CN109942532B - Polynuclear flavonoid complex and preparation method and application thereof - Google Patents
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Abstract
The invention relates to a polynuclear flavonoid complex or pharmaceutically acceptable salt, hydrate or solvate thereof, and discloses a preparation method and application of the complex. The technical scheme of the invention provides a functional polynuclear flavonoid complex and a preparation method thereof. The polynuclear flavonoid complex has a plurality of central ions, inhibits DNA replication, promotes tumor cell apoptosis, and can be used for preparing medicines for preventing and treating tumors and immunodeficiency diseases or preparing animal feeds.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to a polynuclear flavonoid complex and a preparation method and application thereof.
Background
Selenium is a necessary trace element in human and animal bodies and has multiple biological functions. Research shows that selenium plays a biological function in vivo in the form of selenase and selenoprotein, and has the functions of resisting and preventing cancer, resisting oxidation, eliminating free radicals, participating in regulating protein synthesis, improving immune function, regulating gene expression and the like. Compared with organic selenium, inorganic selenium has high toxicity and relatively low utilization rate. Therefore, the search for organic selenium compounds with high biological activity and low toxicity becomes an important task for drug development. The synthetic selenium flavone complex provides a new research idea for developing new organic selenium compounds by taking natural flavonoid compounds as raw materials.
The flavonoid compound is used as a secondary metabolite of plants, and has multiple biological activities such as oxidation resistance, inflammation resistance, antiviral property, antitumor property and the like. The flavonoid compound has a natural plane or almost plane rigid structure, the delocalized large pi bonds of the aromatic ring system are easy to form pi-pi interaction and hydrophobic interaction with DNA base pi bonds, and the specific or non-specific interaction may occur with DNA, so that the function of the DNA is changed or inhibited to achieve the effect of treating or preventing and controlling diseases, and the flavonoid compound has the characteristics of multi-mode action and low toxicity. Meanwhile, the flavonoid compound has good chelating ability and is easy to form complexes with various non-metallic elements, metallic elements and transition elements. Researches show that after the flavonoid compounds are coordinated with metal ions and non-metal ions, the antineoplastic effect of the flavonoid compounds is higher than that of the original ligand, and the toxic and side effects are reduced. Therefore, the coordination of the flavonoids compounds and the selenium can ensure that the complex synthesized by the flavonoids compounds and the selenium not only has higher free radical scavenging capability and stronger antitumor activity than the original flavonoids, but also can reduce the toxic and side effects of the selenium.
The polynuclear complex is a complex containing two or more central ions. Compared with the mononuclear complex, the polynuclear complex has higher anticancer effect due to the characteristics of multiple acting targets, better DNA bonding property and the like. The complex of the flavonoid compound and Se (IV) reported at present is a mononuclear selenium complex, and a polynuclear selenium flavone complex of multicenter ions and multiple ligands is not reported yet. The polynuclear selenium complex has strong bonding capacity with DNA, inhibits the replication of the DNA, has strong anti-tumor activity, and has wide development prospect in the field of research and development of drugs for treating diseases such as tumor, immunodeficiency and the like.
The requirement of trace element selenium in the feed is essential for the animals in the daily feeding process. The lack of selenium can cause the immunity of animals to be low, thereby causing various diseases. Because most areas in China are lack of selenium, selenium element needs to be added into the feed when animals are bred. At present, a feed production plant only adds sodium selenite or selenium yeast into feed to supplement selenium element. They belong to inorganic selenium, and can not achieve the ideal effect of supplementing selenium for animals. Compared with inorganic selenium, the organic selenium is used as a selenium source of animal feed, is more efficient and safer, and has high bioavailability. The polynuclear selenium flavonoid complex is a novel organic selenium compound, and the polynuclear selenium complex is added into animal feed, so that the immunity of animals can be improved, the growth of the animals can be promoted, and a selenium-rich animal product can be obtained. Therefore, the polynuclear selenium complex has wide application prospect in the field of animal feed production.
Disclosure of Invention
The invention aims to provide a functional polynuclear flavonoid complex and a preparation method thereof aiming at the defects of the prior art. The polynuclear flavonoid complex has a plurality of central ions, inhibits DNA replication, promotes tumor cell apoptosis, and can be used for preparing medicines for preventing and treating tumors and immunodeficiency diseases or preparing animal feeds.
