CN114539259A - Active alkaloid compound, radix Sophorae Flavescentis extract and its application in preparing product with skin pruritus resisting effect - Google Patents
Active alkaloid compound, radix Sophorae Flavescentis extract and its application in preparing product with skin pruritus resisting effect Download PDFInfo
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- 239000000284 extract Substances 0.000 title claims abstract description 54
- 229930013930 alkaloid Natural products 0.000 title claims abstract description 53
- 208000003251 Pruritus Diseases 0.000 title claims abstract description 52
- -1 alkaloid compound Chemical class 0.000 title claims abstract description 52
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- HRBMESHSNKKVBJ-OLKYXYMISA-N [(1r,4r,5r,7s)-8-benzyl-7-[[4-(dimethylamino)phenyl]carbamoyl]-8-azabicyclo[3.2.1]octan-4-yl] n-ethylcarbamate Chemical group N1([C@@H]2C[C@@H]([C@H]1CC[C@H]2OC(=O)NCC)C(=O)NC=1C=CC(=CC=1)N(C)C)CC1=CC=CC=C1 HRBMESHSNKKVBJ-OLKYXYMISA-N 0.000 description 1
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Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
- A61K36/489—Sophora, e.g. necklacepod or mamani
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
- A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9783—Angiosperms [Magnoliophyta]
- A61K8/9789—Magnoliopsida [dicotyledons]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
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Abstract
The invention relates to the technical field of pharmaceutical chemistry, and particularly discloses an active alkaloid compound, a sophora flavescens extract and application of the active alkaloid compound and the sophora flavescens extract in preparation of a product with an anti-skin-itch effect. The active alkaloid compound has a structure shown in a formula I or a formula II. The sophora flavescens extract contains a compound with a structure shown in a formula I or a formula II. Research shows that the active alkaloid compounds with the structures shown in the formula I or the formula II have the function of resisting skin itch. Therefore, the active alkaloid compound or the sophora flavescens extract is used as an anti-skin-pruritus active substance, and has wide application prospects in skin care products, cosmetics and medicines.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to an active alkaloid compound, a sophora flavescens extract and application thereof in preparing a product with an anti-skin-itch effect.
Background
Skin aging is a naturally occurring physiological process, but further damage to the skin and acceleration of the aging process are caused by stimulation of certain adverse external factors, wherein skin pruritus is the most common skin disorder of the elderly. Antihistamines are one of the common drugs for clinically treating skin pruritus.
The traditional Chinese medicine has long history and rich experience in treating skin diseases, can control repeated skin diseases or prolong the recurrence time of the skin diseases, reduces or avoids the side effect of chemical drugs, delays the pathological change process and prolongs the survival time, so the trend of pursuing the traditional Chinese medicine with stable curative effect, safety and reliability is more and more obvious. Kuh-seng is first recorded in Shen nong Ben Cao Jing (Shen nong's herbal), has the effects of clearing heat and drying dampness, detoxifying and killing parasites, and inducing diuresis to alleviate edema, and is mainly used for treating dysentery, enteritis, heat stranguria, vulva swelling and pruritus vulvae, eczema and the like. With the continuous research on radix sophorae flavescentis at home and abroad in recent years, the treatment application field of the radix sophorae flavescentis is continuously expanded, and the radix sophorae flavescentis extract is also widely applied to the treatment of related skin diseases. However, whether the sophora flavescens extract has a good treatment effect on skin itch or not is not reported in research; and which compounds in the sophora flavescens extract have a therapeutic effect on skin itch, are required to be further researched and developed by those skilled in the art. Therefore, the active compound with the function of resisting the skin itch is developed by taking the traditional Chinese medicine radix sophorae flavescentis as a raw material, and has important application value.
Disclosure of Invention
In view of the above, the present invention provides an active alkaloid compound and an extract of sophora flavescens ait; research shows that the active alkaloid compound and the sophora flavescens extract have the effect of resisting skin itch.
