CN114747699A - Silybin derivative and preparation method and application thereof - Google Patents
Silybin derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN114747699A CN114747699A CN202210427370.8A CN202210427370A CN114747699A CN 114747699 A CN114747699 A CN 114747699A CN 202210427370 A CN202210427370 A CN 202210427370A CN 114747699 A CN114747699 A CN 114747699A
- Authority
- CN
- China
- Prior art keywords
- silybin
- parts
- substituted
- derivative
- feed
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- SEBFKMXJBCUCAI-HKTJVKLFSA-N silibinin Chemical class C1=C(O)C(OC)=CC([C@@H]2[C@H](OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-HKTJVKLFSA-N 0.000 title claims abstract description 87
- 238000002360 preparation method Methods 0.000 title abstract description 10
- SEBFKMXJBCUCAI-UHFFFAOYSA-N NSC 227190 Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC=C(C=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-UHFFFAOYSA-N 0.000 claims abstract description 34
- 235000014899 silybin Nutrition 0.000 claims abstract description 34
- 241000252230 Ctenopharyngodon idella Species 0.000 claims abstract description 33
- FDQAOULAVFHKBX-UHFFFAOYSA-N Isosilybin A Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC(=CC=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 FDQAOULAVFHKBX-UHFFFAOYSA-N 0.000 claims abstract description 26
- VLGROHBNWZUINI-UHFFFAOYSA-N Silybin Natural products COc1cc(ccc1O)C2OC3C=C(C=CC3OC2CO)C4Oc5cc(O)cc(O)c5C(=O)C4O VLGROHBNWZUINI-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229940043175 silybin Drugs 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
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- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 claims description 10
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- 235000012054 meals Nutrition 0.000 claims description 10
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
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- 229910000278 bentonite Inorganic materials 0.000 claims description 5
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 claims description 5
- YYRMJZQKEFZXMX-UHFFFAOYSA-L calcium bis(dihydrogenphosphate) Chemical compound [Ca+2].OP(O)([O-])=O.OP(O)([O-])=O YYRMJZQKEFZXMX-UHFFFAOYSA-L 0.000 claims description 5
- 239000001506 calcium phosphate Substances 0.000 claims description 5
- 235000012343 cottonseed oil Nutrition 0.000 claims description 5
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 5
- 235000013312 flour Nutrition 0.000 claims description 5
- 229910000150 monocalcium phosphate Inorganic materials 0.000 claims description 5
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- 229910052760 oxygen Inorganic materials 0.000 claims description 5
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 235000009566 rice Nutrition 0.000 claims description 5
- 235000013619 trace mineral Nutrition 0.000 claims description 5
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- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 235000019779 Rapeseed Meal Nutrition 0.000 claims description 4
- 235000019764 Soybean Meal Nutrition 0.000 claims description 4
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- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
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- 125000005059 halophenyl group Chemical group 0.000 claims description 4
- 239000004456 rapeseed meal Substances 0.000 claims description 4
- 239000004455 soybean meal Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- -1 -CHO Chemical group 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 238000009360 aquaculture Methods 0.000 claims description 2
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- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000000951 phenoxy group Chemical class [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000002915 carbonyl group Chemical class [*:2]C([*:1])=O 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 15
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
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- 238000002474 experimental method Methods 0.000 description 17
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- 239000000243 solution Substances 0.000 description 13
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 8
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
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- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 4
- 102000019197 Superoxide Dismutase Human genes 0.000 description 4
- 108010012715 Superoxide dismutase Proteins 0.000 description 4
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- WOGITNXCNOTRLK-VOTSOKGWSA-N (e)-3-phenylprop-2-enoyl chloride Chemical compound ClC(=O)\C=C\C1=CC=CC=C1 WOGITNXCNOTRLK-VOTSOKGWSA-N 0.000 description 3
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
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- WTBAHSZERDXKKZ-UHFFFAOYSA-N octadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCCCC(Cl)=O WTBAHSZERDXKKZ-UHFFFAOYSA-N 0.000 description 3
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- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
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- A—HUMAN NECESSITIES
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- A23K10/30—Animal feeding-stuffs from material of plant origin, e.g. roots, seeds or hay; from material of fungal origin, e.g. mushrooms
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses a silybin derivative and a preparation method and application thereof, the silybin derivative is prepared by the reaction of hydroxyl on a silybin A ring and RCOCl, compared with silybin, the silybin derivative in the invention has more active groups, can provide more active sites, and has better water solubility and lipid solubility. In addition, the silybin derivative can improve the oxidation resistance of liver, pancreas, intestinal tract and organism of the young grass carps, and reduce the oxidation damage; the growth and development of the young grass carp immune organs, namely the head kidney, the spleen and the mucosa immune tissue intestinal tract are promoted, and the body and intestinal tract immune functions of the young grass carp are enhanced, so that the utilization efficiency of nutrient substances by the young grass carp is promoted, the growth of the young grass carp and the body protein deposition are promoted, and the grass carp obtains the remarkably improved growth performance.
