CN117003720A - Compound hibiscus essence and preparation method and application thereof - Google Patents

Compound hibiscus essence and preparation method and application thereof Download PDF

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CN117003720A
CN117003720A CN202210467131.5A CN202210467131A CN117003720A CN 117003720 A CN117003720 A CN 117003720A CN 202210467131 A CN202210467131 A CN 202210467131A CN 117003720 A CN117003720 A CN 117003720A
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compound
ethyl acetate
ethanol
water
petroleum ether
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胡攀
王艺
严鑫
张复中
邓力
冯丽萍
熊静
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Abstract

The invention belongs to the field of medicines and health products, and in particular relates to a novel compound hibiscus essence, a preparation method and application thereof. Compounds of the inventionIs extracted and separated from Hibiscus flower for the first time, and has the structure shown in formula I and chemical formula C 23 H 18 O 8 The chemical names are 1 '-methoxy-3,5,7,4', 3', 4' -hexahydroxyflavone, and are named as hibiscus extract, and the English name Mutabilflorin. The compound has multipurpose application prospect such as anti-inflammatory.

Description

Compound hibiscus essence and preparation method and application thereof
Technical Field
The invention belongs to the field of medicines and health products, and in particular relates to a novel compound hibiscus essence, a preparation method and application thereof.
Background
Hibiscus mutabilis L is a plant of Hibiscus genus of Malvaceae family, and its flowers and leaves can be used as medicines. The medicinal value is recorded in Ben Cao Tu Jing (materia Medica of Song Dynasty),' Di Hibiscus, sheng Ding Zhou. Pungent and flat, and nontoxic. Flowers are mainly malignant sores, and leaves are applied with swelling and pain and collected in September. The Hibiscus sabdariffa is also called birch, frostproof, cup-down (Zhuang) and peng (Miao Ming) and is planted in various places such as Sichuan, zhejiang, fujian, yunnan and Taiwan, and the overseas planting resources are distributed in various places such as Korea, japan, nepal, laos and Thailand. After more than ten years of research, the plant garden in Chengdu city is successfully researched and cultivated to obtain 18 cotton rose varieties. Cottonrose hibiscus She Shouzai in 2020 edition of Chinese pharmacopoeia, flowers are received and loaded in 2019 edition of third book of Chinese medicine Standard, guangdong province. Pungent in flavor and flat in nature, has the effects of removing toxic substances and detumescence, clearing heat and cooling blood and expelling pus, can be used for treating carbuncle on the back, burn and scald, mastitis, traumatic injury and the like by external application, and can be used for treating cough due to lung heat, menorrhagia, leucorrhea and the like by internal application. The description of Ben Cao gang mu: the hibiscus flower and leaves are flat in nature, not cold or hot, slightly pungent in flavor and sticky in drooling, and have the effect of treating carbuncle and swelling. Modern pharmacological researches show that the composition has the effects of resisting inflammation, easing pain, resisting oxidation, resisting allergy, reducing blood sugar and the like, and is widely applied to raw materials or additives of cosmetics and foods.
The Hibiscus sabdariffa has the effects of clearing heat and detoxicating, detumescence and expelling pus, cooling blood and stopping bleeding in the aspect of essential medicinal value. Is used for treating cough due to lung heat, menorrhagia, leucorrhea; it can be used for treating carbuncle, sore, furuncle, mastitis, lymphadenitis, parotitis, burn, scald, snake bite, and traumatic injury. The usage amount is as follows: 0.3 to 1 two; proper amount of the medicine is applied to the affected part by pounding fresh leaves and flowers or dried leaves and flowers are ground into powder and mixed with oil, vaseline, wine, vinegar or concentrated tea. Proved recipe has been reported that: 1. treating hematemesis, metrorrhagia, trachoma, sore and carbuncle on the lung: the cottonrose hibiscus spends three times to one time and two times, and is decocted for taking. ("Shanghai's usual Chinese herbal medicine"; 2. treating carbuncle, cellulitis and toxic swelling: flos Hibisci Mutabilis, leaves, and cortex moutan. Decocting and washing. ("Hunan drug Zhi"); 3. treating snake bite furuncle and snake venom: two flowers of fresh cotton rose and five flowers of winter honey. Pounding and applying, and changing twice to three times daily. (Fujian, "folk Utility herbal"; 4. treating water and scald: sun-drying flos Hibisci Mutabilis, grinding, and concocting with oleum Sesami. ("Hunan drug Zhi"); 5. treating the sores without healing: grinding flos Hibisci Mutabilis into powder and applying. (wonder); 6. treating cough due to deficiency tuberculosis: flos Hibisci Mutabilis two to four, herba Pyrolae one two, brown sugar two, stewing pig heart lung; salt may be added when sugar is not contained. ("Chongqing herbal medicine"; 7. treating menorrhagia: and (5) frost-resisting flower and lotus seedpod shell aliquoting. For the last, two money is put down every meter. (women's improved prescription).
