CN115960155A - Triterpene compounds, preparation method and application thereof in treatment of type 2 diabetes - Google Patents
Triterpene compounds, preparation method and application thereof in treatment of type 2 diabetes Download PDFInfo
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- -1 Triterpene compounds Chemical class 0.000 title claims abstract description 23
- 208000001072 type 2 diabetes mellitus Diseases 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
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- 244000025254 Cannabis sativa Species 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 229940125904 compound 1 Drugs 0.000 claims description 10
- 229940125782 compound 2 Drugs 0.000 claims description 9
- 229940126214 compound 3 Drugs 0.000 claims description 9
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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 triterpene compound, a preparation method and application thereof as a 11 beta-HSD 1 inhibitor in treating type 2 diabetes. The invention is prepared from euphorbia pekinensisEuphorbia sikkimensis) Separated from the whole grass to obtain the compound with remarkable inhibition 11β-compounds 1-3 with HSD1 activity (as represented by formula (I)) as 11βthe-HSD 1 inhibitor has good application prospect in the aspect of treating type 2 diabetes.
Formula (I).
Description
Technical Field
The invention belongs to the field of natural medicines, and particularly relates to a triterpene compound, a preparation method and application thereof as a 11 beta-HSD 1 inhibitor in treating type 2 diabetes.
Background
Diabetes Mellitus (DM) is a disease which causes progressive sugar, fat, protein, water and electrolyte metabolism disorder due to absolute or relative insufficiency of insulin secretion under the long-term combined action of genetic and environmental factors, and takes hyperglycemia as a main marker. There are 2 main types of diabetes: type 1 diabetes (insulin-dependent, IDDM), and type 2 diabetes (non-insulin-dependent, NIDDM), with type 2 diabetes occurring most commonly accounting for more than 90% of the total diabetes. Glucocorticoids (GC), a class of biologically active substances secreted by the adrenal cortex fasciculate band that regulate the metabolism of carbohydrates, lipids and proteins in the body, are important insulin antagonists. Abnormal elevation of GC levels in local tissues, especially in tissues with vigorous carbohydrate metabolism, such as liver, fat and skeletal muscle, can cause insulin resistance. Insulin resistance is a central link in the onset of type 2 diabetes, and therefore, GC, an important antagonist of insulin, plays an important role in the onset of type 2 diabetes. 11 β -HSD1 belongs to the short chain dehydro/reductase protein Superfamily (SDR), is a metabolic enzyme of GC in organisms, and catalyzes the interconversion between bioactive Cortisol (Cortisol) and inactive corticosterone (Cortisone). In tissues with vigorous metabolism, 11 β -HSD1 acts primarily as a reductase, which, together with reducing coenzyme II (nicotinamide adenine dinucleotide phosphate, NADPH), reduces corticosterone to active cortisol, increasing the GC levels in local tissues. The structural diversity and the characteristic of easy combination with biological macromolecules of the natural product determine incomparable advantages of the natural product in the process of participating in life physiology, and the natural product has important position irreplaceable in the research and development of new drugs and is an important source for finding candidate drugs and drug lead structures. Knoxia flavipes serves as an important traditional Chinese medicine resource, and secondary metabolites of the Knoxia flavipes are reported to have structural and biological activity diversity.
Disclosure of Invention
Numerous studies have demonstrated that 11 β -HSD1 is closely associated with the onset of type 2 diabetes. Through receptor premodulation, the activity of 11 beta-HSD 1 is inhibited, the GC level of local tissues is reduced, the insulin resistance can be improved, and the purpose of treating type 2 diabetes is achieved. Therefore, the discovery of metabolites from euphorbia lathyris which inhibit the activity of 11 β -HSD1 is of great importance for the development of novel drugs for the treatment of type 2 diabetes.
The invention is realized by the following measures:
the first purpose of the invention is to provide a triterpene compound which can inhibit the activity of 11 beta-HSD 1.
The triterpene compound has a structure shown in a formula (I):
formula (I)
The second object of the present invention is to provide a process for producing a triterpene compound represented by the formula (I).
The invention discloses a preparation method of a triterpene compound shown as a formula (I), which is characterized by comprising the following steps:
(1) Obtaining the whole plant resource of the euphorbia pekinensis;
(2) Air-drying and crushing the whole herb obtained in the step (1), soaking and extracting for 4 times with 95% ethanol for 7 days each time, concentrating under reduced pressure to obtain a crude extract, extracting with ethyl acetate, and concentrating under reduced pressure to obtain an ethyl acetate extract;
(3) And (3) subjecting the ethyl acetate extract obtained in the step (2) to macroporous resin and positive and negative phase silica gel column chromatography, using ethanol-water, petroleum ether-ethyl acetate and methanol-water as an elution system, and finally purifying by high performance liquid chromatography to obtain a compound 1, a compound 2 and a compound 3 shown in the formula (I) in the patent claim 1.