Description
Technical Field
The invention belongs to the field of chemical industry, and particularly relates to a silybin derivative, and a preparation method and application thereof.
Background
Silybin is a flavonoid compound extracted and separated from the fruit of Silybum marianum (Silybum marianum) which is a Chrysanthemum plant, has obvious functions of protecting and stabilizing liver cell membrane, can improve liver function, has enzyme reduction effect, and is not easy to generate enzyme rebound. Silibinin can stabilize hepatic cell membrane and maintain its integrity, promote the ultrastructure restoration of hepatic cell, promote the division and growth of normal hepatic cell, improve the ability of hepatic cell to synthesize RNA and protein, improve the ability of reticuloendothelial system to produce macrophage, enhance the activity of macrophage, and accelerate the removal of virus. Meanwhile, the silybin can promote fat transfer and antioxidation, prevent excessive oxidation and infiltration of fat and relieve liver steatosis; and can promote metabolism of liver, enhance its antidotal effect, and reduce damage of toxic substance to liver cell. Therefore, the silibinin has the effects of protecting normal liver cells and promoting the recovery of damaged cell membranes. In the application research of animal husbandry, silybin has various biological functions of promoting the growth of organisms, improving immunity, regulating fat metabolism and the like.
The silybin has a certain promotion effect on the growth of aquatic animals, and is mainly used for regulating and controlling intestinal health, digesting and absorbing, fat deposition, promoting organism immunity and the like. However, silybin has a series of problems of poor water solubility, poor fat solubility, low bioavailability and the like, and the defects limit the market of the medicine as a feed additive.
Disclosure of Invention
In order to overcome the problems of the prior art, one of the objects of the present invention is to provide a silybin derivative.
The second purpose of the invention is to provide a preparation method of the silybin derivative.
The invention also aims to provide an aquatic feed additive.
The fourth purpose of the invention is to provide an aquatic feed.
The fifth purpose of the invention is to provide a method for feeding grass carps.
The sixth purpose of the invention is to provide an application of the silybin derivative in feed additives or feeds.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the first aspect of the present invention provides a silybin derivative, which has a structure represented by general formula (I):
wherein R is substituted or unsubstituted C 1-20Alkyl, substituted or unsubstituted C2-20Alkenyl or alkynyl, substituted or unsubstituted C1-20An alkoxy group, a substituted or unsubstituted aryl group, a substituted or unsubstituted five-or six-membered heterocyclic group; the five-membered or six-membered heterocyclic group contains oxygen, sulfur or nitrogen on the heterocyclic ring;
each substituent is independently selected from halogen, -CN, -NO2、C1-6Alkyl or alkoxy, -CHO, phenyl, halophenyl, C1-8Alkyl or C1-6Alkoxy-substituted phenyl, C2-12Alkynyl or alkenyl, benzoyl, C1-6Alkoxy substitutionCarbonyl group of (C)1-6Alkyl-substituted phenoxy.
Preferably, C1-8The alkyl group comprising C1-8Alkyl or C3-8A cycloalkyl group.
Preferably, the aryl group comprises an aromatic hydrocarbon or an aromatic heterocyclic group; the aromatic heterocyclic group contains oxygen, sulfur or nitrogen in the ring.
Preferably, said C1-20The alkyl group may be C1-20Straight chain alkyl, C3-20Branched alkyl or C3-20A cyclic alkyl group.
Preferably, the structural general formula of the derivative is shown as the formula (I), wherein R is substituted or unsubstituted C1-20An alkyl group, a substituted or unsubstituted vinyl group, a substituted or unsubstituted aryl group; each of said substituents being independently selected from halogen, -CN, -NO2、C1-6Alkyl radical, C1-6Alkoxy, -CHO, phenyl, halophenyl, C1-6Alkyl-substituted phenyl, C 1-6Alkoxy-substituted phenyl.
Preferably, the compound of formula (I) is selected from:
the second aspect of the present invention provides a method for preparing the silybin derivative provided by the first aspect of the present invention, comprising the following steps:
s1: mixing the compound 1 with a chlorination reagent and a nucleophilic reagent for reaction to obtain a compound 2;
s2: the compound 2 reacts with silybin to prepare the silybin derivative,
the specific reaction formula is as follows:
Preferably, the chlorinating agent is selected from at least one of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, phosgene, diphosgene and triphosgene.
Preferably, the nucleophilic reagent is selected from at least one of pyridine, triethylamine, N-dimethylformamide and caprolactam.