The chemical components in the cottonrose hibiscus are mainly flavonoids and glycosides thereof, organic acids, volatile components and the like, wherein the flavonoids and glycosides thereof are characteristic components and active components of the cottonrose hibiscus, 73 flavonoid compounds which are separated and identified from the cottonrose hibiscus, including 48 flavonoid components separated and identified from the cottonrose hibiscus leaves and 36 flavonoid components separated and identified from the cottonrose hibiscus, are mainly flavonoid glycoside compounds taking kaempferol, quercetin, apigenin and the like as parent nuclei. In the application background, the inventor of the invention discovers a novel compound in the research of the cotton rose.
Disclosure of Invention
The first technical problem to be solved by the invention is to provide a novel compound with the structure as shown in the formula I and the chemical formula as C 23 H 18 O 8 。
The chemical name of the compound of the formula I is 1 '-methoxy-3,5,7,4', 3', 4' -hexahydroxyflavone, and is named as hibiscus extract, and the English name is Mutabilflorin. Nuclear magnetic data (600 MHz, CD) of the compounds of formula I of the invention 3 OH, J inHz) is shown in Table 1.
TABLE 1
a) The measurement frequency is 600MHz; b) the measurement frequency was 150MHz.
The physicochemical properties of the compounds of formula I of the present invention are: tan powder, readily soluble in methanol.
Spectroscopic data for compounds of formula I:(c＝0.05，MeOH)，IR(KBr)v max 3458,1733,1682,1560；UVλ max 205nm；LC-MS：m/z423.16； 1 H NMR(600MHz,Methanol-d 4 )δ7.62(2H,d,J＝8.2Hz,H-2',6'),6.78(2H,d,J＝8.1Hz,H-3',5'),6.75(1H,d,J＝2.1Hz,H-2″′),6.70(1H,d,J＝8.3Hz,H-5″′),6.65(1H,dd,J＝8.4,2.2Hz,H-6″′),6.29(1H,s,H-6),4.81(1H,q,J＝7.2Hz,H-1″),1.66(3H,d,J＝7.2Hz,2″-CH 3 )； 13 C NMR(151MHz,MeOD)δ160.4(C-2),123.8(C-3),177.7(C-4),160.3(C-5),98.9(C-6),163.0(C-7),112.5(C-8),155.7(C-9),105.1(C-10),136.8(C-1'),131.1(C-2'),116.1(C-3'),148.6(C-4'),116.1(C-5'),131.1(C-6'),33.0(C-1″),18.5(2″-CH 3 ),138.2(C-1″′),115.4(C-2″′),144.0(C-3″′),146.0(C-4″′),116.0(C-5″′),119.1(C-6″′)。
optical rotation of the compounds of formula I of the present invention(c 0.05, methanol), 3458cm can be observed from the IR spectrum -1 、1733cm -1 、1682cm -1 、1560cm -1 There is absorption indicating that the compound has hydroxyl, carbonyl and benzene rings. The ultraviolet spectrum shows that the compound has stronger absorption at 205nm and 280 nm. LC-MS excimer ion peak at M/z423.16[ M+H ]] + Where present (calculated as 423.11), unsaturation Ω=15, formula C was determined 23 H 18 O 8 。
The invention relates to the compounds of formula I 1 H NMR spectra 1 H- 1 The HCOSY spectrum (see Table 1) shows characteristic signals of δ7.62 (2H, J=8.2 Hz, H-2', 6'), δ6.87 (2H, J=8.1 Hz, H-3', 5') for 4 '-hydroxyflavonol, and the HSQC spectrum shows δ0.2.6' H 7.62 and delta C 131.1 are connected, delta H 6.87 and delta C 116.1. 24 of the compound 13 C data and kaempferol 13 C nuclear magnetic resonance data are compared to determine that the flavone parent nucleus part in the molecule is kaempferol. By passing through 1 H NMR spectra combined with coupling values to derive delta H 6.75 (1 h, d, j=2.1 Hz), 6.70 (1 h, d, j=8.3 Hz), 6.65 (1 h, dd, j=8.4, 2.2 Hz) are ABX system hydrogen signals on benzene rings. Delta display by HSQC spectra and HMBC spectra C 160.3 (C-5) and delta C 163.0 (C-7) proton-attached hydroxy group, delta C 105.9 (C-4) is a tertiary carbon proton, delta C 98.9 (C-6) is a single peak(s), indicating that the C-8 position of the kaempferol parent nucleus is substituted. 1 H NMR spectra 1 H- 1 HCOSY spectrum shows delta H At 4.81 is a methylene proton signal with a quartet (q), j=7.2 Hz, coupled with three protons, δ H At 1.66 is a methyl proton signal, coupled with two protons, so it is judged that there is one ethyl group in compound 24. HMBC spectra show tertiary carbon delta C 33.0 and delta C 18.5,112.5,115.4,119.1,138.2 the positions of benzene ring, ethyl and kaempferol parent nucleus of ABX system can be determined, and it is known from the unsaturation degree Ω=15 that there is no cyclic structure between kaempferol parent nucleus part and phenyl substituent part. In view of the above, it was determined that the compounds of formula I of the present invention have the structure 1 '-methoxy-3,5,7,4'3', 4' -hexahydroxyflavone, i.e., 1 "-methoxy-3, 5,7,4',3 '", 4' -hexahydroxflavone, named hibiscus, mutabilflorin.