The technical scheme adopted by the invention for realizing the purpose is as follows: a polynuclear flavonoid complex or a pharmaceutically acceptable salt, hydrate or solvate thereof is characterized in that the structure is shown as formula I, II or III.
In the formulae I, II or III, R 1 、R 2 、R 3 、R 4 、R 5 Are all independently selected from hydrogen, hydroxy, C 1 ～C 6 Alkoxy or C 1 -C6 alkyl, M being a tetravalent element;
further, M is a tetravalent nonmetallic trace element;
further, M is selenium;
further, R 1 、R 2 、R 3 、R 4 、R 5 Are each independently selected from hydrogen, hydroxy, methoxy, methyl, ethyl, propyl, isopropyl;
further, in the formula I, R 1 、R 3 Are each hydroxy, R 2 、R 4 Are all hydrogen; in the formula II, R 1 、R 2 、R 3 、R 4 Are all hydroxyl; in the formula III, R 1 、R 3 、R 4 、R 5 Are each hydroxy, R 2 Is hydrogen.
The invention also provides a preparation method of the polynuclear flavonoid complex, which comprises the following steps:
respectively dissolving a flavonoid compound and a tetravalent element compound with alcohol, adding an acidic reagent to adjust the pH of an alcoholic solution of the flavonoid compound to 3-6, mixing the alcoholic solution of the flavonoid compound and the alcoholic solution of the tetravalent element compound, reacting in a high-pressure reaction kettle for 6-12 hours in a dark place under the conditions of nitrogen protection, 0.1-5 MPa and 30-80 ℃, filtering clear liquid, repeatedly purifying precipitates, and performing vacuum freeze drying to obtain a product;
further, the flavonoid compound is a flavonoid compound with a basic parent nucleus of 2-phenylchromone;
further, the alcohol used includes ethanol, methanol, isopropanol, ethylene glycol;
further, the tetravalent element compound is one or more of selenium oxychloride, selenium dioxide, selenium tetrachloride or selenium bromide.
The invention also provides a composition comprising a compound of formula I, II or III, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as hereinbefore defined, in association with an excipient or carrier;
the invention also provides the application of the compound of the formula I, II or III or the pharmaceutically acceptable salt, hydrate or solvate thereof or the composition for preparing the medicine for preventing and treating the tumor;
the invention also provides the use of a compound of formula I, II or III, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described above, or a composition as described above, for the manufacture of a medicament for the prevention or treatment of immunodeficiency;
the invention also provides the use of a compound of formula I, II or iii, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described above, or a composition as described above, in an animal feed additive;
further, the animal is a pig, a bird, a ruminant, an aquatic animal, a laboratory animal or a special economic animal.
The invention has the advantages and effects that:
1) the polynuclear selenium flavonoid complex of the invention contains higher selenium content than the existing mononuclear selenium flavonoid complex, has higher selenium content than 12%, has a plurality of selenium coordination sites and a plurality of action targets, has the function of inhibiting DNA replication, and shows good biological activity in vitro molecular experiments and cell experiments: the binding ability with DNA is strong, which can inhibit HIV pathogenic DNA sequence replication and promote tumor cell apoptosis; the polynuclear selenium flavonoid complex is used for treating a plurality of human tumor cells cultured in vitro, and the death rate and apoptosis rate of the tumor cells treated by the complex are greatly increased through a CCK-8 method and a flow cytometry, so that the complex has strong antitumor activity;
2) the polynuclear selenium flavonoid complex provided by the invention can be used as an additive of animal feed, can be used for preparing animal feed rich in organic selenium, improves the organic selenium content in the animal feed, has high bioavailability, improves the organic selenium content of animal products after being absorbed by animals, promotes the growth performance of the animals, improves the immunity, prevents diseases and improves the survival rate of the animals.
In conclusion, the polynuclear selenium flavonoid complex provided by the invention can be used for preparing medicines for preventing and treating tumors and immunodeficiency diseases or preparing selenium-rich animal feeds.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of a polynuclear selenium quercetin complex;
FIG. 2 is a mass spectrum (ESI-MS) of a polynuclear selenium quercetin complex;
FIG. 3 is a diagram showing the inhibition of the polynuclear selenium quercetin complex on the rolling circle amplification of HIV pathogenic DNA by agarose gel electrophoresis;
FIG. 4 is a graph of detecting apoptosis of HepG2 tumor cells induced by polynuclear selenium quercetin complex by flow cytometry;
FIG. 5 is a graph of flow cytometry for detecting MCF-7 tumor cell apoptosis induced by polynuclear selenium quercetin complex;
FIG. 6 is a graph of apoptosis of A549 tumor cells induced by the polynuclear selenium quercetin complex detected by flow cytometry.