Preferably, the step S2 is specifically: compound 2 is dissolved and then added dropwise to the silibinin solution and the reaction is carried out in the presence of a base.
Preferably, the base is an organic base and/or an inorganic base.
Preferably, the organic base is at least one selected from triethylamine, pyridine and triethylene diamine.
Preferably, the inorganic base is at least one selected from potassium carbonate, sodium carbonate and sodium hydroxide.
Preferably, an organic solvent is added in both the step S1 and the step S2.
Preferably, the organic solvent in step S1 and the organic solvent in step S2 are each independently selected from at least one of 1,4 dioxane, methanol, ethanol, acetonitrile, toluene, DMSO, and DMF.
Preferably, the mixing reaction temperature in the step S1 is 0-100 ℃; further preferably, the mixing reaction temperature in the step S1 is 30-70 ℃; still more preferably, the mixing reaction temperature in the step S1 is 40 to 60 ℃.
Preferably, the mixing reaction time in the step S1 is 2-48 h; further preferably, the mixing reaction time in the step S1 is 4-20 h; still more preferably, the mixing reaction time in the step S1 is 5 to 10 hours.
Preferably, the reaction temperature in the step S2 is 0-50 ℃; further preferably, the reaction temperature in the step S2 is 0-40 ℃; still more preferably, the reaction temperature in the step S2 is 0 to 30 ℃.
Preferably, the reaction time in the step S2 is 6-18 h; further preferably, the reaction time in the step S2 is 8-16 h; still more preferably, the reaction time in the step S2 is 8 to 12 hours.
Preferably, in the step S1, the molar ratio of the compound 1, the chlorinating agent and the nucleophilic agent is 1 (0.3-1): (0.01-0.2).
Preferably, in the step S1, the molar ratio of the compound 1 to the chlorinating agent is 1 (0.4-0.8); more preferably, in the step S1, the molar ratio of the compound 1 to the chlorinating agent is 1 (0.6-0.8).
Preferably, in the step S1, the molar ratio of the compound 1 to the nucleophilic reagent is 1 (0.05-0.2); more preferably, in the step S1, the molar ratio of the compound 1 to the nucleophile is 1 (0.1-0.2).
Preferably, the step S2 further includes a post-processing step.
Preferably, the post-treatment step specifically comprises: after the compound 2 reacts with silybin, the reaction solution is concentrated and then purified by silica gel column chromatography.
Preferably, the elution solvent used in the silica gel column chromatography step is a mixed solvent of petroleum ether/ethyl acetate, a mixed solvent of dichloromethane/ethyl acetate.
In a third aspect, the invention provides an aquatic product feed additive, which comprises the silibinin derivative provided by the first aspect of the invention.
The fourth aspect of the invention provides an aquatic feed, which comprises the silybin derivative in the first aspect of the invention, wherein the weight ratio of the silybin derivative is 0.1-1 per mill.
Preferably, the weight ratio of the silybin derivative is 0.2-0.8 per mill; further preferably, the weight ratio of the silybin derivative is 0.4-0.6 per mill; still further preferably, the weight ratio of the silibinin derivative is 0.5 per mill.
Preferably, the feed further comprises the following components in parts by weight: 200-300 parts of rapeseed meal, 200-300 parts of soybean meal, 80-120 parts of rice bran, 80-120 parts of cottonseed meal, 40-80 parts of corn distiller's grains, 50-80 parts of flour, 40-60 parts of corn germ meal, 20-60 parts of distiller's grain powder, 40-80 parts of oxidized soybean oil, 10-30 parts of zeolite powder, 10-30 parts of bentonite, 10-30 parts of monocalcium phosphate and 0.01-0.1 part of trace elements.
Preferably, the feed further comprises the following components in parts by weight: 200-260 parts of rapeseed meal, 200-260 parts of soybean meal, 80-110 parts of rice bran, 80-110 parts of cottonseed meal, 45-75 parts of corn distiller's grains, 50-70 parts of flour, 45-55 parts of corn germ meal, 25-55 parts of distiller's grain powder, 45-75 parts of oxidized soybean oil, 15-25 parts of zeolite powder, 15-25 parts of bentonite, 15-25 parts of monocalcium phosphate and 0.01-0.08 part of trace elements.
Preferably, the feed further comprises the following components in parts by weight: 220-240 parts of rapeseed meal, 220-240 parts of soybean meal, 90-110 parts of rice bran, 90-110 parts of cottonseed meal, 50-70 parts of corn distiller's grains, 55-65 parts of flour, 45-55 parts of corn germ meal, 30-50 parts of distiller's grain powder, 50-70 parts of oxidized soybean oil, 18-23 parts of zeolite powder, 15-25 parts of bentonite, 15-25 parts of monocalcium phosphate and 0.03-0.06 part of trace elements.