The second technical problem to be solved by the invention is to provide a preparation method of the compound, the compound shown in the formula I is prepared by an extraction method, and the adopted raw materials are dried cotton rose flowers, namely flowers which are picked to be opened at the beginning of a blooming period or buds which are to be opened, and the compound is obtained by sun drying or baking.
The preparation method of the compound shown in the formula I comprises the following steps:
A. pulverizing and drying Hibiscus Mutabilis flower, extracting with ethanol, collecting filtrate, and removing ethanol to obtain Hibiscus Mutabilis flower ethanol extract crude extract;
B. suspending the ethanol extract crude extract of Hibiscus Mutabilis obtained in step A with water, sequentially extracting with petroleum ether (60-90deg.C), ethyl acetate and n-butanol (water saturation) for 3-5 times, respectively collecting extractive solutions, removing extractive solutions to obtain petroleum ether part, ethyl acetate part and n-butanol part, and water phase part as the rest;
C. subjecting the ethyl acetate part to normal phase silica gel column chromatography, gradient eluting with petroleum ether-ethyl acetate as eluting system, collecting fractions, performing detection and combination by TLC to obtain 7 components, named Fr.YA-Fr.YG, and collecting Fr.YC for use;
D. separating Fr.YC obtained in the step C by using an MCI medium-pressure column, performing gradient elution by using a methanol-water solvent system, collecting fractions, detecting and combining by using TLC, sequentially obtaining the following components which are named as Fr.YC1-13 respectively, and collecting Fr.YC6 for later use;
E. and D, performing semi-preparative liquid phase purification on Fr.YC6 obtained in the step D, and taking a methanol solution with the volume fraction of 62% as a mobile phase to obtain the compound shown in the formula I.
The technical scheme of the preparation method is as follows:
the ethanol in the step A is ethanol with the volume fraction of 70-100%; preferably, the volume fraction is 90% ethanol.
The extraction method in the step A is reflux extraction.
The extraction conditions of the reflux extraction in the extraction method in the step A are 1-3 times, and each time is 0.5-3 hours; preferably, the extraction conditions are 2 times, each for 2 hours.
The method for removing the ethanol in the step A adopts decompression recovery, and takes no alcohol smell as an end point.
B, adding 8-12 times of water into the ethanol extract crude extract of the cottonrose hibiscus; preferably 10 times.
The water in the step B is ultrapure water.
And step B, extracting by sequentially adopting petroleum ether (60-90 ℃), ethyl acetate and n-butanol (saturated water) with equal volumes.
The step B adopts petroleum ether (60-90 ℃), ethyl acetate and n-butyl alcohol (saturated water) to extract for 1-5 times, preferably 3 times.
Step C Petroleum ether-ethyl acetate solvent system is eluted according to a gradient of 20:1,8:1,5:1,2:1,1:1,1:2,1:4,1:10,0:100, and collected.
And D, sequentially carrying out 50:50,60:40,70:30,80:20,90:10 and 100:0 on a methanol-water solvent elution system, collecting fractions, detecting and combining by TLC, and sequentially obtaining the following components which are named as Fr.YC1-13 respectively.
And C, separating 80g of ethyl acetate part by normal phase silica gel column chromatography, eluting with petroleum ether-ethyl acetate as an eluting system according to a gradient of 20:1,8:1,5:1,2:1,1:1,1:2,1:4,1:10,0:100, and collecting the fraction 127 bottles. The collected 127 fractions were then combined by TLC to give 7 fractions, designated Fr.YA-Fr.YG, where 1-15 was Fr.YA,26-37 was Fr.YB,38-52 was Fr.YC,53-68 was Fr.YD,69-90 was Fr.YE,91-109 was Fr.YF, and 110-127 was Fr.YG. Collecting Fr.YC for later use;
the fr.yc obtained in step C corresponds to petroleum ether: ethyl acetate = 2:1 eluted fraction.
Step D, according to 80g of ethyl acetate part, the methanol-water solvent elution systems are sequentially 50:50,60:40,70:30,80:20,90:10,100:0, and the total fraction is 90 bottles. Detection and combination are carried out by TLC, and the following components are obtained in sequence and are respectively named as Fr.YC1-13, wherein: 1-4 is fr.yc1, 5-9 is fr.yc 2, 10-13 is fr.yc 3, 14-19 is fr.yc4, 20-24 is fr.yc 5, 25-28 is fr.yc6, 29-33 is fr.yc7, 34-38 is fr.yc8, 39-44 is fr.yc9, 45-48 is fr.yc 10, 49-62 is fr.yc11, 63-79 is fr.yc 12, 80-90 is fr.yc13.
Step D results in fr.yc6 corresponding to the fraction eluted with methanol-water solvent system=60:40, i.e. 60% methanol.
Step E, semi-preparative liquid phase purification, wherein a methanol solution with the volume fraction of 62% is taken as a mobile phase, and the peak time is 33min.