Detailed Description
The present invention will be further specifically described below with reference to examples, but the present invention is not limited to these examples.
Example 1
The polynuclear selenium quercetin complex in the embodiment has the following structure:
the molecular weight is: 1061.9297.
the nuclear magnetic hydrogen spectrum of the polynuclear selenium quercetin complex is shown in figure 1;
the mass spectrum (ESI-MS) of the polynuclear selenium quercetin complex is shown in figure 2;
ESI-MS(m/z)：1060.9158,680.9757,576.9495,301.0310。
ICP-MS elemental analysis: se (%) -, 14.9%.
The preparation method of the polynuclear selenium quercetin complex in the embodiment comprises the following steps:
dissolving 0.906g quercetin (3mmol) with 30mL anhydrous methanol, and adjusting pH to 5 with concentrated hydrochloric acid with mass concentration of 36.5%; 0.222g of selenium dioxide (2mmol) is dissolved in 20ml of anhydrous methanol, and then the two are mixed and reacted in an autoclave with the temperature of 70 ℃ and the pressure of 3MPa for 12 hours under the protection of nitrogen, and yellow solid is separated out. Stopping reaction, filtering out yellow solid, repeatedly washing and purifying with anhydrous methanol, and vacuum freeze-drying at-40 ℃ overnight; 0.42g of brown yellow solid polynuclear selenium quercetin complex is obtained.
Example 2
The polynuclear selenium myricetin complex in the embodiment has the following structure:
the preparation method of the polynuclear selenium myricetin complex in the embodiment comprises the following steps:
dissolving 0.955g myricetin (3mmol) in 20mL anhydrous ethanol, and adjusting pH to 3.5 with 50% citric acid; 0.426g of selenium oxychloride (2.5mmol) is taken and dissolved by 30ml of absolute ethyl alcohol, then the two are mixed and reacted for 8 hours in an autoclave with 50 ℃ and 1.5MPa under the protection of nitrogen, and yellow solid is separated out. Stopping the reaction, filtering out a yellow solid, purifying by using ethyl acetate-petroleum ether column chromatography, and carrying out vacuum freeze drying at-40 ℃ overnight; 0.34g of brown solid polynuclear selenium myricetin complex is obtained.
Example 3
The polynuclear selenium kaempferol complex in the embodiment has the following structure:
the preparation method of the polynuclear selenium kaempferol complex in the embodiment comprises the following steps:
dissolving 0.859g of kaempferol (3mmol) in 50mL of 40 ℃ absolute ethyl alcohol, and adjusting the pH value to 4 by using glacial acetic acid with the mass concentration of 76%; 0.662g of selenium tetrachloride (3mmol) is taken and dissolved in 30ml of absolute ethyl alcohol, then the two are mixed and reacted in an autoclave with the pressure of 2MPa and the temperature of 60 ℃ under the protection of nitrogen for 10 hours, and yellow solid is separated out. Stopping the reaction, filtering out yellow solid, repeatedly washing and purifying by using hot absolute ethyl alcohol, and carrying out vacuum drying at-30 ℃ overnight; 0.27g of yellow solid polynuclear kaempferol complex is obtained.
Example 4
A polynuclear selenium quercetin complex inhibits replication of target DNA:
the polynuclear selenium quercetin complex prepared in example 1 was added to a rolling circle amplification reaction system of HIV pathogenic gene sequence "ACTGCTAGAGA TT TT CCACAT", and the concentrations of the polynuclear selenium quercetin complex were 2. mu.M, 20. mu.M, and 80. mu.M, respectively, as compared with quercetin concentrations. DMSO (dimethyl sulfoxide) was a blank control. The result of detecting the inhibition of the polynuclear selenium quercetin complex on target DNA rolling circle amplification by an agarose gel electrophoresis method is shown in figure 4.
As shown in FIG. 4, the blank control group target DNA replicated normally in the system, and a bright DNA band appeared on the electrophoretogram. When the concentration of the complex is 20. mu.M and 80. mu.M, no DNA band is present on the electrophoretogram. This shows that the polynuclear selenium quercetin complex has obvious inhibiting effect on the replication of target DNA, and the inhibiting effect is stronger than that of raw material quercetin.
