CN114031592A - Chalcone derivative, preparation thereof and application thereof in preparation of antitumor drugs or functional foods - Google Patents
Chalcone derivative, preparation thereof and application thereof in preparation of antitumor drugs or functional foods Download PDFInfo
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- CN114031592A CN114031592A CN202111170833.9A CN202111170833A CN114031592A CN 114031592 A CN114031592 A CN 114031592A CN 202111170833 A CN202111170833 A CN 202111170833A CN 114031592 A CN114031592 A CN 114031592A
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- hexane
- ethyl acetate
- chalcone derivative
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- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 claims abstract description 17
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
The invention discloses a chalcone derivative, a preparation method thereof and an application thereof in preparing an anti-tumor medicament or functional food, wherein dry goldenseal is subjected to ethanol reflux extraction to obtain a crude extract; subjecting the crude extract to silica gel column chromatography, and gradient eluting with n-hexane-ethyl acetate eluting system; carrying out secondary chromatographic separation on the 4 th fraction n-hexane-ethyl acetate solvent system on silica gel packing to obtain a compound 1 and a compound 2; and (3) carrying out secondary chromatographic separation on the 5 th fraction on a silica gel filler by adopting an n-hexane-ethyl acetate solvent system to obtain a compound 3, a compound 4 and a compound 5. Lays a foundation for further research and application of goldenseal.
Description
Technical Field
The invention belongs to the technical field of new compound extraction, and particularly relates to a chalcone derivative, and a preparation method and an application thereof in preparation of an anti-tumor drug or functional food.
Background
The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art.
Plants produce natural products with diverse chemical structures through various biosynthetic pathways, and play an increasingly important role in the drug discovery process. Notably, more than 50% of the approved innovative drugs were derived from natural products during the years 1981-2014. The results of FDA surveys in the united states indicate that innovative drugs derived from natural products account for more than one-third of the approved chemical classes of drugs.
Chalcones are the main components of flavonoid family, and the natural products are characterized by open-chain flavonoids, which have two aromatic rings and contain an alpha, beta-unsaturated carbonyl core unit through a three-carbon atom connecting chain. Historically, chalcone-containing plants have also been used in traditional medicine to treat a variety of diseases. After phytochemical studies of these chalcone-containing plants, a number of chalcone compounds have been isolated, some of which have been used in clinical trials for the treatment of cancer, cardiovascular disease and viral infections. In addition, chalcones have been reported to exhibit antibacterial, antiprotozoal, anticancer, cardioprotective, antidiabetic, neuroprotective, antioxidant, anti-inflammatory and anti-HIV effects in vitro and in vivo.
Ranunculus japonicus belongs to Ranunculus, and is widely distributed in Pakistan, Himalayas, India and Russia. Buttercup is used in traditional medicine for the treatment of eye diseases such as conjunctivitis and wound healing. The plant juice is used for treating gout, intermittent fever and asthma, and the Ranunculus japonicus leaf is used for treating arthralgia and stomach qi. In addition, other plants in buttercup are widely used for treating malaria, scrofula, hemorrhoids, scrofula and arthritis, but the composition of compounds in buttercup is less studied.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a new chalcone compound in ranunculus asiaticus as well as an extraction method and application thereof.
In order to solve the above technical problems, the present invention provides, in a first aspect, a chalcone derivative having a structural formula selected from:
in a second aspect, the present invention provides a method for preparing the chalcone derivative, comprising the steps of:
extracting dried goldenseal with ethanol under reflux to obtain crude extract;
subjecting the crude extract to silica gel column chromatography, and gradient eluting with n-hexane-ethyl acetate eluting system;
carrying out secondary chromatographic separation on the 4 th fraction n-hexane-ethyl acetate solvent system on silica gel packing to obtain a compound 1 and a compound 2;
and (3) carrying out secondary chromatographic separation on the 5 th fraction on a silica gel filler by adopting an n-hexane-ethyl acetate solvent system to obtain a compound 3, a compound 4 and a compound 5.