Preferably, the feed further comprises the following components in parts by weight: 230 parts of rapeseed dregs, 230 parts of soybean dregs, 100 parts of rice bran, 100 parts of cottonseed dregs, 60 parts of corn distiller's grains, 60 parts of flour, 50 parts of corn germ dregs, 40 parts of distiller's grain powder, 60 parts of oxidized soybean oil, 21 parts of zeolite powder, 20 parts of bentonite, 20 parts of monocalcium phosphate and 0.05 part of trace elements.
Preferably, the aquaculture feed is a feed for fish.
Preferably, the fish species are: grass carp, weever, and Anhui fish.
The fifth aspect of the invention provides a grass carp feeding method, wherein a feed and the silybin derivative provided by the first aspect of the invention are mixed, and the mass ratio of the feed to the silybin derivative is 1000: (0.1 to 1); and then feeding the grass carps for three times, wherein the feeding amount of each time is 0.5% -5% of the weight of the grass carps, and the interval time of each feeding is 4-8 h.
Preferably, the mass ratio of the feed to the silibinin derivative is 1000: (0.2-0.8); further preferably, the mass ratio of the feed to the silibinin derivative is 1000: (0.4-0.6); still further preferably, the mass ratio of the feed to the silibinin derivative is 1000: 0.5.
preferably, the feeding amount of each time is 1 to 4 percent of the weight of the grass carp; further preferably, the feeding amount of each time is 2-3% of the body weight of the grass carp.
Preferably, the feeding interval is specifically: the time interval between the first feeding and the second feeding is 4-6 h, and the time interval between the second feeding and the third feeding is 6-8 h; further preferably, the feeding interval is specifically: the time interval between the first feeding and the second feeding is 4-5 hours, and the time interval between the second feeding and the third feeding is 6-7 hours; still further preferably, the feeding interval is specifically: the time interval between the first feeding and the second feeding is 4 hours, and the time interval between the second feeding and the third feeding is 6 hours.
A sixth aspect of the present invention provides the use of the silybin derivative provided in the first aspect of the present invention in a feed additive or feed.
The invention has the beneficial effects that: compared with silybin, the silybin derivative has more active groups, can provide more active sites, and has better water solubility and lipid solubility. In addition, the silybin derivative can improve the oxidation resistance of liver, pancreas, intestinal tracts and organisms of young grass carps and reduce oxidation damage; the growth and development of the head kidney and spleen of the immune organs of the grass carp and the intestinal tract of the immune tissue of the mucosa are promoted, and the immune function of the organism and the intestinal tract of the grass carp is enhanced, so that the utilization efficiency of the grass carp on nutrient substances is promoted, the growth of the grass carp and the body protein deposition are promoted, and the grass carp obtains remarkably improved growth performance.
In addition, the silybin derivative is added into the aquatic feed, so that the oxidation resistance of liver, pancreas, intestinal tracts and organisms of the young grass carps can be improved, and the oxidation damage is reduced; the growth and development of the head kidney and spleen of the immune organs of the grass carp and the intestinal tract of the immune tissue of the mucosa are promoted, and the immune function of the organism and the intestinal tract of the grass carp is enhanced, so that the utilization efficiency of the grass carp on nutrient substances is promoted, the growth of the grass carp and the body protein deposition are promoted, and the grass carp obtains remarkably improved growth performance.
Detailed Description
The following examples are included to further illustrate certain embodiments of the invention, but are not intended to limit the invention. It is noted that the following processes, if not described in particular detail, are all realizable or understandable by those skilled in the art with reference to the prior art. The reagents or apparatus used are not indicated to the manufacturer, and are considered to be conventional products available by commercial purchase.
The silibinin and the remaining reagents used in the examples are all conventionally available from the market.
Example 1:
the structural formula of the silybin derivative in the embodiment is as follows:
the silybin derivative in the embodiment is prepared by the following preparation method, which specifically comprises the following steps:
(1) Preparation of cinnamoyl chloride
Taking dry triphosgene (0.11g,0.36mmol) and putting the mixture into a 100mL three-neck flask, adding toluene and stirring; adding 0.1g (1.2mmol) of pyridine, 0.18g (1.2mmol) of cinnamic acid and 2mL of toluene into a drying beaker, fully stirring to obtain a colorless solution, then sucking the colorless solution by using a syringe, slowly dripping the colorless solution into a three-neck flask, cooling the three-neck flask by using an ice water bath, and absorbing gas released by the reaction by using a sodium hydroxide solution; after the dropwise addition, the ice bath is removed, the stirring is carried out for 30 minutes, the temperature is raised to 50 ℃, the reflux is carried out for 5 hours, and the tail end of a condensing tube is connected with a calcium chloride drying tube. After the reaction, the reaction solution was filtered, and the filtrate was distilled under reduced pressure to remove toluene, to obtain a yellow liquid. The obtained product is directly used for the next reaction without purification.