Most preferably, the compounds of formula I of the present invention are prepared as follows:
A. pulverizing dry flos Hibisci Mutabilis into coarse powder, reflux-extracting with 90% ethanol for 2 times and 2 hr each time, filtering, mixing filtrates, and recovering under reduced pressure until no ethanol smell exists to obtain crude extract of flos Hibisci Mutabilis ethanol extract;
B. adding 10 times of ultrapure water suspension extract, sequentially extracting with equal volume of petroleum ether (60-90deg.C), ethyl acetate and n-butanol (water saturation) for 3 times, mixing the extractive solutions, and recovering under reduced pressure to obtain petroleum ether part, ethyl acetate part and n-butanol part, and water phase part as the rest;
C. subjecting the ethyl acetate part to normal phase silica gel column chromatography, gradient eluting with petroleum ether-ethyl acetate as eluting system, collecting fractions, performing detection and combination by TLC to obtain 7 components, named Fr.YA-Fr.YG, and collecting Fr.YC for use;
D. separating Fr.YC obtained in the step C by using an MCI medium-pressure column, performing gradient elution by using a methanol-water solvent system, collecting fractions, detecting and combining by using TLC, sequentially obtaining the following components which are named as Fr.YC1-13 respectively, and collecting Fr.YC6 for later use;
E. and D, removing Fr.YC6 obtained in the step D, and performing semi-preparative liquid phase purification, wherein a volume fraction of 62% methanol solution is taken as a mobile phase, and the peak time is 33min, so as to obtain the compound of the formula I.
Taking 20kg of dry cotton rose as an example, the preparation method can obtain 3.34kg of cotton rose ethanol extract crude extract in the step A; step B can obtain 93.6g petroleum ether part, 89.7g ethyl acetate part, 389g n-butanol part, and the rest is water phase part; and C, taking 80g of ethyl acetate part, eluting with petroleum ether-ethyl acetate as an eluting system according to a gradient of 20:1,8:1,5:1,2:1,1:1,1:2,1:4,1:10 and 0:100, and collecting the eluate, wherein the eluate is commonly connected with 127 bottles. The collected 127 fractions were then combined by TLC to give 7 fractions, designated Fr.YA-Fr.YG, where 1-15 was Fr.YA,26-37 was Fr.YB,38-52 was Fr.YC,53-68 was Fr.YD,69-90 was Fr.YE,91-109 was Fr.YF, and 110-127 was Fr.YG. Collecting Fr.YC for later use; collecting the obtained fraction Fr.YC 14.97g; the Fr.YC was then separated using an MCI medium pressure column, eluted through a methanol-water solvent system (50:50, 60:40,70:30,80:20,90:10, 100:0), and the fractions were co-connected to 90 bottles. 1-4 is fr.yc1, 5-9 is fr.yc 2, 10-13 is fr.yc 3, 14-19 is fr.yc4, 20-24 is fr.yc 5, 25-28 is fr.yc6, 29-33 is fr.yc7, 34-38 is fr.yc8, 39-44 is fr.yc9, 45-48 is fr.yc 10, 49-62 is fr.yc11, 63-79 is fr.yc 12, 80-90 is fr.yc13. The collected fr.yc6 fraction, which corresponds to the methanol-water solvent system=60:40 elution, i.e. 60% methanol, is subjected to semi-preparative liquid phase purification to give the compound of formula i according to the invention.
The third technical problem solved by the invention is to provide at least one new use of the compound shown in the formula I.
Pharmacological tests prove that the compound of the formula I also has new application in preparing anti-inflammatory drugs, health care products and cosmetics.
The fourth technical problem to be solved by the invention is to provide a derivative product prepared by taking a compound shown as a formula I as a raw material.
The medicine is prepared by taking the compound shown in the formula I as a raw material and adding pharmaceutically acceptable auxiliary components.
The health-care product is prepared by taking the compound shown in the formula I as a raw material and adding auxiliary components acceptable in the health-care product.
The cosmetic is prepared by taking the compound shown in the formula I as a raw material and adding auxiliary components acceptable in cosmetics.
The veterinary drug is prepared by taking the compound shown in the formula I as a raw material and adding auxiliary components acceptable in veterinary drugs.
The invention has the beneficial effects that: the invention obtains a brand new compound of the formula I through an extraction separation technology, confirms the anti-inflammatory medical application of the compound, and provides a brand new compound, a preparation method and a plurality of application prospects for the public.
Drawings
FIG. 1 is a flow chart of extraction, separation and purification.
FIG. 2 effects of the compounds of formula I of the present invention on RAW264.7 cell proliferation.
FIG. 3 effects of the compounds of formula I of the present invention on TNF- α release.
Note that: comparison with blank group ## P<0.01; comparison with model group * P<0.05， ** P<0.01， **** P<0.001
FIG. 4 effect of the compounds of formula I of the present invention on NO release.
Note that: comparison with blank group ## P<0.01; comparison with model group ** P<0.01， *** P<0.001
Detailed Description
The following description of the embodiments of the invention illustrates, but does not limit, the invention.
The compound has the structure shown in the formula I and the chemical formula C 23 H 18 O 8 。
The chemical name of the compound is 1 '-methoxy-3,5,7,4', 3', 4' -hexahydroxyflavone, and is named as hibiscus extract, and the English name is Mutabilflorin.
The compound shown as the formula I is a monomer compound which is obtained by separating and purifying chemical components from ethanol extract of cotton rose.
The cotton rose sample is collected in 10 middle ten days of 2019 in a planting base of the cotton rose in Sanhe Zhenhua in City of Sichuan province, and dried in the shade naturally, and is identified as the dried cotton rose of Hibiscus mutabilis L.