In some embodiments, the gradient elution with n-hexane-ethyl acetate elution system is performed in a sequence of n-hexane, n-hexane-ethyl acetate, ethyl acetate from 0:100 to 0: 100.
In some embodiments, the reflux extraction is performed with 3-4L ethanol per kg of dry goldenseal.
Further, after the reflux extraction is finished, the solvent is removed by rotary evaporation at 35-45 ℃.
In some embodiments, the 4 th fraction is subjected to the second chromatographic separation with a volume ratio of n-hexane to ethyl acetate of 16: 84.
In some embodiments, the 5 th fraction is subjected to secondary chromatography with a gradient elution of n-hexane and ethyl acetate at a volume ratio of 15:85, 20:80, 25: 75.
In some embodiments, the method further comprises the step of subjecting the 2 nd fraction to a second chromatographic separation to obtain 4-methoxylonchocarpin.
Further, in the case of performing secondary chromatography, the volume ratio of n-hexane to ethyl acetate was 5:95, 10:90, and 15: 85. The 4-methoxylonchocaripin is isolated as compound 6.
In a third aspect, the invention provides the use of 4-methoxynchocarpin in the manufacture of a medicament for the treatment of ewing's sarcoma;
or, the application of 4-methoxylonchocarpin in preparing anti-cancer drugs for treating triple negative breast cancer;
or, 4-methoxylonchocarpin for use in the preparation of functional food.
The beneficial effects obtained by one or more of the embodiments of the invention are as follows:
the chalcone compounds in the goldenseal are extracted by the separation and extraction method to obtain 5 new chalcone compounds and a known chalcone compound, and a certain foundation is laid for the research and further application of the goldenseal.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention without limiting the invention to the proper forms disclosed herein.
FIG. 1 is a COSY and HMBC correlation plot for compound 1 and compound 2;
FIG. 2 is a COSY and HMBC correlation plot for compound 3, compound 4 and compound 5;
FIG. 3 is a graph of the effect of Compound 6 on SK-N-MC (Ewing's sarcoma), HEL (erythroleukemia), MCF-7 and MDA-MB-468 (both breast cancer) and PC-3 (prostate cancer) viability;
FIG. 4 is a drawing of Compound A (1)1Nuclear magnetic resonance pattern of H-NMR;
FIG. 5 is a drawing of Compound A (1)13C-NMR nuclear magnetic resonance image;
FIG. 6 is a DEPT diagram of Compound A (1);
FIG. 7 is a COSY diagram of Compound A (1);
FIG. 8 is a HSQC plot for Compound A (1);
FIG. 9 is a HMBC diagram of compound A (1);
FIG. 10 is a HRESIMS mass spectrum of Compound A (1);
FIG. 11 is a drawing of Compound B (2)1H-NMR nuclear magnetic resonance image;
FIG. 12 is a drawing of Compound B (2)13C-NMR nuclear magnetic resonance image;
FIG. 13 is a DEPT diagram of Compound B (2);
FIG. 14 is a COSY diagram of Compound B (2);
FIG. 15 is a HSQC plot of Compound B (2);
FIG. 16 is a HMBC diagram of compound B (2);
FIG. 17 is a HRESIMS mass spectrum of Compound B (2);
FIG. 18 is of Compound C (3)1H-NMR nuclear magnetic resonance image;
FIG. 19 is of Compound C (3)13C-NMR nuclear magnetic resonance image;
FIG. 20 is a COSY diagram of compound C (3);
FIG. 21 is an HSQC plot for compound C (3);
FIG. 22 is a HMBC diagram of compound C (3);
FIG. 23 is a HRESIMS mass spectrum of Compound C (3);
FIG. 24 is of Compound D (4)1H-NMR nuclear magnetic resonance image;
FIG. 25 is of Compound D (4)13C-NMR nuclear magnetic resonance image;
FIG. 26 is a COSY diagram of compound D (4);
FIG. 27 is an HSQC plot of Compound D (4);
FIG. 28 is a HMBC diagram of compound D (4);
FIG. 29 is a HRESIMS mass spectrum of Compound D (4);
FIG. 30 is of Compound E (5)1H-NMR nuclear magnetic resonance image;
FIG. 31 is a COSY diagram of compound E (5);
FIG. 32 is an HSQC plot for Compound E (5);
FIG. 33 is a HMBC diagram of compound E (5);
FIG. 34 is a HRESIMS mass spectrum of Compound E (5).