(2) The esterification reaction of cinnamoyl chloride and silybin has the following reaction formula:
in a dry 100mL single-neck flask were added 0.48g (1mmol) of silibinin and 0.15g (1.5mmol) of triethylamine, dissolved by adding 2mL of dichloromethane, and stirred in an ice-water bath. Cinnamoyl chloride was dissolved in 1mL of dichloromethane, sucked up with a syringe, and poured dropwise into a single-neck flask. After the injection, the ice-water bath was removed and stirred at room temperature overnight. After the reaction, 10mL of dichloromethane was added to dilute the mixture, the mixture was washed with a saturated sodium bicarbonate solution and a saturated brine, respectively, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed by distillation under reduced pressure, and the mixture was diluted with petroleum ether: purification on a silica gel column with ethyl acetate (1:1) gave 0.61g (yield 65%) of a yellow solid.
The following characterization data demonstrate the successful synthesis of the target product:
1h NMR (400MHz, deuterated dimethyl sulfoxide) δ:12.06(s,1H),9.96(s,1H),7.54(m,2H),7.48(m,1H),7.38-7.33(m,3H),6.97(m,2H),6.87-6.79(m,4H),6.40(s,1H),6.37(s,1H),6.31(m,1H),5.98(m,1H),5.83(s,1H),5.51(d, J ═ 12, OHz,1H),5.38(d, J ═ 8.0Hz,1H),4.58(m,1H),3.94(s,1H),3.82(m,1H),3.77(s,3H),3.76(m, 1H).
13C NMR (100MHz, deuterated dimethyl sulfoxide) delta 196.9,164.3,162.8,162.6,157.7,147.9,147.6,147.0,146.0,142.9,135.2,128.6,128.5,127.9,127.3,127.2,120.7,118.2,115.7,115.5,110.8,109.5,104.8,103.3,102.7,87.4,81.9,79.5,71.9,61.1, 56.1.
Example 2
The structural formula of the silybin derivative in the embodiment is as follows:
the silybin derivative in the embodiment is prepared by the following preparation method, which specifically comprises the following steps:
(1) preparation of octadecanoyl chloride
Taking dry triphosgene (0.11g,0.36mmol) and putting the mixture into a 100mL three-neck flask, adding toluene and stirring; adding 0.1g (1.2mmol) of pyridine, 0.34g (1.2mmol) of octadecanoic acid and 2mL of toluene into a drying beaker, fully stirring to obtain a colorless solution, sucking by using a syringe, slowly dropwise adding into a three-neck flask, cooling in an ice-water bath, and absorbing gas released by reaction by using a sodium hydroxide solution; after the dropwise addition, the ice bath is removed, the stirring is carried out for 30 minutes, the temperature is raised to 50 ℃, the reflux is carried out for 5 hours, and the tail end of a condensing tube is connected with a calcium chloride drying tube. After the reaction, the reaction solution was filtered, and the filtrate was distilled under reduced pressure to remove toluene, to obtain a yellow liquid. The obtained product is directly used for the next reaction without purification.
(2) Esterification reaction of octadecanoyl chloride and silybin
In a dry 1100mL single-neck flask, 0.48g (1mmol) of silibinin and 0.0.15g (1.5mmol) of triethylamine were added, dissolved by 2mL of dichloromethane, and stirred in an ice-water bath. Octadecanoyl chloride was dissolved in 1mL of methylene chloride, and the solution was taken up by a syringe and introduced dropwise into a single-neck flask. After the injection, the ice-water bath was removed and stirred at room temperature overnight. After the reaction, 10mL of dichloromethane was added to dilute the mixture, the mixture was washed with a saturated sodium bicarbonate solution and a saturated brine, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure, and petroleum ether: purification on a silica gel column with ethyl acetate (1:1) gave 0.25g (yield 33%) of a yellow solid.
The following characterization data illustrate the successful synthesis of the target product:
1h NMR (400MHz, deuterated dimethyl sulfoxide)
δ:12.06(s,1H),9.96(s,1H),6.97(m,2H),6.87-6.79(m,4H),6.40(m,2H),5.98(m,2H),5.83(s,1H),5.51(d,J＝12.OHz,1H),5.38(d,J＝8.0Hz,1H),4.58(m,1H),3.94(s,1H),3.82(m,1H),3.77(s,3H),3.76(m,1H),2.52(m,2H),1.66(m,2H),1.26(m,28H),0.88(t,3H)。
13C NMR (100MHz, deuterated dimethyl sulfoxide)
δ:196.9,172.3,162.8,162.6,157.7,147.6,147.0,146.0,142.9,127.3,127.2,120.7,118.2,115.7,110.8,109.5,109.1,104.8,103.3,102.7,87.4,81.9,79.5,71.9,61.1,56.1,33.5,31.9,29.6,29.3,29.0,25.0,22.7,14.1。
Example 3
The structural formula of the silybin derivative in the embodiment is as follows:
the silybin derivative in this example was prepared by the preparation method in examples 1 to 2.