1. The invention relates to the extraction, separation and purification of the compound of the formula I
1 extraction separation and purification
1.1 extraction
20kg of dried cotton rose is crushed into coarse powder, reflux-extracted with 90% ethanol for 2 times each for 2 hours, filtered, combined with filtrate, and recovered under reduced pressure until no ethanol smell exists, thus obtaining cotton rose ethanol extract crude extract (3.34 kg). Adding 10 times of ultrapure water suspension extract, sequentially extracting with equal volume of petroleum ether (60-90deg.C), ethyl acetate and n-butanol (water saturation) for 3 times, mixing the extractive solutions, and recovering under reduced pressure to obtain petroleum ether fraction (93.6 g), ethyl acetate fraction (89.7 g) and n-butanol fraction (389.0 g), and water phase part as the rest.
1.2 isolation and purification
Separating ethyl acetate extract 80.0g with normal phase silica gel column chromatography, gradient eluting with petroleum ether-ethyl acetate as eluting system, collecting fractions, and combining by TLC to obtain 7 components named Fr.YA-Fr.YG. Fr.YA (10.97 g) and YC (14.97 g) sections were separated by MCI medium pressure column, gradient elution was performed by methanol-water solvent system, and fractions were collected and combined by TLC to obtain fractions Fr.YA 1-11 and Fr.YC1-13. Wherein Fr.YC6 is purified by semi-preparation liquid phase, and a methanol solution with the volume fraction of 62% is taken as a mobile phase, so as to obtain the compound shown in the formula I. The extraction, separation and purification flow chart is shown in figure 1 below.
The compound of the formula I is tan powder which is obtained by an extraction and purification method and is easy to dissolve in methanol. Optical rotation(c 0.05, methanol), 3458cm can be observed from the IR spectrum -1 、1733cm -1 、1682cm -1 、1560cm -1 There is absorption indicating that the compound has hydroxyl, carbonyl and benzene rings. The ultraviolet spectrum shows that the compound has stronger absorption at 205nm and 280 nm. LC-MS excimer ion peak at M/z423.16[ M+H ]] + Where present (calculated as 423.11), unsaturation Ω=15, formula C was determined 23 H 18 O 8 。 1 H NMR spectra 1 H- 1 The HCOSY spectrum (see Table 1) shows characteristic signals of δ7.62 (2H, J=8.2 Hz, H-2', 6'), δ6.87 (2H, J=8.1 Hz, H-3', 5') for 4 '-hydroxyflavonol, and the HSQC spectrum shows δ0.2.6' H 7.62 and delta C 131.1 are connected, delta H 6.87 and delta C 116.1. 24 of the compound 13 C data and kaempferol 13 C nuclear magnetic resonance data are compared to determine that the flavone parent nucleus part in the molecule is kaempferol. By passing through 1 H NMR spectra combined with coupling values to derive delta H 6.75 (1 h, d, j=2.1 Hz), 6.70 (1 h, d, j=8.3 Hz), 6.65 (1 h, dd, j=8.4, 2.2 Hz) are ABX system hydrogen signals on benzene rings. Delta display by HSQC spectra and HMBC spectra C 160.3 (C-5) and delta C 163.0 (C-7) proton-attached hydroxy group, delta C 105.9 (C-4) is a tertiary carbon proton, delta C 98.9 (C-6) is a single peak(s), indicating that the C-8 position of the kaempferol parent nucleus is substituted. 1 H NMR spectra 1 H- 1 HCOSY spectrum shows delta H At 4.81 is a methylene proton signal with a quartet (q), j=7.2 Hz, coupled with three protons, δ H At 1.66 is a methyl proton signal, coupled with two protons, so it is judged that there is one ethyl group in compound 24. HMBC spectra show tertiary carbon delta C 33.0 and delta C 18.5,112.5,115.4,119.1,138.2 the positions of benzene ring, ethyl and kaempferol parent nucleus of ABX system can be determined, and it is known from the unsaturation degree Ω=15 that there is no cyclic structure between kaempferol parent nucleus part and phenyl substituent part. In view of the above, it was determined that the compounds of formula I of the present invention have the structure 1 '"methoxy-3, 5,7,4',3", 4 "-hexahydroxyflavone, namely 1 '-methoxy-3,5,7,4', 3', 4' -hexahydroxflavone, and named as hibiscus extract, english name Mutabilflorin.
Spectroscopic data for compounds of formula I:(c＝0.05，MeOH)，IR(KBr)v max 3458,1733,1682,1560；UVλ max 205nm；LC-MS：m/z423.16； 1 H NMR(600MHz,Methanol-d 4 )δ7.62(2H,d,J＝8.2Hz,H-2',6'),6.78(2H,d,J＝8.1Hz,H-3',5'),6.75(1H,d,J＝2.1Hz,H-2″′),6.70(1H,d,J＝8.3Hz,H-5″′),6.65(1H,dd,J＝8.4,2.2Hz,H-6″′),6.29(1H,s,H-6),4.81(1H,q,J＝7.2Hz,H-1″),1.66(3H,d,J＝7.2Hz,2″-CH 3 )； 13 C NMR(151MHz,MeOD)δ160.4(C-2),123.8(C-3),177.7(C-4),160.3(C-5),98.9(C-6),163.0(C-7),112.5(C-8),155.7(C-9),105.1(C-10),136.8(C-1'),131.1(C-2'),116.1(C-3'),148.6(C-4'),116.1(C-5'),131.1(C-6'),33.0(C-1″),18.5(2″-CH 3 ),138.2(C-1″′),115.4(C-2″′),144.0(C-3″′),146.0(C-4″′),116.0(C-5″′),119.1(C-6″′)。
2. use of the compounds of formula I according to the invention
Mouse macrophage cell line RAW264.7 in DMEM complete medium containing antibiotics (100U/mL penicillin, 100. Mu.g/mL streptomycin) and 10% Fetal Bovine Serum (FBS) at 37deg.C, 5% CO 2 Is cultured in a incubator.