The detailed technical scheme of the invention is as follows:
an active alkaloid compound having a structure represented by formula I or formula II;
the active alkaloid compound with the structure shown in the formula I or the formula II is separated from the sophora flavescens extract, and researches show that the active alkaloid compound with the structure shown in the formula I or the formula II has the effect of resisting skin itch. The inventor also surprisingly found in the research that: the active alkaloid compound with the structure shown in the formula I has far better skin itch resisting effect than the active alkaloid compound with the structure shown in the formula II; the active alkaloid compounds with the structures shown in the formula I and the formula II are different in that the ring containing carbonyl of the active alkaloid compound with the structure shown in the formula II is conjugated with 2 unsaturated double bonds, and the ring containing carbonyl of the active alkaloid compound with the structure shown in the formula I is substituted by H for 2 unsaturated double bonds; this indicates that: after 2 unsaturated double bonds on a carbonyl-containing ring of the active alkaloid compound with the parent nucleus structure are substituted by H, the anti-skin-itch effect of the active alkaloid compound is greatly improved.
The invention also provides a sophora flavescens extract which contains a compound with a structure shown in a formula I or a formula II.
The active alkaloid compound with the structure shown in the formula I or the formula II has the effect of resisting skin itch; therefore, it is known to those skilled in the art that active alkaloid compounds having the structures represented by formula I or formula II have an anti-itch effect on skin.
Preferably, the sophora flavescens extract is prepared by a method comprising the following steps: extracting radix Sophorae Flavescentis with organic solvent, concentrating the extractive solution, and drying to obtain radix Sophorae Flavescentis organic solvent extract.
Further preferably, the organic solvent is ethanol water solution with volume fraction of 50-95%.
Most preferably, the organic solvent is ethanol water solution with the volume fraction of 70-80%.
Further preferably, the sophora flavescens organic solvent extract is further prepared into the sophora flavescens extract by silica gel column chromatography;
the specific elution conditions of the silica gel column chromatography are as follows: eluting with a mixed organic solvent consisting of chloroform and methanol with the volume fraction of 90-95: 10-5, collecting eluent, concentrating and drying to obtain a fraction A; eluting with a mixed organic solvent consisting of chloroform and methanol with the volume fraction of 80-85: 20-15, collecting eluent, concentrating and drying to obtain a fraction B; collecting fraction B to obtain the radix Sophorae Flavescentis extract.
Most preferably, the specific elution conditions of the silica gel column chromatography are as follows: eluting with a mixed organic solvent consisting of chloroform and methanol with the volume fraction of 93:7, collecting eluent, concentrating and drying to obtain a fraction A; eluting with a mixed organic solvent consisting of chloroform and methanol with the volume fraction of 83:7, collecting eluent, concentrating and drying to obtain a fraction B; collecting fraction B to obtain the radix Sophorae Flavescentis extract.
The silica gel column elution condition plays a decisive role in preparing the sophora flavescens extract with the function of resisting skin itch; the sophora flavescens extract prepared by optionally selecting the silica gel column elution condition has the function of resisting skin itch; the research shows that: the fraction B prepared under the silica gel column elution condition has excellent skin itch resisting effect which is far higher than that of the organic solvent extract of sophora flavescens ait, and the extract of sophora flavescens ait obtained from other fractions.
The invention also provides application of the active alkaloid compound or the sophora flavescens extract in preparing a product with an anti-skin itch effect.
Preferably, the anti-skin itch is anti-aging skin itch.
Preferably, the product is a medicament, skin care product or cosmetic.
Has the advantages that:
(1) the invention provides an active alkaloid compound or a sophora flavescens extract. The test result shows that the active alkaloid compound or the sophora flavescens extract can obviously prolong the latent scratching time of pruritus of aged mice with cutaneous pruritus and reduce the scratching times of the mice with cutaneous pruritus. This indicates that: the active alkaloid compound and radix Sophorae Flavescentis extract with structure shown in formula I or formula II have skin pruritus resisting effect. Particularly, the active alkaloid compound with the structure shown in the formula I has the most obvious anti-itch effect, and the anti-itch effect is far better than that of the active alkaloid compound with the structure shown in the formula II and the positive contrast medicament diphenhydramine; an unexpected antipruritic effect was achieved.