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
Examples
Experimental methods and reagents
All cell lines were purchased from ATCC (manassas, usa). RPMI1640, DMEM and MEM basal cell culture medium, FCS, L-glutamine, PBS and trypsin/EDTA for cell culture were purchased from Capricorn Scientific GmbH (Ebsdorfergrund, Germany). Culture flasks, multi-well plates and other cell culture plastics were purchased from TPP (Trasadinggen, Switzerland) and Greiner Bio-One GmbH (Frickenhausen, Germany), respectively. Resazurin was purchased from Sigma-Aldrich Chemie GmbH (Taufkirchen, Germany).
Experimental Material
Ranunculus japonicus was collected in the hilly area of Burr-Puherwa province of Basstein in 7 months of 2018.
Extraction and separation process
4.0kg of dried goldenseal herb is extracted under reflux with 15L of ethanol, and the solvent is removed by rotary evaporation at 40 ℃ to obtain 5.3g of plant extract. The crude extract was subjected to silica gel column chromatography (n-hexane, n-hexane-ethyl acetate, ethyl acetate elution from 0:100 to 0:100) to divide into nine fractions (F1-9).
Fraction F4(200mg) was subjected to secondary chromatography using a solvent system n-hexane-ethyl acetate (16:84) on 30g of a silica gel plug to give compound A (1, 4.9mg) and compound B (2, 4.1 mg).
Fraction F5(120mg) was subjected to secondary chromatography using a solvent system n-hexane-ethyl acetate (15:85 to 25:75) on 30g of a silica gel packing to give compound C (3, 2.1mg), compound D (4, 2.6mg) and compound E (5, 2.4 mg).
Fraction F2(90mg) was subjected to secondary chromatography using a solvent system n-hexane-ethyl acetate (5:95 to 15:85) on 15g of silica gel packing to give 4-methoxynocharpin (6, 7 mg).
Cell culture
Five human cancer cell lines were used: PC-3 (prostate cancer), MCF-7 (breast cancer), MDA-MB-468 (triple negative breast cancer cell line), SK-N-MC (Ewing sarcoma), and HEL (erythroleukemia cells).
MCF-7, PC-3 and HEL were maintained in RPMI1640 medium supplemented with 10% heat-inactivated FCS, 2mM L-glutamine and 1% penicillin/streptomycin. The MDA-MB-468 cell line was cultured in DMEM medium containing 10% heat-inactivated FCS and 1% penicillin/streptomycin. SK-N-MC cells were added to MEM medium with 10% FCS and 1% penicillin/streptomycin. All cell lines were routinely cultured in T-75 flasks at 5% CO2In a humid environment at 37 ℃ to reach sub-confluence (-80%), and then subcultured or measured. Adherent cells MCF-7, MDA-MB-468, PC3 and SK-N-MC were washed with PBS and detached with trypsin/EDTA (0.05% in PBS) prior to cell passage and seeding. Before use, the HEL suspension cells were resuspended in standard medium, collected and centrifuged (800 rpm at RT).
In vitro cell viability assay
The antiproliferative and cytotoxic effects of the compounds were studied separately by fluorescence resazurin cell viability assay. Cancer cells were seeded into 96-well plates at 6000 cells/100 μ L/well for adherent cell lines and 20,000 cells/100 μ L/well for suspension cell lines. Subsequently, the cells were adhered for 24 hours and treated with the compound for 48 hours.
Stock solutions of chalcone compounds (DMSO) were prepared and diluted in the standard medium described above to reach the desired concentration for cell culture.
