenolide dimer and application of aromatic butenolide dimer in preparation of antibacterial drugs

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
CN107586721A (en) * 2016-07-07 2018-01-16 中国科学院海洋研究所 A kind of benzophenone compound with antioxidation activity and its preparation method and application
CN111321095A (en) * 2020-03-25 2020-06-23 济南大学 Butenolide dimer with α -glucosidase inhibition effect and application thereof
CN111334438A (en) * 2020-03-25 2020-06-26 济南大学 Preparation method of aromatic butenolide dimer and application of aromatic butenolide dimer in preparation of antibacterial drugs

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NUCLEAR, P等: "Butenolide and Furandione from an Endophytic Aspergillus terreus", 《CHEMICAL & PHARMACEUTICAL BULLETIN》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111334438A (en) * 2020-03-25 2020-06-26 济南大学 Preparation method of aromatic butenolide dimer and application of aromatic butenolide dimer in preparation of antibacterial drugs

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Application publication date: 20200605