(2) The active alkaloid compound or the sophora flavescens extract has excellent anti-skin pruritus activity, so the active alkaloid compound or the sophora flavescens extract can be used as an anti-skin pruritus active substance and has wide application prospect in cosmetics or medicaments.
(3) The active alkaloid compound or the sophora flavescens extract can be obtained by extracting and separating from traditional Chinese medicine sophora flavescens, and has rich sources; and the matrine or the sophora flavescens ait has simple preparation process and convenient operation, and is beneficial to the application of the matrine or the sophora flavescens ait in medicines and cosmetics.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only drawings of some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is an MS spectrum of an active alkaloid compound having the structure shown in formula I.
FIG. 2 is a schematic representation of an active alkaloid compound of the structure shown in formula I1H-NMR spectrum.
FIG. 3 is a schematic representation of an active alkaloid compound of the structure shown in formula I13C-NMR spectrum
FIG. 4 is an MS spectrum of an active alkaloid compound having the structure shown in formula II.
FIG. 5 is a schematic representation of an active alkaloid compound having the structure shown in formula II1H-NMR spectrum.
FIG. 6 is a schematic representation of an active alkaloid compound having the structure shown in formula II13C-NMR spectrum.
Detailed Description
The technical solution of the present invention will be clearly and completely described with reference to the following examples. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Preparation of sophora flavescens extract and active alkaloid compound with structures shown in formula I and formula II
(1) Mixing 300g of dried radix sophorae flavescentis with 6000mL of ethanol water solution with volume fraction of 50%, soaking for 24 hours, and drying an extracting solution to obtain an ethanol extract of the radix sophorae flavescentis;
(2) packing the column with 200-300 mesh silica gel 30 times the weight of the kuh-seng alcohol extract, and loading the kuh-seng alcohol extract on a silica gel column; eluting with a mixed organic solvent consisting of chloroform and methanol with 3 times of column volume and volume fraction of 93:7, collecting eluent, concentrating and drying to obtain a fraction A; eluting with a mixed organic solvent consisting of chloroform and methanol with the volume fraction of 83:7, collecting eluent, concentrating and drying to obtain a fraction B; collecting fraction B to obtain radix Sophorae Flavescentis extract;
(3) preparing active alkaloid compounds with structures shown in formula I and formula II from the radix sophorae flavescentis extract prepared in the step (2) by using preparative HPLC; the specific conditions for preparative HPLC were: using a C18 preparative chromatographic column, taking 0.1% trifluoroacetic acid water solution as a mobile phase A, taking 0.1% trifluoroacetic acid acetonitrile solution as a mobile phase B, wherein the ratio of the mobile phase A: the mobile phase B is 70:30, and the measuring wavelength is 300 mu m; collecting fractions corresponding to chromatographic peaks at 10.3min and 11.9min, concentrating, and drying to obtain compound 1 and compound 2;
and (3) measuring the separated compound 1 and compound 2 by using mass spectrum and NMR, wherein the mass spectrum measurement conditions comprise ESI positive ion mode capillary voltage of 3kV, taper hole voltage of 50V, extraction voltage of 5V, desolvation temperature of 350 ℃, and atomized gas flow of 350L/h.
The compound 1 is white powder, the color development of the potassium bismuth iodide is positive,
(c 0.75,CH3OH). HR-ESI-MS showed an excimer peak m/z 249.1970(calcld for C)15H25N2O,249.1961), suggesting that the molecular weight of the compound is 248, and the molecular formula is C15H24N2O, unsaturation degree is 5.13C NMR(100MHz,CDCl3) The spectrum shows a total of 15 carbons, including 1 acyl carbonyl signal (. delta.)C169.5), 2 methine carbon signals (. delta.) attached to the heteroatomC63.8,53.2) and 3 methylene carbon signals (. delta.) attached to heteroatomsC57.3,57.2,43.3)。1H NMR(400MHz,CDCl3)δ:4.27(1H,dd,J＝12.8,4.4Hz,H-17),3.72(1H,dt,J＝9.6,6.0Hz,H-11),2.92(1H,t,J＝12.8Hz,H-17),2.67～2.98(2H,m,H-2,10),2.30(1H,m,H-14),2.12(1H,m,H-14),1.96(2H,m),1.60～1.971(3H,m),1.20～1.55(12H,m)；13C NMR(100MHz,CDCl3) Delta. 169.5(C-2),63.8(C-6),57.3(C-10),57.2(C-2),53.2(C-11),43.3(C-7),41.5(C-17),35.4(C-5),32.9(C-14),27.8(C-12),27.2(C-4),26.5(C-8),21.2(C-9),20.8(C-3),19.0 (C-13). Finally, compound 1 was identified as the active alkaloid compound of formula i.