The following characterization data illustrate the successful synthesis of the target product:
1h NMR (400MHz, deuterated dimethyl sulfoxide)
δ:12.00(s,1H),9.98(s,1H),6.97-9.96(m,2H),6.87(m,1H)，6.81-6.79(m,3H),6.406.36(m,3H),6.00(m,2H),5.85(s,1H),5.70(d,J＝8.0Hz,1H),5.50(d,J＝12.OHz,1H),3.77(s,3H),3.42(s,3H),2.29(s,3H)
13C NMR (100MHz, deuterated dimethyl sulfoxide)
δ:197.0,169.1,162.8,162.6,157.6,147.6,147.3,143.0,134.0,127.3,120.7,120.0,118.2,115.8,115.5,110.0,142.8,104.8,103.2,103.0,90.5,87.4,71.6,56.1,55.8,20.5。
Examples 4 to 6
The aquatic feeds in the embodiments 4 to 6 are respectively prepared by the following formula in the table 1, wherein 0.5 weight part of the silybin derivative in the embodiment 1 is added in the embodiment 4; in example 5, 0.5 part by weight of the silibinin derivative of example 2 was added; in example 6, 0.5 part by weight of the silibinin derivative of example 3 was added.
Comparative examples 1 to 2
The aquatic feeds in the comparative examples 1 to 2 are prepared by the following formulas in the following table 1, wherein the silybin is not added in the comparative example 1, and 0.5 part by weight of the silybin is added in the comparative example 2.
TABLE 1 aquatic feeds (in parts by weight) in examples 4 to 6 and comparative examples 1 to 2
Test example 1: feeding test of silibinin esterified product as aquatic feed additive
1. Materials and methods
1.1 experimental fish:
the experimental fish is young grass carp, has good health condition, no diseases and injuries and similar specifications, is from the same pond in the same batch, and has an average specification of 46 g/tail.
1.2 Experimental silybin and its derivatives, experimental feed
Gradient variable experiments on silybin and derivatives thereof serving as an aquatic feed additive show that the liver protection effect on grass carps is the best when 50ppm of silybin is added into the feed. Therefore, the test example was conducted with the feed to which 0.5 parts by weight of silibinin and its derivatives were added. The feed formulas of examples 4-6 and comparative examples 1-2 were used. The experimental grass carp is fed with the common grass carp feed purchased in the market in the temporary rearing period and the pre-feeding period. After the beginning of the official experiment, the feeds of examples 4 to 6 and comparative examples 1 to 2 were fed as experimental feeds. 6% of oxidized soybean oil added to the feeds of examples 4 to 6 and comparative examples 1 to 2 was prepared by a method according to the prior art, for example: invar ever wind, leaf element soil, Chua Chuan Chun Fang, forest facing, the influence of the oxidation time on the soybean oil oxidation index in a self-made oxidation device [ J ]. Anhui agricultural science, 2011,39(07): 4052-. Experimental feed ingredient analysis was performed according to the method of AOAC (2005).
1.3 Experimental design and Breeding management
The experiment was set up with 5 groups, two control groups and three example groups, each set up with three replicates. Before the formal experiment of the experimental fish, the experimental fish is temporarily cultured in a temporary culture pond (a cement pond with the length of 1.6 meters multiplied by 1.2 meters multiplied by 0.8 meter) for 7 days in a centralized way, and the ordinary grass carp feed without the addition of the oxidized grease is fed. After the temporary culture is finished, selecting healthy grass carps with consistent specifications, transferring the healthy grass carps into an experimental pond (a 1.2 m multiplied by 0.8 m cement pond) for pre-feeding for 5 days, wherein the culture density is 30 fish/pond, and feeding commercial ordinary grass carp feed without adding oxidized grease in the period. In the pre-feeding period, when the fish dies or is abnormal, the healthy fish with similar specifications are supplemented from the temporary culture pond. On the 6 th day of the formal experiment, the feeds in the examples 4-6 and the comparative examples 1-2 are fed respectively, and if dead fish appear in the period, only weighing and recording are carried out, and the fish are not supplemented. The formal experiment period is 8 weeks, during the experiment period, the water quality of the culture pond is controlled under the condition suitable for the survival of the grass carp, and the water quality of each experiment pond is basically kept consistent through measures such as water changing, pollution discharging and the like (unified operation of each pond). 3 meals are regularly fed in the morning (8:00), in the middle (12:00) and at the evening (18:00) during the official experiment period, and the meals are fed after being fed with full food, on the premise that basically no residual materials exist. The indexes of feeding, fish health condition and the like are recorded in detail every day, and the water quality indexes of dissolved oxygen, pH and the like of each pool are detected and recorded.