The whole plant of the euphorbia pekinensis in the step (1) is collected in Longli county, guiyang city, and a specimen of the euphorbia pekinensis is stored to create a Shandong province laboratory (specimen number: rcmcm-0001) with a new medicine, namely Nicotiana tabacum.
The extraction solvent in the step (2) is 95% ethanol, the extraction solvent is ethyl acetate, and the concentration method is vacuum concentration.
The macroporous resin column chromatography eluent in the step (3) has ethanol-water ratio of 30%,50%,80% and 95%; the ratio of petroleum ether-ethyl acetate eluent for silica gel column chromatography is 15; the ratio of methanol to water of the eluent for reverse phase column chromatography is 30-100 percent; the proportions of the high-efficiency liquid phase eluent acetonitrile-water are respectively 55%,55% and 94%, the time is respectively 55 min,59 min and 35 min, and the flow rate is 3 mL/min.
The third object of the present invention is to provide the use of three triterpene compounds represented by the formula (I) as 11 β -HSD1 enzyme inhibitors in the development of a drug for treating type 2 diabetes, which comprises an effective amount of the three triterpene compounds according to claim 1 as an active ingredient and a pharmaceutically acceptable carrier.
Through in vitro enzyme activity experiments, results show that the triterpene compound shown as the formula (I) can obviously inhibit the activity of 11 beta-HSD 1 and IC of the triterpene compound 50 The values are shown in table 2.
The invention has the following beneficial effects:
first, the invention provides a method for separating and extracting three triterpene compounds.
Secondly, three novel triterpene compounds are provided, and a compound library is enriched.
Thirdly, the three novel triterpene compounds provided by the invention have obvious 11 beta-inhibition effect
The activity of HSD1 makes it have good application prospect in the aspect of treating type 2 diabetes as 11 beta-HSD 1 inhibitor.
Drawings
FIG. 1 shows the ECD spectrum of Compound 1 in methanol;
FIG. 2. ECD spectrum of Compound 2 in methanol;
FIG. 3. ECD spectrum of Compound 3 in methanol;
FIG. 4 key ROESY-related signals for Compound 1;
FIG. 5 key ROESY-related signals for Compound 2.
Detailed Description
The following examples are further illustrative of the present invention and are not intended to be limiting thereof.
Example 1: preparation and structural identification of triterpene compounds 1-3 shown in formula (I).
Formula (I)
(1) Extraction and separation of triterpene compounds 1-3
Whole plant of Euphorbia bracteolata (10 kg) is collected from Longli county in Guiyang city, air dried, pulverized, and extracted with 95% ethanol for 4 times (25L each time) for 7 days. Mixing the ethanol extractive solutions, and concentrating under reduced pressure to obtain 1.4 kg crude extract. The crude extract was suspended in 2L of water and extracted three times with 3L of ethyl acetate each time. The ethyl acetate layers were combined and concentrated under reduced pressure to obtain 331 g of an ethyl acetate extract. The extract was subjected to macroporous resin (D101) column chromatography, eluting with ethanol-water (v/v, 30%,50%,80% and 95%) to give 4 fractions a-D. Fraction C (143 g) was subjected to column chromatography on normal phase silica gel (100-200 mesh) and eluted with petroleum ether-ethyl acetate (v/v, 15.
And (3) carrying out reverse phase silica gel column chromatography on the C7, taking methanol-water as an elution system, and carrying out gradient elution from 30-100% in volume ratio to obtain 4 components C7-1-C7-4. The component C7-1 was separated and purified by semi-preparative high performance liquid chromatography (column YMC-Pack ODS-A250X 10.0 mm, detection wavelengths 210 nm and 254 nm, flow rate 3 mL/min, mobile phase 94% acetonitrile-water) to give compound 3 (1.6 mg,35 min). The component C7-2 was separated and purified by semi-preparative high performance liquid chromatography (YMC-Pack ODS-A250X 10.0 mm, detection wavelength 210 nm and 254 nm, flow rate 3 mL/min, mobile phase 55% acetonitrile-water) to give compound 1 (1.8 mg,55 min) and compound 2 (1.6 mg,59 min).
(2) Structural characterization of Compounds 1-3
The chemical structure of the compound 1-3 is determined by data testing and analysis such as Nuclear Magnetic Resonance (NMR), mass Spectrometry (MS), optical rotation, circular dichroism (ECD), and the like.