Example 5
The inhibition effect of the polynuclear selenium quercetin complex on 3 human tumor cells is as follows:
the polynuclear selenium quercetin complex prepared in example 1 was evaluated for its inhibitory effect on human tumor cells by the CCK-8 method.
Calculating the survival rate of each well cell according to the formula of cell survival rate (%) (drug OD-blank OD)/(solvent control OD-blank OD). times.100%), calculating the average value of parallel groups, and obtaining the IC of the polynuclear selenium quercetin complex to the tumor cells by linear fitting 50 Values, results are shown in table 1:
TABLE 1 inhibitory Effect of polynuclear selenium quercetin Complex on 3 human tumor cells (IC) 50 Value)
The result shows that the multinuclear selenium quercetin complex has stronger toxicity to 3 cancer cells, namely HepG2, MCF-7 and A549, and has stronger killing effect on the same cells than the killing effect of quercetin and 5-fluorouracil.
Example 6
A polynuclear selenium quercetin complex induces apoptosis of 3 human tumor cells:
the prepared polynuclear selenium quercetin complex in example 1 was treated with HepG2, MCF-7, A549 cells for 24 hours, respectively, with quercetin, 5-fluorouracil or doxorubicin as controls. Washing twice, centrifuging and discarding supernatant to collect cells, staining with Annexin V-APC/7AAD two dyes for 15 min in sequence, filtering and detecting on a MoFlo XDP flow cytometer. The results of flow cytometry for detecting the apoptosis of 3 tumor cells induced by the polynuclear selenium quercetin complex are shown in FIGS. 4-6.
The result shows that the polynuclear selenium quercetin complex has apoptosis inducing effect on HepG2, MCF-7, A549 and other tumor cells, and the effect is enhanced with the increase of the concentration in a certain concentration range. The capacity of the polynuclear selenium quercetin complex for inducing apoptosis of each cell under the same concentration is obviously higher than that of quercetin and better than that of 5-fluorouracil. The polynuclear selenium quercetin complex has strong capacity of inducing tumor cell apoptosis.
Example 7
The application of the polynuclear selenium flavonoid complex as a layer feed additive can improve the organic selenium content in chicken and eggs:
the polynuclear selenium flavonoid complexes prepared in examples 1 to 3 (hereinafter, each referred to simply as complexes 1 to 3) were used in a feeding test of laying hens. 160 healthy and similar 134-day-old kalimeris indica white commercial laying hens are selected and randomly divided into a control group and three treatment groups, wherein each group is 4 in number, and each group is provided with 10 chickens (each half of a male hen). The control group was fed with corn-soybean meal type basal diet, and the treatment group added 70mg/kg of the complex 1, the complex 2, and the complex 3 to the basal diet, respectively. Feeding for 5 weeks, and randomly taking 4 eggs after 5 weeks for determining selenium content in the eggs; slaughtering laying hens by group, removing feathers, and collecting fresh chicken meat sample for determining selenium content in chicken. The results are shown in table 2 below.
TABLE 2 influence of polynuclear selenium flavonoid complexes on egg chicken and selenium content in eggs
As can be seen from Table 2, the organic selenium content in the chicken and eggs of the treated group is higher than that of the control group, the organic selenium content in the chicken of the treated group is 2-2.31 times of that of the control group, and the organic selenium content in the eggs is 4-4.59 times of that of the control group. Therefore, the polynuclear selenium flavonoid complex serving as the feed additive can improve the content of organic selenium in the feed, and the selenium content of chicken bodies is obviously improved through biotransformation, so that selenium-enriched eggs and chicken are obtained, and selenium-enriched products are provided for supplementing selenium to human bodies and improving resistance.
