CN111944702A - Preparation method and application of aromatic butenolide - Google Patents

Preparation method and application of aromatic butenolide Download PDF

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CN111944702A
CN111944702A CN202010840459.8A CN202010840459A CN111944702A CN 111944702 A CN111944702 A CN 111944702A CN 202010840459 A CN202010840459 A CN 202010840459A CN 111944702 A CN111944702 A CN 111944702A
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aspergillus
aromatic
scau011
cox
fungus
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CN111944702B (en
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张华�
鲍洁
贺菲
李秀秀
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Laizhou Jinxing Chemical Co ltd
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University of Jinan
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
    • C12P17/162—Heterorings having oxygen atoms as the only ring heteroatoms, e.g. Lasalocid

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Abstract

The invention discloses an aromatic butenolide compound, a preparation method thereof and application thereof in preparing COX-2 inhibitors and anti-oxidation medicaments. The invention relates to an Aspergillus fungusAspergillus terreusThe aromatic butenolide compound with COX-2 inhibitory activity and antioxidant activity (shown in figure 1) is obtained by separating the fermentation product of SCAU011 CGMCC No. 19270, and has good application prospect in the aspect of preparing COX-2 inhibitor and antioxidant drugs.

Description

Preparation method and application of aromatic butenolide
Technical Field
The invention belongs to the field of marine natural medicines, and particularly relates to an aromatic butenolide compound 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 compound with COX-2 inhibitory activity and antioxidant activity separated from Aspergillus fungus 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 preservation number: CGMCC number 19270, preservation date: 12 and 27 days 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 structural formula of the aromatic butenolide compound generated from SCAU011 is 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) the extract obtained in the step (2) is subjected to normal phase silica gel column chromatography, rapid medium pressure chromatography and reverse phase C18Separating by column chromatography and high performance liquid chromatography.
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 COX-2 inhibitor or antioxidant of the extract in step (2), or the compound shown in figure 1 or 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 compound 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 shows the structural formula of aromatic butenolide compounds.
FIG. 2 is a drawing of the culture of strain SCAU011 on a plate.
FIG. 3 is a high resolution mass spectrum of the compound of FIG. 1.
FIG. 4 is a hydrogen spectrum of the compound shown in FIG. 1.
FIG. 5 is a carbon spectrum of the compound shown in FIG. 1.
FIG. 6 is a two-dimensional COSY spectrum of the compound shown in FIG. 1.
FIG. 7 is a two-dimensional HSQC spectrum of the compound shown in FIG. 1.
FIG. 8 is a two-dimensional HMBC spectrum of the compound shown in FIG. 1.
FIG. 9 is a two-dimensional NOESY spectrum of the compound shown in FIG. 1.
FIG. 10 is a hydrogen (600 MHz) and carbon (150 MHz) spectra data (CDCl) for the compound shown in FIG. 13）。
And (3) strain preservation information: according to the inventionAspergillus terreusSCAU011 is preserved in China general microbiological culture Collection center (CGMCC), and the address is as follows: western road No. 1, north zhou yang ward, beijing, institute for microbiology, china academy of sciences, accession number: CGMCC number 19270, preservation date: 12 and 27 days 2019.
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.
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, 120 mL 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.4 further subjected to normal phase silica gel (200-300 mesh) column chromatography using methylene chloride-acetone as an eluent, and the respective fractions were combined according to the case of thin layer chromatography to obtain 9 fractions (Fr.4-1-Fr.4-9). Component Fr.4-5 Rapid Medium pressure with methanol-Water as eluent (reverse C)18) The fractions were separated by chromatography, and the fractions were combined according to the thin layer chromatography to obtain 5 fractions (Fr.4-5-1-Fr.4-5-5). The component Fr.4-5-1 was purified by chiral high performance liquid chromatography (column chromatography was xylonite AD-H, flow rate was 1.0 mL/min, detection wavelength was 254 nm, mobile phase was 20% isopropanol-n-hexane), the component was collected for 21.9 min, and the solvent was removed to obtain pure compound (0.7 mg) as shown in FIG. 1.