Experimental example 1: proliferation of RAW264.7 cells
RAW264.7 cells in logarithmic growth phase were selected at 3X 10 5 Density per mL, 100 μl per well was inoculated in 96-well plates to 37 ℃, 5% co 2 After 24h incubation in an incubator of (1) in which the supernatant was removed, 1mL of DEME solution was added to the blank, 1mL of DEME solution containing LPS (1. Mu.g/mL) was added to the model and experimental groups, DEME solutions containing different concentrations (3.125, 6.25, 12.5, 25, 50. Mu. Mol/L) of the compound of formula I of the present invention were added to the experimental groups, 100. Mu.g/mL of dexamethasone was added to the positive control group, and 5% CO was added at 37 ℃C 2 Culturing in an incubator for 24 hours respectively. The original culture solution in the 96-well plate is discarded, 100. Mu.L of serum-free culture solution and 10. Mu.L of CCK-8 solution are added under the condition of avoiding light, and the cell-free compound well is set as a blank group. The cell plate is placed in a cell incubator to be incubated for 3 hours in a dark place, the absorbance (A450) value of the enzyme label instrument is parallelly measured for 3 times at 450nm, and the relative survival rate of the cells is calculated. As shown in FIG. 2, the compound of the formula I of the invention can obviously inhibit RAW264.7 macrophage proliferation (P) in a certain molar concentration range (25-50 mu mol/L)<0.05 Has concentration dependence and obvious inhibiting effect on RAW264.7 cell proliferation.
Experimental example 2: elisa method for detecting release amount of RAW264.7 cell inflammatory factor TNF-alpha
RAW264.7 cells in logarithmic growth phase were selected at 3X 10 5 Density per mL, 100 μl per well was inoculated in 96-well plates to 37 ℃, 5% co 2 After 0.5h, 1mL of DEME solution containing LPS (1. Mu.g/mL) was added to the model group and the experimental group, 1mL of DEME solution containing compound (25. Mu. Mol/L) was added to the experimental group, and the culture was carried out in a 5% CO2 incubator at 37℃for 24 hours, and the inflammatory factor TNF-. Alpha.level was detected by an Elisa kit and the content thereof was calculated according to a standard curve. From fig. 3, it can be seen that LPS can increase the TNF- α release of RAW264.7 macrophages compared to the blank group, with a significant difference (P<0.05). After the compound (25 mu mol/L) of the formula I is added for treatment, the capability of the RAW264.7 cell to secrete TNF-alpha inflammatory factors can be effectively reduced, which shows that the compound of the formula I of the invention shows anti-inflammatory activity by reducing the release of TNF-alpha.
Experimental example 3: determination of NO Release by Griess method
RAW264.7 cells in logarithmic growth phase were selected at 3X 10 5 Density per mL, 100 μl per well was inoculated in 96-well plates to 37 ℃, 5% co 2 Is cultured in an incubator of (2) and a NO standard curve is prepared according to the kit instructions. Blank and experimental groups 1mL of DEME solution, model and experimental groups 1mL of DEME solution containing LPS (1 μg/mL), 0.5h later 1mL of DEME solution containing the compound of formula i of the invention (6.25, 12.5 μmol/L) was added to each experimental group, after 24h, centrifugation (1 g,15 min), 50 μl of culture supernatant was aspirated into 96-well cell plates, 50 μl of Griess reagent a was added to each well and mixed, standing for 5min at room temperature in the dark, 50 μl of Griess reagent B was added to each well and mixed, standing for 10min at room temperature in the dark, absorbance (a 540) was measured at 540nm by the enzyme-labeled instrument, and 6 wells were repeated for each group using a calibration curve. The inhibition of Nitric Oxide (NO) was evaluated. The NO inhibition rate is calculated according to the following formula: NO inhibition = (a-model-a drug group)/(a-model-a blank group) ×100%.
As shown in fig. 4, LPS can increase NO release in macrophage supernatant with a significant difference (P < 0.05). After the compound (6.25, 12.5 mu mol/L) of the formula I is added for treatment, the content of NO in the supernatant of RAW264.7 macrophages treated by the compound (6.25, 12.5 mu mol/L) of the formula I is obviously reduced (P is less than 0.05), and the concentration dependence shows that the compound of the formula I can show anti-inflammatory activity by reducing the release amount of NO.