The structural analysis of compound 1 and compound 2 is as follows:
high resolution Mass Spectrometry (HR-ESIMS) showed that Compound 1 (II)m/z [M + H] + 471.3838, calcd 471.3833) and 2 (C: (1)m/z [M + H] + 471.3828, calcd 471.3833) have the same formula C 31 H 50 O 3 And are therefore isomeric. By comparing the hydrogen-carbon spectrum data (table 1), the data for compounds 1 and 2 were found to be similar, indicating that they are structural analogs. By analysis 1 H- 1 H COSY, HSQC and HMBC spectra, and it was found that compounds 1 and 2 have the same planar structure. In particular, HMBC correlation signal H 3 -19/C-9 (δ165.4 in 1, δ165.0 in 2); H 3 -30/C-14 (δ47.8 in 1, δ47.9 in 2); H 2 6/C-7 (. Delta.198.4 in 1,. Delta.199.2 in 2) indicates that the α, β -unsaturated ketone of Compounds 1 and 2 is located at. Delta. 8 The carbonyl group is at C-7; the methoxy, hydroxy, trans double bonds of compounds 1 and 2 were also judged to be at C-25, C-3 and Δ, respectively, by HMBC correlation 23 A bit. Comparison of the hydrogen spectra of compounds 1 and 2 (Table 1) shows that there is a clear difference in the signals around the chiral carbons C-13, C-14, C-17 and C-20, indicating that they have different stereo configurations. The ECD curves of comparative compounds 1 and 2 (FIGS. 1 and 2), especially around 220 nm, are opposite in the Cotton effect, indicating that their C-14 configurations are opposite. The above reasoning was confirmed by analyzing the ROESY spectra of compounds 1 and 2 together, and the relative configurations as shown in the figure were established. The key ROESY related signals are as follows: h 3 -19/H-11β, H-11α/H 3 -18, H 3 -18/H-20, H 3 -30/H-17 and H 3 -21/H 2 -16 for 1 (fig. 4); h 3 -19/H-11β, H-11β/H 3 -18, H 3 -30/H-17 and H 3 21/H-12. Beta. For 2 (FIG. 5). Finally, as shown in figures 1 and 2, the measured ECD curves of compounds 1 and 2 were matched to their calculated values, thereby establishing that the absolute configuration of compound 1 was 3S, 5R, 10S, 13S, 14S, 17S, 20RThe absolute configuration of Compound 2 is 3S, 5R, 10S, 13R, 14R, 17R, 20R. The compound 1 is reported for the first time as white powder, is easily dissolved in methanol and dichloromethane, and has a specific luminosity value of alpha] 25 D +18.6 (c0.1, meOH). Compound 2 is first reported as white powderFinally, the product is easily dissolved in methanol and dichloromethane, and has a specific rotation luminosity value of [ alpha ]] 25 D +13.5 (c 0.1, MeOH)。
The structural analysis of compound 3 is as follows:
comprehensive analysis high resolution mass spectrum and 13 c NMR data suggest that Compound 3 has the formula C 30 H 50 O 3 . Analysis of the hydrogen-carbon spectrum (Table 1) revealed that Compound 3 contained a carbonyl group (. Delta.215.0), a trisubstituted double bond (. Delta.118.1), and 1 vicinal oxymethylene group (. Delta.118.1) ,H 3.25, δ 79.4) and one vicinal quaternary carbon (δ 76.3). The 2D nuclear magnetic spectrum is comprehensively analyzed, and the structure shown in the figure is finally established. HMBC correlation signal H 3 -28/H 3 -29 to C-3 (. Delta.79.4) indicates that the C-3 position is linked to a hydroxyl group, the signal H 2 6 to C-7 (. Delta.118.1), H-7 to C-5 (. Delta.50.7), C-9 (. Delta.49.0) and C-14 (. Delta.51.4) indicate that the trisubstituted double bond is located at. Delta. 7 Of the correlation signal H 3 -26/H 3 27 to C-24 (. Delta.215.0) and C-25 (. Delta.76.3) revealed that the carbonyl and the vicinal quaternary carbon are located at the C-24 and C-25 positions, respectively. Combining the measured and calculated values of ROESY and ECD (figure 3), determining that the absolute configuration is 3S, 5R, 9R, 10R, 13S, 14S, 17S. The compound 3 is white powder with novel structure, is easily soluble in methanol and dichloromethane, and has specific optical rotation value [ alpha ]] 25 D +26.0 (c 0.1, MeOH)。
The hydrogen and carbon spectra data for compounds 1-3 are shown in table 1:
example 2: 11 beta-HSD 1 enzyme activity test of the triterpene compound shown in the formula (I):
the compound 1-3 shown in the formula (I) is tested for the 11 beta-HSD 1 inhibitory activity by an LC-MS/MS method. 173.8. Mu.L of buffer A (100 mM KCl, 20 mM NaCl, 20 mM Hepes, pH 7.9), 2.0. Mu.L of 11. Beta. -HSD1 enzyme, 4.0. Mu.L of NADP were added to 96-well plates + (50 mM, dissolved in double distilled water), 0.2. Mu.L of test Compound (20 mM, dissolved in DMSO), 0.2. Mu.L of DMSO (negative control), 0.2. Mu.L of glycyrrhetinic acid (20 mM, dissolved in DMSO, positive control), mixed well, placed in a 37 ℃ environment, and incubated for 30 minutes. mu.L hydrocortisone (500. Mu.M, dissolved in buffer A) was added, mixed well and left to react at 37 ℃ A for 30 minutes. Adding 200. Mu.L ethyl acetate to terminate the reaction, mixing well, centrifuging, sucking 150. Mu.L ethyl acetate, and volatilizing the solvent. Dissolving in 400 μ L acetonitrile, detecting hydrocortisone and cortisone concentration with LC-MS/MS instrument (Waters VIONIMS Q-TOF) under liquid phase separation condition of 0.5 mL/min,65% methanol-water system, and calculating 11 β -HSD1 enzyme inhibition rate for 10 min.