The compound shown in figure 1 is a light yellow colloidal solid, is easily soluble in chloroform, methanol and dimethyl sulfoxide, and is hardly soluble in water; specific rotation photometric value [ alpha ]]29 D–1.4（c0.07, MeOH); circular dichroism (0.18 mg)mL–1, MeOH) λ(Δ) 203 (21.5), 231 (-4.9), 248 (2.3), 286 (-4.6), 318 (2.2) nm. Subjecting the separated compound of FIG. 1 to high resolution mass spectrometry (HR-ESIMS),1H NMR、13C NMR、2D 1H-1H COSY, HSQC and HMBC analysis (figure 3-figure 8) determines the plane structure; and determining that the two are trans by analyzing the coupling constant of the two chiral carbons of the furan ring connected with hydrogen. The absolute configuration of the chiral center of the lactone ring is first determined as R by comparison with ECD data of known compounds, and then it is determined by analysis of the NOESY spectrum (fig. 9) that all chiral carbons on the furan ring are in the S configuration. The structure and absolute configuration of the new component are thus fully determined. Hydrogen (600 MHz) and carbon (150 MHz) spectra (CDCl) data3) See fig. 10.
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 a cyclooxygenase (COX-2) inhibitor screening kit (Biyuntian, Nanjing), using celecoxib provided in the kit as a positive control.
The experimental results show that at the tested concentration of 20 nM, the COX-2 inhibition rate of the compound shown in FIG. 1 is 41.2%, which is close to the inhibition rate of 56.7% of the celecoxib positive control.
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 (%) = [ (A)C–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, IC5016.1 μ M, comparable to the 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 (CGMCC), with the preservation number of CGMCC No. 19270 and the preservation date: 12 and 27 days 2019.
2. An aromatic butenolide compound produced by Aspergillus according to claim 1, which has the formula shown in FIG. 1.
3. An Aspergillus fungus as claimed in claim 1Aspergillus terreusUse of SCAU011 for preparing a compound of formula (I) according to claim 2, 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 using methods such as normal-phase silica gel column chromatography, rapid medium-pressure chromatography, reverse-phase C18 column chromatography, high-performance liquid chromatography and the like.
A COX-2 inhibitor drug comprising an effective amount of the Aspergillus fungus of the above-mentioned step (2) as an active ingredientAspergillus terreusThe SCAU011 fermented extract, or the aromatic butenolide compound or the salt thereof according to claim 2, 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, or the aromatic butenolide compound or the 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 the aromatic butenolide compound of claim 2 or a salt thereof in the preparation of COX-2 inhibitor and antioxidant pharmaceutical or pharmaceutical intermediate.
CN202010840459.8A 2020-08-20 2020-08-20 Preparation method and application of aromatic butenolide Active CN111944702B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112574146A (en) * 2020-12-17 2021-03-30 自然资源部第三海洋研究所 Preparation method of butenolide compound composite nanocrystal

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108245508A (en) * 2018-02-26 2018-07-06 广东海洋大学深圳研究院 A kind of preparation method and application of marine fungi Aspergillus terreus butyrolactone compound Butyrolactone I
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 (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108245508A (en) * 2018-02-26 2018-07-06 广东海洋大学深圳研究院 A kind of preparation method and application of marine fungi Aspergillus terreus butyrolactone compound Butyrolactone I
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

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BAO, J等: "Asperbutenolide A, an unusual aromatic butenolide dimer with diverse bioactivities from a marine-derived fungus Aspergillus terreus SCAU011", 《 TETRAHEDRON LETTERS》 *
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
CN112574146A (en) * 2020-12-17 2021-03-30 自然资源部第三海洋研究所 Preparation method of butenolide compound composite nanocrystal

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