LPS is used as an inducer to stimulate RAW264.7 macrophages to establish an inflammation model, and the isolated compound shown in the formula I is subjected to in vitro anti-inflammatory activity evaluation research. Firstly, the cytotoxicity of the compound of the formula I in different concentrations is detected by adopting a CCK-8 method, and the compound of the formula I in the invention can inhibit the proliferation of inflammatory cells and form concentration dependence in a certain concentration range (25-50 mu mol/L). Then detecting the release amount of TNF-alpha inflammatory factors by an Elisa method, and finding that 25 mu mol/L of the compound of the formula I can reduce the release amount of TNF-alpha compared with a model group; the Griess method detects the NO release amount, and the compounds of the formula I of the invention with the concentration of 6.25 and 12.5 mu mol/L can reduce the NO release amount of RAW264.7 macrophages compared with a model group, and the experimental result shows that the anti-inflammatory effect of the compounds of the formula I of the invention is mainly related to the inhibition of the release amounts of inflammatory factors TNF-alpha and NO.
In conclusion, the compound has the structure shown in the formula I and the chemical formula C 23 H 18 O 8 The chemical name is 1 '-methoxy-3,5,7,4', 3', 4' -hexahydroxyflavone, and is named hibiscus flower element, english name Mutabilflorin. Is prepared from the extract of the cotton rose for the first time through extraction, separation and purification, and has definite anti-inflammatory effect.

Claims (10)

1. A compound characterized by: the structure is shown as formula I, the chemical formula is C 23 H 18 O 8 ：
2. A process for the preparation of a compound as claimed in claim 1, characterized in that: the method comprises the following steps:
A. pulverizing and drying Hibiscus Mutabilis flower, extracting with ethanol, collecting filtrate, and removing ethanol to obtain Hibiscus Mutabilis flower ethanol extract crude extract;
B. the crude extract of the ethanol extract of the Hibiscus Mutabilis obtained in the step A is suspended by adding water, petroleum ether, ethyl acetate and water saturated n-butanol at 60-90 ℃ are respectively used for extracting for 3-5 times in sequence, extract liquid is respectively collected, extract liquid is removed, petroleum ether part, ethyl acetate part and n-butanol part are respectively obtained, and the rest is water phase part;
C. subjecting the ethyl acetate part to normal phase silica gel column chromatography, gradient eluting with petroleum ether-ethyl acetate as eluting system, collecting fractions, performing detection and combination by TLC to obtain 7 components, named Fr.YA-Fr.YG, and collecting Fr.YC for use;
D. separating Fr.YC obtained in the step C by using an MCI medium-pressure column, performing gradient elution by using a methanol-water solvent system, collecting fractions, detecting and combining by using TLC, sequentially obtaining the following components which are named as Fr.YC1-13 respectively, and collecting Fr.YC6 for later use;
E. and D, performing semi-preparative liquid phase purification on Fr.YC6 obtained in the step D, and taking a methanol solution with the volume fraction of 62% as a mobile phase to obtain the compound of the formula I.
3. A process for the preparation of a compound according to claim 2, characterized in that: at least any one of the following is satisfied:
picking the flowers which are initially opened or the buds to be opened in the flowering period, and airing or drying the flowers to be opened to obtain the dry cotton rose;
the ethanol in the step A is ethanol with the volume fraction of 70-100%;
preferably, the ethanol in the step A is 90% ethanol by volume fraction;
the extraction method in the step A is reflux extraction;
the extraction conditions of the reflux extraction in the extraction method in the step A are 1-3 times, and each time is 0.5-3 hours;
preferably, the extraction conditions of the reflux extraction in the extraction method in the step A are 2 times, each time for 2 hours;
the method for removing the ethanol in the step A adopts decompression recovery, and takes no alcohol smell as the end point;
b, adding 8-12 times of water into the ethanol extract crude extract of the cottonrose hibiscus;
preferably, the water addition amount of the ethanol extract crude extract of the cottonrose hibiscus in the step B is 10 times of that of the ethanol extract crude extract of the cottonrose hibiscus;
the water in the step B is ultrapure water;
step B, extracting by sequentially adopting petroleum ether, ethyl acetate and water saturated n-butanol with the same volume at 60-90 ℃;
step B, petroleum ether, ethyl acetate and water saturated n-butanol with the temperature of 60-90 ℃ are sequentially adopted for extraction for 1-5 times;
preferably, the step B sequentially adopts petroleum ether, ethyl acetate and water saturated n-butanol with the temperature of 60-90 ℃ for extraction for 3 times;
step C, eluting the petroleum ether-ethyl acetate solvent system according to a gradient of 20:1,8:1,5:1,2:1,1:1,1:2,1:4,1:10 and 0:100, and collecting;
the fr.yc obtained in step C corresponds to petroleum ether: ethyl acetate = 2:1 eluted fraction;
step D, a methanol-water solvent elution system sequentially comprises 50:50,60:40,70:30,80:20,90:10 and 100:0, fractions are collected and detected and combined by TLC, and the following components are sequentially obtained and respectively named as Fr.YC1-13;
step D results in fr.yc6 corresponding to the fraction eluted with methanol-water solvent system=60:40, i.e. 60% methanol.