The compound 2 is white powder, the color development of the potassium bismuth iodide is positive,
(c 0.69,CH3OH). Positive ion ESI-MS shows M/z 245[ M + H ]]+It is suggested that the molecular weight of the compound is 244 and the molecular formula is C15H20N2O, unsaturation Ω ═ 5.13The C NMR spectrum showed 15 carbons, including 1 acyl carbonyl signal (. delta.)C122.2), 4 aromatic carbon signals (. delta.)C150.3,141.3,116.6,106.6), 1 methine carbon signal (. delta.) attached to a heteroatomC61.6) and 3 methylene carbon signals (. delta.) attached to the heteroatomC 57.9,57.7,45.4)。1H NMR(300MHz,CD3OD) spectrum shows 20 hydrogen proton signals, including 3 alkene hydrogen signals [ delta ]H7.51(1H,dd,J＝7.5,8.7Hz),6.55(1H,dd,J＝7.5Hz),6.45(1H,dd,J＝9.0Hz)]. The attribution of the data is performed,1H NMR(300MHz,CD3OD)δ:7.51(1H,dd,J＝7.5,8.7Hz),6.55(1H,dd,J＝7.5Hz),6.45(1H,dd,J＝9.0Hz),4.10(1H,dd,J＝7.2,15.0Hz),3.80(1H,dd,J＝12.3,15.0Hz),3.50(1H,s),3.10(1H,s),2.65(1H,d,J＝14.1Hz),2.21～2.34(4H,m),2.03～2.11(2H,m),1.74～1.79(3H,m),1.51～1.60(3H,m)；13C NMR(75MHz,CD3OD) delta 166.2(C-15),150.3(C-11),141.3(C-13),116.6(C-14),106.6(C-12),61.6(C-6),57.9(C-2),57.7(C-10),45.4(C-17),39.7(C-7),33.0(C-5),28.8(C-8),27.9(C-4),22.4(C-9),21.4 (C-3). Finally, compound 2 was identified as the active alkaloid compound of formula II.
Examples of the experiments
In order to evaluate the biological activity of the active alkaloid compounds represented by the structures of formula i and formula II of the present invention (abbreviated as formula i compound and formula II compound) and the extract of sophora flavescens ait prepared in step (2) of example 1, the following effect examples were conducted.
Kunming mice are bred in an SPF (specific pathogen free) grade male environment with the weight of 40 +/-2 g and the temperature of 20 +/-2 ℃ and the humidity of 40-70% in a constant temperature environment, the breeding environment is 12h to 12h (6:00-18:00) in a light rhythm, water is freely fed, and adaptive breeding is carried out for 1 week. Randomly dividing the mice into 5 groups, wherein each group comprises 8 mice, and the groups are normal groups respectively; skin aging pruritus model group; diphenhydramine group; bitter tasteGinseng alkaloid-1 group; matrine-2 group; radix Sophorae Flavescentis extract group. After the start of the experiment, the neck and back of each group of mice were injected subcutaneously with 125/mg-kg of D-galactose injection in addition to the normal group for 6 weeks (normal group was given physiological saline of the same dose). Starting at week 7, mice in each group were dosed at 0.5mg/cm2The application is carried out 1 time in the evening for 7 days (the normal group and the skin aging and pruritus model group are respectively provided with distilled water with the same dose every day). In the experiment process, the hair of the neck and the back of the mouse is shaved by scissors, so that no hair exists on the neck and the back of the mouse.
After 1h of medicine application on the 7 th day, 0.025% low molecular dextran-40 injection is injected intravenously, and after 30min, the scratching performance of the mice is recorded by a video camera.