1.4 data detection and analysis
And (3) randomly taking 3 fish from each experimental pond at the end of the experiment, taking blood from the tail vein, mixing, putting one half of the mixture in a 1.5mL centrifugal tube for measuring the concentration of lymphocyte, hemoglobin, serum potassium and serum sodium ions, standing for 2 hours, centrifuging at 4000r/min for 15min, taking the upper serum, and storing at-80 ℃ for later use. The kit of Nanjing institute of biotechnology is selected to detect and measure the activities of serum glutamic-oxaloacetic transaminase (AST) and glutamic-pyruvic transaminase (ALT) and the contents of Cortisol (COR) and blood sugar (GLU). Meanwhile, 3 fish in each experimental pond are randomly taken out for dissection, photographed, livers are taken and mixed, and the kit built into the biotechnology research institute from Nanjing is used for detecting Catalase (CAT), Malondialdehyde (MDA), superoxide dismutase (SOD), Lipase (LPS), lipoprotein lipase (LPL) and liver esterase (HL).
The feeding amount is recorded in detail in the experimental process, and the weight of the experimental fish in each pond is accurately weighed before and after the experiment. And (3) calculating a relevant index: (ii) Weight Gain Ratio (WGR) ═ final weight-initial weight)/initial weight; feed Factor (FCR) weight gain/feed consumption; survival rate (SWR) ═ number of fish before experiment-number of fish after experiment)/number of fish before experiment × 100.
The raw data were analyzed for One-way analysis of variance (One-way ANOVA) using SPSS22.0 software and multiple comparisons were performed using the Duncan method with P <0.05 as the significance level of difference.
2. Results and analysis
2.1 Water quality status during the experiment
The water quality conditions of each experimental group and the control group were tested, and the results of the tests were recorded in table 2 below.
Table 2: comparison of Water quality indexes of examples 4 to 6 and comparative examples 1 to 2
| Experimental groups | Dissolved oxygen | pH | Water temperature | Alkalinity of | Hardness of |
| Comparative example 1 | 7.6 | 7.1 | 24.3 | 70 | 80 |
| Comparative example 2 | 7.6 | 7.1 | 24.3 | 70 | 80 |
| Example 4 | 7.6 | 7.1 | 24.3 | 70 | 80 |
| Example 5 | 7.7 | 7.1 | 24.3 | 70 | 80 |
| Example 6 | 7.5 | 7.1 | 24.3 | 70 | 80 |
The water quality conditions of the experimental ponds are good and basically consistent during the experiment, the requirements of the grass carp on the water quality are met, and the water quality indexes of the experimental groups have no significant difference through SPSS variance inspection. As can be seen from Table 2, the water quality index was not changed when the grass carp was fed with the feeds of examples 4 to 6, as compared with the group of comparative example 1.
2.2 growth index comparison
Grass carp is fed by the feed in comparative examples 1-2 and examples 4-6, and then growth indexes of each group are tested, and specific results are shown in the following table 3.
Table 3: comparative data on growth index for groups of comparative examples 1-2 and examples 4-6
As can be seen from Table 3, the feed coefficients of the experimental grass carp are remarkably reduced and the survival rate and the weight gain rate are improved due to the addition of silybin and derivatives thereof in the feed in the comparative example 2 and the feed in the examples 4-6.
2.3 Biochemical Immunity index comparison
The experimental grass carps were fed with the feeds of comparative examples 1-2 and examples 4-6, and then the biochemical immunity indexes of each group were tested, and the specific results are shown in tables 4, 5 and 6 below.
Table 4: hematological index analysis data for comparative examples 1-2 and examples 4-6
From the hematology index analysis results in table 4, it can be seen that the addition of silybin and its derivatives significantly increases the number of lymphocytes and hemoglobin in the experimental grass carp, significantly reduces the concentrations of aspartate Aminotransferase (AST) and alanine Aminotransferase (ALT), and also has an effect on serum potassium and sodium ions.
Table 5: biochemical index analysis data of liver and pancreas for comparative examples 1-2 and examples 4-6
From the analysis results of the biochemical indexes of liver and pancreas in table 5, it can be seen that the addition of silybin and its derivatives significantly increases the concentration of Catalase (CAT), superoxide dismutase (SOD), Lipase (LPS), lipoprotein (LPL), and liver esterase (HL), and significantly reduces the concentration of Malondialdehyde (MDA).