For control samples, cells were treated in parallel with 0.5% DMSO (negative control, final DMSO content representing the highest concentration of test compound) and 100 μ M digitonin (positive control, data normalized to 0% cell viability), both in standard growth medium.
After the 48 hour incubation was complete, cells were incubated with 50 μ M resazurin (2.5mM aquabid. stock) in cell line specific growth medium for 4 hours under standard growth conditions.
Conversion of Resazurin to haloxynil (λ exc.: 540/λ em.: 590nm) by viable metabolically active cells was measured by using a SpectraMax M5 multiwell plate reader (Molecular Devices, San Jose, CA, USA). Data were determined in biological triplicate, each duplicate having technical quadruplicate. Data analysis was performed using GraphPad Prism version 8.0.2 and Microsoft Excel 2013.
Results and discussion
Structural analysis
Compound a (1): yellow solid, hressms: m/z 519.2188[ M + H ]]+(calculated value: C)34H31O5 +，519.2166)。1H(400MHz，CDCl3) And13C-NMR (100MHz，CDCl3) The results are shown in Table 1. IR (KBr) v as a result of infrared spectroscopymax： 3310、1655、1610、1420、1000cm-1The infrared spectrum result shows that hydroxyl (3310 cm) exists-1) Aromatic ring core Unit (1615 cm)-1) And conjugated ketones (1655 cm)-1). In addition, to1Analysis of the H-NMR spectrum (table 1) indicated the presence of signals at δ 7.33(1H, J ═ 16.0Hz) and 7.76(1H, J ═ 16.0Hz), these large coupling constants of 16.0Hz were typical for trans chalcones (H- α and H- β respectively). Passing through delta 127.9 (C-. alpha.) and 144.1 (C-. beta.)13The presence of the chalcone backbone is further evidenced by the C-NMR signal and the trans alpha, beta-unsaturated ketone signal at delta 191.8.
In addition to this, the present invention is,1the H-NMR spectrum showed a difference of delta 5.59 (J10.0 Hz, H-2 "), 6.76 (J10.0 Hz, H-1") and two magnetic propertiesThe equivalent methyl singlet at δ 1.476H identifies the remainder of the pyran ring. In that1An AB spin system was observed in the H-NMR spectrum, with two orthogonally coupled doublets at δ 6.38 and 7.47(J ═ 9.0Hz) accounting for all six positions of ring a. The HMBC correlation of these two protons (FIG. 1) has been established to partition at H-5 'and H-6' of Ring A, respectively. On the other hand, in the case of a liquid,1the H-NMR spectrum also has a strongly hydrogen bonded low field 1-proton signal at δ 13.74, and the position of this hydroxyl group at C-2 'is correlated with its HMBC spectra C-1', C-2 'and C-3'.
1The H-NMR spectrum also illustrates the ABX spin system at δ 6.95(d, J ═ 8.0Hz, H-5), 7.18(d, J ═ 2.0Hz, H-2) and 7.2(dd, J ═ 2.0, 8.0). The positions of the protons at δ 6.95, 7.18 and 7.20 were determined to be attached at ring B based HMBC correlations C-5, C-2 and C-6, δ 6.95 to C-1, C-3, C-4 and C-6, δ 7.18 to C-1, C-3, C-4 and C-6, δ 7.20 to C-1, C-2, C-4 and C-5. Furthermore, the position of the pyran ring at C-3 'and C-4' of ring A is established by HMBC correlation of H-2 'to C-3'. OH-2 'to C-3', H-1 'to C-2', C-3 'and C-4'.1The H-NMR spectrum data are similar to that of 3, 4-dihydroxyphosphorylcholine, except that delta 5.22(4H, s, CH)2Ph) and two benzyl moieties of 7.33-7.49(10H, m, Ph)1H-NMR signal. Furthermore, the presence of these two additional benzyl groups is according to delta 127.1(C-2 'and C-6'), 128.2(C-3 'and C-5')13C-NMR signals, and 127.9(C-4 '), 136.9 (C-1'), delta 70.9 and 71.5 (CH)2Ph). In addition, based on HMBC correlation, two benzyl groups are placed at C-3 and C-4 of Ring A: delta 5.22(4H, CH)2Ph; two benzyl groups overlap) to C-3 and C-4. Based on the results of the spectrum, the structure of Compound 1 was identified as (E) -3- (3,4-bis (phenyloxy) phenyl) -1- (5-hydroxy-2,2-dimethyl-2H-chrome n-6-yl) prop-2-en-1-one.