TABLE 1 Effect of alkaloid compounds and Sophora flavescens Aiton extracts on mouse pruritus latency and pruritus frequency
Note: comparison with skin itch model group*p＜0.05,**p＜0.01.
As can be seen from the data in Table 1, the skin pruritus model group has short pruritus latency time and increased pruritus times. Compared with a skin itch model group, the incubation time of itch of each medicine group is obviously prolonged after the medicine is used, and the itch frequency is obviously reduced.
As can be seen from the data in Table 1, the incubation time and the itching frequency of the radix sophorae flavescentis extract group prepared by the method are equivalent to those of the diphenhydramine group. The result shows that the prepared sophora flavescens extract has the same effect of treating pruritus as a positive control medicament diphenhydramine, and has very excellent anti-pruritus effect.
As can be seen from the data in table 1, the active alkaloid compound groups of the structures shown in formula i and formula II have significantly longer pruritus latency than the diphenhydramine group; in addition, the pruritus times of the active alkaloid compound group with the structure shown in the formula I are obviously less than that of the diphenhydramine group, and the pruritus times of the active alkaloid compound group with the structure shown in the formula II are far greater than that of the diphenhydramine group and the active alkaloid compound group with the structure shown in the formula I. This indicates that: the differences of the anti-pruritus effects of alkaloid compounds with different structures are huge; when 2 unsaturated double bonds on a carbonyl-containing ring of the active alkaloid compound with the structure shown in the formula II are substituted by H, the obtained active alkaloid compound with the structure shown in the formula I has a far better skin itch resisting effect than the active alkaloid compound with the structure shown in the formula II; and is much better than the positive control drug diphenhydramine.
While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not to be limited to the disclosed embodiment, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
Claims (10)
1. An active alkaloid compound is characterized by having a structure shown in a formula I or a formula II;
2. the sophora flavescens extract is characterized by containing a compound with a structure shown in a formula I or a formula II.
3. The sophora flavescens extract is characterized by being prepared by a method comprising the following steps: extracting radix Sophorae Flavescentis with organic solvent, concentrating the extractive solution, and drying to obtain radix Sophorae Flavescentis organic solvent extract.
4. The sophora flavescens ait extract as claimed in claim 3, wherein the organic solvent is an aqueous solution of ethanol with a volume fraction of 50-95%.
5. The Sophora flavescens extract as claimed in claim 4, wherein the organic solvent is 70-80% by volume of ethanol aqueous solution.
6. The Sophora flavescens Aiton extract as claimed in claim 3, wherein the Sophora flavescens Aiton organic solvent extract is further subjected to silica gel column chromatography to obtain a Sophora flavescens Aiton extract;
the specific elution conditions of the silica gel column chromatography are as follows: eluting with a mixed organic solvent consisting of chloroform and methanol with the volume fraction of 90-95: 10-5, collecting eluent, concentrating and drying to obtain a fraction A; eluting with a mixed organic solvent consisting of chloroform and methanol with the volume fraction of 80-85: 20-15, collecting eluent, concentrating and drying to obtain a fraction B; collecting fraction B to obtain the radix Sophorae Flavescentis extract.
7. The Sophora flavescens Aiton extract as claimed in claim 6, wherein the Sophora flavescens Aiton organic solvent extract is further subjected to silica gel column chromatography to obtain a Sophora flavescens Aiton extract;
the specific elution conditions of the silica gel column chromatography are as follows: eluting with a mixed organic solvent consisting of chloroform and methanol with the volume fraction of 93:7, collecting eluent, concentrating and drying to obtain a fraction A; eluting with a mixed organic solvent consisting of chloroform and methanol with the volume fraction of 83:7, collecting eluent, concentrating and drying to obtain a fraction B; collecting fraction B to obtain the radix Sophorae Flavescentis extract.
8. Use of the active alkaloid compound or sophora flavescens ait as claimed in any one of claims 1 to 7 for preparing a product having an anti-itch effect on skin.
9. The use according to claim 8, wherein the anti-pruritus is anti-senile pruritus.
10. Use according to claim 8, wherein the product is a pharmaceutical, a skin-care or a cosmetic product.
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