Example 8
The application of the polynuclear selenium flavonoid complex as a feed additive for improving immunity in the feed of chicks is as follows:
80 healthy Aijia (Arbor Acres, AA) broilers of 1 day old are selected and randomly divided into a control group and three treatment groups. Each group had 2 replicates, each replicate 10 chickens. The control group is fed with corn-soybean meal type basic ration, and the three treatment groups are respectively added with 30mg/kg of complex 1, complex 2 and complex 3. Regular immunization and chicken house disinfection management are carried out according to the conventional broiler feeding program, chicks eat and drink water freely, and the test period is 42 d. After the test is finished, slaughtering and dissecting are carried out after fasting for 10 hours, blood is collected, the content of immunoglobulin A (IgA) in serum is detected, and spleen and thymus are taken aseptically, peripheral adipose tissues are removed, and fresh weight is weighed. The results show that the thymus index, the spleen index and the IgA content of each treatment group are improved compared with the control group, and have significant difference (P <0.05) compared with the control group. The thymus index of the chicks of the three treatment groups is respectively improved by 27.3%, 26.2% and 24.1%, the spleen index is respectively improved by 17.3%, 16.6% and 15.1%, and the immunoglobulin IgA content in serum is respectively improved by 11.3%, 10.7% and 8.2%. Therefore, the feed added with the polynuclear selenium flavonoid complex can promote the growth and development of thymus and spleen of chicks, stimulate humoral immunity to generate more antibodies, enhance the immune function of organisms and further improve the immunity of the organisms.
Example 9
The application of the polynuclear selenium flavonoid complex as a feed additive for promoting the growth of weaned piglets in pig feed comprises the following steps:
selecting 128 healthy disease-free weaned piglets with the same breed and weight of about 5.5kg (Du multiplied by length multiplied by big) and the age of 28 days, randomly dividing the piglets into a control group and three treatment groups, wherein each group comprises 4 repetitions, each repetition comprises 8 pigs, the control group is fed with basic diet, and 83mg/kg of complex 1, complex 2 and complex 3 are respectively added into the basic diet in the treatment groups. The feeding time is 30d, the daily feed intake of each group of test piglets is recorded during the test period, and the average daily gain, the average daily feed intake and the feed-weight ratio are calculated. The results show that the daily gain of piglets of each treatment group is increased, the feed-weight ratio and the diarrhea rate are lower, and the piglets have significant difference (P <0.05) compared with the control group. The daily gain of the piglets of the three treatment groups is respectively improved by 8.1 percent, 7.6 percent and 7.2 percent, the feed-weight ratio is respectively reduced by 7.7 percent, 6.4 percent and 6.0 percent, and the diarrhea incidence rate is respectively reduced by 63.5 percent, 61.7 percent and 59.9 percent.
The above embodiments are only for illustrating the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention accordingly, and not to limit the protection scope of the present invention accordingly. All equivalent changes or modifications made in accordance with the spirit of the present disclosure are intended to be covered by the scope of the present disclosure.
Claims (7)
1. A polynuclear flavonoid complex or a pharmaceutically acceptable salt, hydrate or solvate thereof is characterized in that the structure is shown as formula I, II or III,
in the formula I, R 1 、R 3 Are each hydroxy, R 2 、R 4 Are all hydrogen; in the formula II, R 1 、R 2 、R 3 、R 4 Are all hydroxyl; in the formula III, R 1 、R 3 、R 4 、R 5 Are each hydroxy, R 2 Is hydrogen; m is selenium.
2. The preparation method of the polynuclear flavonoid complex according to claim 1, wherein the flavonoid compound and the selenium tetravalent element compound are respectively dissolved in alcohol, an acidic reagent is added to adjust the pH of an alcoholic solution of the flavonoid compound to 3-6, the alcoholic solution of the flavonoid compound and the alcoholic solution of the tetravalent element compound are mixed, and the mixture is subjected to light-shielding reaction in a high-pressure reaction kettle for 6-12 hours under the conditions of nitrogen protection, 0.1-5 MPa and 30-80 ℃, clear liquid is filtered, and after repeated purification by precipitation, a product is obtained by vacuum freeze drying; the flavonoid compound is a flavonoid compound with a basic parent nucleus of 2-phenyl chromone.
3. The method for preparing polynuclear flavonoid complexes according to claim 2, wherein the tetravalent element compound is one or more of selenium oxychloride, selenium dioxide, selenium tetrachloride or selenium bromide.
4. A composition comprising an excipient or carrier and a compound of formula I, II or iii according to claim 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
5. Use of a compound of formula I, II or iii according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof or a composition according to claim 4 for the preparation of a medicament for the prophylaxis or treatment of tumours.
6. Use of a compound of formula I, II or iii according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof or a composition according to claim 4 for the manufacture of a medicament for the prophylaxis or treatment of immunodeficiency.
7. Use of a compound of formula I, II or iii, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, according to claim 1, or a composition thereof, according to claim 4, for use in an animal feed additive.
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