Compound B (2): yellow solid, hressms: m/z 611.2819[ M + H ]]+(calculated value: C)41H39O5 +,611.2792). IR (KBr) v as a result of infrared spectroscopymax：1605、 1415、1010cm-1。1H(400MHz，CDCl3) And13C-NMR(100MHz， CDCl3) The results are shown in Table 1.1H-NMR results (table 1) showed two independent AB spin systems, one coupled to 6.54(1H, d, J-10.0 Hz) at δ 6.62(1H, d, J-9.0 Hz), and the other at δ 5.63(1H, d, J-10.0 Hz). In addition to this, the present invention is,1H-NMR spectra indicated ABX systems at δ 6.64(dd, J ═ 2.0,8.0Hz), 6.79(t, J ═ 8.0Hz) and 7.76(d, J ═ 2.0 Hz). From1It was confirmed from the H-NMR signal that the delta 5.09(2H, s, CH2Ph), 5.05(2H, s, CH2Ph)2Ph), 4.81(2H, s, CH2Ph) and 7.30-7.41(15H, m, Ph). The complete structure of compound 2 was established by COZY and HMBC spectroscopic analysis (fig. 1). Based on 1D and 2D-NMR studies, the structure of compound B (2) was identified as 1- (5- (phenyloxy) -2,2-dimethyl-2H-chromen-6-yl) -3- (3,4-bis (phenyloxy) phenyl) propan-1-one.
TABLE 1 preparation of Compound 1 and Compound 21H-NMR (400MHz) and13C-NMR (100MHz) data
Compound C (3): yellow solid, hressms: m/z 405.2081[ M + H ]]+(calculated value: C)26H29O4 +405.2060). IR (KBr) v as a result of infrared spectroscopymax：3350、 1610、1430、1000cm-1。1H(400MHz，DMSO-d6) And13C-NMR(100 MHz，DMSO-d6) The results are shown in Table 2.1H-NMR spectra (table 2) show typical bimodal signals of trans chalcones at δ 7.48(H- α) and 7.72(H- β), with large coupling constants (J ═ 16.0Hz),13the C-NMR signals showed C-. alpha. (delta.124.3), C-. beta. (142.4) and conjugated keto groups (. delta.190.6).1The H-NMR spectrum further illustrates the 6 proton singlet state of the two Me groups at δ 5.68(J ═ 10.0Hz, H-1 "), 5.68(J ═ 10.0Hz, H-2"). In addition, a single aromatic AB spin doublet was observed on ring AThe systems were at δ 6.63 and 7.56(J ═ 9.0Hz) and correlated by HMBC, indicating assignment of these proton signals to H-5 'and H-6', respectively (fig. 2).
To pair1Further analysis of the H-NMR spectrum showed the presence of the AA 'BB' system at δ 6.91(2H, AA ', H-3 and H-5), 7.58(2H, BB', H-2 and H-6), a methoxy signal at δ 3.85, and the position of the methoxy group at C-4 as confirmed by HMBC correlation with C-4. The pyran rings at C-3 'and C-4' of Ring A are established by HMBC correlations, H-1 'to C-2', C-3 'and C-4', H-2 'to C-3'. Furthermore, the NMR data for compound 3 is similar to 4-hydroxynecharpin, except that the isoprenyl groups are at δ 4.35(2H, d, J ═ 8.0Hz), 5.41(1H, m), 1.48(3H, s) and 1.65(3H, s). Isoprenyl at δ 73.0(C-1 "'), 119.4 (C-2" '), 139.7(C-3 "'), 25.7 (C-4" '), 17.8(C-5 "')13This was confirmed by the C-NMR signal. Furthermore, based on the correlation of HMBC to the signal at δ 4.35(H-1 ' ") to C-2', the O-isoprene group is placed at C-2 '. Thus, Compound 3 was identified as (E) -1- (2,2-dimethyl-5- ((3-methylbout-2-en-1-yl) oxy) -2H-chromen-6-yl) -3- (4-methoxyphenyl) prop-2-en-1-one.