The experimental result shows that the compound 1-3 shown in the formula (I) can obviously inhibit the activity of 11 beta-HSD 1, and the IC of the compound 50 The values are shown in Table 2. Therefore, the triterpenoid 1-3 shown in the formula (I) can be used as an inhibitor of 11 beta-HSD 1 for developing a new medicament for treating type 2 diabetes.
TABLE 2 inhibitory Activity (IC) of Compounds 1-3 on 11 β -HSD1 50 ，µM）
a Positive control
Claims (8)
1. A triterpene compound has a structure shown in formula (I).
2. A method for producing the triterpene compound according to claim 1, comprising the steps of:
(1) Obtaining the whole plant resource of the euphorbia pekinensis;
(2) Air-drying and crushing the whole grass obtained in the step (1), soaking and extracting for 4 times with 95% ethanol for 7 days each time, concentrating under reduced pressure to obtain a crude extract, extracting with ethyl acetate, and concentrating under reduced pressure to obtain an ethyl acetate extract;
(3) And (3) subjecting the ethyl acetate extract obtained in the step (2) to macroporous resin and positive and negative phase silica gel column chromatography, using ethanol-water, petroleum ether-ethyl acetate and methanol-water as an elution system, and finally purifying by high performance liquid chromatography to obtain a compound 1, a compound 2 and a compound 3 shown in the formula (1) in the patent claim 1.
3. The preparation method according to claim 2, wherein the whole euphorbia pekinensis in the step (1) is obtained from Longli county, guiyang city.
4. The production method according to claim 2, wherein in the step (2): the extraction solvent is 95% (v/v) ethanol, and the extraction solvent is ethyl acetate.
5. The production method according to claim 2, wherein in step (3): the ratio of ethanol to water of the macroporous resin column chromatography eluent is 30 percent, 50 percent, 80 percent and 95 percent; the ratio of petroleum ether-ethyl acetate eluent for silica gel column chromatography is 15; the ratio of methanol to water of the eluent for reverse phase column chromatography is 30-100 percent; the proportions of the high-efficiency liquid phase eluent acetonitrile-water are respectively 55%,55% and 94%, the time is respectively 55 min,59 min and 35 min, and the flow rate is 3 mL/min.
6. Use of a triterpene compound as claimed in claim 1 as 11 β -HSD1 inhibitor in the treatment of type 2 diabetes.
7. The use of claim 6, wherein the triterpene compound is compound 1, compound 2 or compound 3 as defined in claim 1.
8. An 11 β -HSD1 inhibitor comprising an effective amount of the triterpene compound of claim 1 as an active ingredient and a pharmaceutically acceptable carrier.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106220701A (en) * | 2016-06-29 | 2016-12-14 | 浙江工业大学 | Triterpenoid and preparation method and application |
| CN108314616A (en) * | 2017-01-17 | 2018-07-24 | 浙江工业大学 | Triterpene compound and its preparation and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106220701A (en) * | 2016-06-29 | 2016-12-14 | 浙江工业大学 | Triterpenoid and preparation method and application |
| CN108314616A (en) * | 2017-01-17 | 2018-07-24 | 浙江工业大学 | Triterpene compound and its preparation and application |
Non-Patent Citations (2)
| Title |
|---|
| JIN-HAI YU ET AL: "Ricinodols A-G: new tetracyclic triterpenoids as 11β-HSD1 inhibitors from Ricinodendron heudelotii", RSC ADV., vol. 5, 9 March 2015 (2015-03-09), pages 26777 - 26784 * |
| STEPHEN S. CHANG ET AL: "Neritriterpenols A-G, euphane and tirucallane triterpenes from Euphorbia neriifolia L. and their bioactivity", PHYTOCHEMISTRY, no. 199, 12 April 2022 (2022-04-12), pages 1 - 10 * |
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