4. A process for the preparation of a compound according to claim 2, characterized in that: at least any one of the following is satisfied:
in the step C, 80g of ethyl acetate part is taken, normal phase silica gel column chromatography is carried out, petroleum ether-ethyl acetate is taken as an elution system to carry out gradient elution according to the ratio of 20:1,8:1,5:1,2:1,1:1,1:2,1:4,1:10 and 0:100, and 127 bottles of fractions are collected and connected together; then, the collected 127 bottles of fractions are inspected and combined by TLC to obtain 7 components, which are named as Fr.YA-Fr.YG, wherein 1-15 are Fr.YA,26-37 are Fr.YB,38-52 are Fr.YC,53-68 are Fr.YD,69-90 are Fr.YE,91-109 are Fr.YF, and 110-127 are Fr.YG; collecting Fr.YC for later use, wherein the obtained Fr.YC corresponds to petroleum ether: ethyl acetate = 2:1 eluted fraction;
in the step D, 80g of ethyl acetate is taken according to the step C, and the methanol-water solvent elution system is sequentially 50:50,60:40,70:30,80:20,90:10 and 100:0, and the mixture is connected with a fraction 90 bottle; detection and combination are carried out by TLC, and the following components are obtained in sequence and are respectively named as Fr.YC1-13, wherein: 1-4 is fr.yc1, 5-9 is fr.yc2, 10-13 is fr.yc3, 14-19 is fr.yc4, 20-24 is fr.yc5, 25-28 is fr.yc6, 29-33 is fr.yc7, 34-38 is fr.yc8, 39-44 is fr.yc9, 45-48 is fr.yc10, 49-62 is fr.yc11, 63-79 is fr.yc12, 80-90 is fr.yc13. The resulting fr.yc6 corresponds to the methanol-water solvent system=60:40 eluted fraction, i.e. 60% methanol;
step E, semi-preparative liquid phase purification, wherein a methanol solution with the volume fraction of 62% is taken as a mobile phase, and the peak time is 33min.
5. A process for the preparation of a compound according to claim 2, characterized in that: the method comprises the following steps:
A. pulverizing dry flos Hibisci Mutabilis into coarse powder, reflux-extracting with 90% ethanol for 2 times and 2 hr each time, filtering, mixing filtrates, and recovering under reduced pressure until no ethanol smell exists to obtain crude extract of flos Hibisci Mutabilis ethanol extract;
B. adding 10 times of ultrapure water suspension extract, sequentially extracting with petroleum ether, ethyl acetate and water saturated n-butanol with equal volume of 60-90deg.C for 3 times, mixing the extractive solutions, recovering under reduced pressure to obtain petroleum ether part, ethyl acetate part and n-butanol part, and water phase part as the rest;
C. separating ethyl acetate part by normal phase silica gel column chromatography, gradient eluting with petroleum ether-ethyl acetate=20:1, 8:1,5:1,2:1,1:1,1:2,1:4,1:10,0:100 as eluting system, collecting fraction 127 bottle, and performing detection and combination by TLC to obtain 7 components sequentially, named Fr.YA-Fr.YG, wherein 1-15 is Fr.YA,26-37 is Fr.YB,38-52 is Fr.YC,53-68 is Fr.YD,69-90 is Fr.YE,91-109 is Fr.YF,110-127 is Fr.YG, and Fr.YC is collected for use; D. separating Fr.YC obtained in the step C by using an MCI medium pressure column, performing gradient elution by using a methanol-water=50:50, 60:40,70:30,80:20,90:10 and 100:0 as a solvent system, collecting fractions, and commonly connecting 90 bottles of the fractions, detecting and combining by using TLC to sequentially obtain the following components named as Fr.YC1-13, wherein: 1-4 is fr.yc1, 5-9 is fr.yc2, 10-13 is fr.yc3, 14-19 is fr.yc4, 20-24 is fr.yc5, 25-28 is fr.yc6, 29-33 is fr.yc7, 34-38 is fr.yc8, 39-44 is fr.yc9, 45-48 is fr.yc10, 49-62 is fr.yc11, 63-79 is fr.yc12, 80-90 is fr.yc13, and fr.yc6 is collected for use.
E. And D, performing semi-preparative liquid phase purification on Fr.YC6 obtained in the step D, and taking a methanol solution with the volume fraction of 62% as a mobile phase, wherein the peak time is 33min, so as to obtain the compound of the formula I.
6. The use of the compound of claim 1 in the preparation of anti-inflammatory drugs, health products, cosmetics, veterinary drugs.
7. A medicament prepared from the compound of claim 1, wherein: the medicine is prepared by taking the compound shown in the formula I as a raw material and adding pharmaceutically acceptable auxiliary components.
8. The health product prepared by the compound of claim 1, which is characterized in that: the health care product is prepared by taking the compound shown in the formula I as a raw material and adding auxiliary components acceptable in the health care product.
9. A cosmetic product prepared from the compound of claim 1, characterized in that: the cosmetic is prepared by taking the compound shown in the formula I as a raw material and adding auxiliary components acceptable in cosmetics.
10. A cosmetic product prepared from the compound of claim 1, characterized in that: the veterinary drug is prepared by taking the compound of the formula I as a raw material and adding auxiliary components acceptable by veterinary drugs.
CN202210467131.5A 2022-04-29 2022-04-29 Compound hibiscus essence and preparation method and application thereof Pending CN117003720A (en)

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