TABLE 2 of Compound 3 and Compound 41H-NMR (400MHz) and13C-NMR (100MHz) results
Compound D (4): white solid, HRESIMS: m/z 405.2081[ M + H ]]+(calculated value: C)26H29O4 +405.2060). IR (KBr) v as a result of infrared spectroscopymax：1600、 1420、1000cm-1。1H(400MHz，CDCl3) And13C-NMR(100MHz， CDCl3) The results are shown in Table 2.1The results of H-NMR spectroscopy (table 2) show that the trans-chalcone backbone is δ 7.45(H- α) and 7.86(H- β) and the expected large coupling constant (J ═ 16.0 Hz). In addition to this, the present invention is,13C-NMR spectrum shows that a low-field signal at delta 190.6 is a typical conjugated carbonyl carbon, and the existence of chalcone skeleton is confirmed. NMRThe data are similar to 4-hydroxynechorpin, with the prenyl group linked to C-5' by C-prenylation, confirmed by the high field chemical shift of H-1 "' at δ 3.25(2H, d, J ═ 8.0Hz) and its HMBC coupling to C-4', C-5' and C-6 '. In addition, there is a chelating signal for the OH group at δ 13.65(OH-2') but no H-5' signal, and the H-6' singlet at δ 7.52 further establishes the structure of 4-Ring A. Compound 4 was identified as (E) -1- (5-hydroxy-2,2-dimethyl-8- (3-methylbout-2-en-1-yl) -2H-chromen-6-yl) -3- (4-methoxyphenyl) prop-2-en-1-one.
Compound E (5): white solid, HRESIMS: m/z 473.2706[ M + H ]]+(calculated value: C)31H37O4 +473.2686). IR (KBr) v as a result of infrared spectroscopymax：1600、 1420、1000cm-1。1H(400MHz，CDCl3) And13C-NMR(100MHz， CDCl3) The results are shown in Table 3.1H-NMR spectroscopy results (table 3) show typical bimodal signals of trans chalcones at δ 7.43(H- α) and 7.85(H- β), with large coupling constants (J ═ 16.0 Hz).13The C-NMR spectrum showed that the low field signal at delta 190.6 is typical of conjugated carbonyl groups and is typical of the presence of chalcone scaffolds. NMR data are similar to 4-hydroxynechorpin, except that the prenyl group at C-5' has been substituted with a geranyl group by C-gernanylation. The following geranyl1This is confirmed by the presence of the H-NMR spectroscopic signal: δ 3.26(2H, d, J ═ 8.0Hz, H-1 "'), 5.15(1H, m, H-2"'), 1.75(3H, s, H-4 "'), 2.05(2H, m, H-5"'), 2.13(2H, m, H-6 "'), 5.26 (1H, m, H-7"'), 1.59(3H, s, H-9 "') and 1.66(3H, s, H-10"'), as given in table 313The C-NMR spectroscopic signal was further confirmed. Thus, Compound 5 was identified as (E) -1- (8- ((E) -3,7-dimethylocta-2,6-dien-1-yl) -5-hydroxy-2, 2-dimethyl-2H-chromen-6-yl) -3- (4-methoxyphenyl) prop-2-en-1-one.
TABLE 3 preparation of Compound E1H-NMR (400MHz) and13C-NMR (100MHz) data
Evaluation of cytotoxicity
The cytotoxicity effect of the separated chalcone 1-6 on five cancer cells, namely PC-3 (prostatic cancer), MCF-7 (breast cancer), MDA-MB-468 (triple negative breast cancer cell line), SK-N-MC (Ewing sarcoma) and HEL (erythroleukemia cell) is tested. All compounds were tested at four fixed concentrations, 10nM, 10. mu.M, 50. mu.M, with the highest concentration being 100. mu.M. Preliminary screening results showed that compounds 1-5 had no significant antiproliferative effect at concentrations up to 100. mu.M in all cell lines tested, with the exception of compound 6, where antiproliferative activity was observed at a concentration of 50. mu.M.
Thus, compound 6 was further investigated to determine the IC of all five cancer cell lines50The value is obtained. As shown in FIG. 3, Compound 6 produced a cytotoxic effect, IC, on SK-N-MC (Ewing's sarcoma) cells5025.9 μ M. Compound 6 has cytostatic/antiproliferative activity, IC, against the other four cancer cell lines HEL, MCF-7, MDA-MB-468 and PC-350The values were 43.5. mu.M, 92.2. mu.M, 50.4. mu.M and 139.2. mu.M. Notably, the anticancer activity of compound 6 was detected to be the lowest in PC-3 cells, and the cell line had higher sensitivity to various anticancer agents. However, Compound 6 showed better cytotoxic effects (IC) against MDA-MB-468 (triple negative breast cancer cell line) and SK-N-MC (Ewing's sarcoma)50) These data have potential application in the treatment of orphan ewing's sarcoma and triple negative breast cancer.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. Chalcone derivatives characterized in that: the structural formula is selected from:
2. the process for producing a chalcone derivative according to claim 1, wherein: the method comprises the following steps:
extracting dried goldenseal with ethanol under reflux to obtain crude extract;
subjecting the crude extract to silica gel column chromatography, and gradient eluting with n-hexane-ethyl acetate eluting system;
carrying out secondary chromatographic separation on the 4 th fraction n-hexane-ethyl acetate solvent system on silica gel packing to obtain a compound 1 and a compound 2;
and (3) carrying out secondary chromatographic separation on the 5 th fraction on a silica gel filler by adopting an n-hexane-ethyl acetate solvent system to obtain a compound 3, a compound 4 and a compound 5.
3. The method for producing a chalcone derivative according to claim 2, wherein: the gradient elution procedure of the n-hexane-ethyl acetate elution system comprises the steps of eluting n-hexane, n-hexane-ethyl acetate and ethyl acetate from 0:100 to 0: 100.
4. The method for producing a chalcone derivative according to claim 2, wherein: reflux-extracting dried Ranunculus japonicus with 3-4L ethanol.
5. The method for producing a chalcone derivative according to claim 4, wherein: after the reflux extraction is finished, the solvent is removed by rotary evaporation at 35-45 ℃.
6. The method for producing a chalcone derivative according to claim 2, wherein: when the 4 th fraction was subjected to secondary chromatography, the volume ratio of n-hexane to ethyl acetate was 16: 84.
7. The method for producing a chalcone derivative according to claim 2, wherein: when the 5 th fraction is subjected to secondary chromatographic separation, the volume ratio of n-hexane to ethyl acetate is 15:85, 20:80 and 25: 75.
8. The method for producing a chalcone derivative according to claim 2, wherein: further comprising the step of subjecting the 2 nd fraction to a second chromatographic separation to obtain compound 6.
9. The method for producing a chalcone derivative according to claim 8, wherein: and when the secondary chromatographic separation is carried out, the volume ratio of the n-hexane to the ethyl acetate is 5:95, 10:90 and 15: 85.
10. The use of compound 6 of claim 8 in the preparation of a medicament for the treatment of ewing's sarcoma;
or, the compound 6 is applied to the preparation of the anti-cancer medicine for treating triple negative breast cancer;
or the application of the compound 6 in preparing functional food.
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