Table 6: comparative analysis data of exposure stress serum of comparative examples 1-2 and examples 4-6 groups
| Experiment grouping | Cortisol (COR) ng/ml | Blood Glucose (GLU) nmol/L |
| Comparative example 1 | 65.93 | 4.59 |
| Comparative example 2 | 34.57 | 2.96 |
| Example 4 | 34.22 | 2.72 |
| Example 5 | 33.99 | 2.56 |
| Example 6 | 34.43 | 2.91 |
As can be seen from the exposure stress serum data in table 6, the addition of silybin and its derivatives significantly reduced Cortisol (COR), blood Glucose (GLU) concentrations.
Test example 2: fat-soluble experiment
The fat-soluble data of the silybin derivatives in examples 1 to 3 were respectively tested, and the fat-soluble data were compared with the fat-soluble data of silybin, and the specific test results are shown in table 7 below.
TABLE 7 lipid solubility data for Silybin and its derivatives
| Silybin | Example 1 | Example 2 | Example 3 | |
| N-hexane | 0.3mg/mL | 0.4mg/mL | 0.5mg/mL | 0.3mg/mL |
| Acetic acid ethyl ester | 24.5mg/mL | 43.7mg/mL | 57.2mg/mL | 32.08mg/mL |
Therefore, the compounds in embodiments 1 to 3 of the present invention have lipid solubility significantly better than that of silybin, and have lipid solubility better than that of silybin in different polar solvents, and the better lipid solubility can facilitate absorption of silybin derivatives.
The embodiments of the present invention have been described in detail, but the present invention is not limited to the embodiments, and various changes can be made without departing from the gist of the present invention within the knowledge of those skilled in the art. Furthermore, the embodiments of the present invention and features of the embodiments may be combined with each other without conflict.
Claims (10)
1. A silybin derivative is characterized in that: the structure is shown as the general formula (I):
wherein R is substituted or unsubstituted C1-20Alkyl, substituted or unsubstituted C2-20Alkenyl or alkynyl, substituted or unsubstituted C1-20An alkoxy group, a substituted or unsubstituted aryl group, a substituted or unsubstituted five-or six-membered heterocyclic group; the five-membered or six-membered heterocyclic group contains oxygen, sulfur or nitrogen on the heterocyclic ring;
Each substituent is independently selected from halogen, -CN, -NO2、C1-6Alkyl or alkoxy, -CHO, phenyl, halophenyl, C1-8Alkyl or C1-6Alkoxy-substituted phenyl, C2-12Alkynyl or alkenyl, benzoyl, C1-6Alkoxy-substituted carbonyl, C1-6Alkyl-substituted phenoxy.
2. The silybin derivative according to claim 1, wherein: the structural general formula is shown as a formula (I), wherein R is substituted or unsubstituted C1-20An alkyl group, a substituted or unsubstituted vinyl group, a substituted or unsubstituted aryl group; each of said substituents being independently selected from halogen, -CN, -NO2、C1-6Alkyl radical, C1-6Alkoxy, -CHO, phenyl, halophenyl, C1-6Alkyl-substituted phenyl、C1-6Alkoxy-substituted phenyl.
3. The silybin derivative according to claim 1, wherein: the compound in the general formula (I) is selected from:
4. a method for producing a silibinin derivative according to any one of claims 1 to 3, characterized in that: the method comprises the following steps:
s1: mixing the compound 1 with a chlorination reagent and a nucleophilic reagent for reaction to obtain a compound 2;
s2: the compound 2 reacts with silybin to prepare the silybin derivative,
the specific reaction formula is as follows:
5. The method for producing a silibinin derivative according to claim 4, wherein: the nucleophilic reagent is selected from at least one of pyridine, triethylamine, N-dimethylformamide and caprolactam.
6. An aquatic feed additive, which is characterized in that: comprising a silibinin derivative according to any one of claims 1 to 3.
7. An aquatic feed, which is characterized in that: the silybin derivative comprises the silybin derivative according to any one of claims 1 to 3, wherein the weight ratio of the silybin derivative is 0.1 to 1 per thousand.
8. An aquaculture feed according to claim 7 wherein: the feed also comprises the following components in parts by weight: 200-300 parts of rapeseed meal, 200-300 parts of soybean meal, 80-120 parts of rice bran, 80-120 parts of cottonseed meal, 40-80 parts of corn distiller's grains, 50-80 parts of flour, 40-60 parts of corn germ meal, 20-60 parts of distiller's grain powder, 40-80 parts of oxidized soybean oil, 10-30 parts of zeolite powder, 10-30 parts of bentonite, 10-30 parts of monocalcium phosphate and 0.01-0.1 part of trace elements.
9. A method for feeding grass carp is characterized in that: mixing a feed and the silybin derivative according to any one of claims 1 to 3, wherein the mass ratio of the feed to the silybin derivative is 1000: (0.1-1), and feeding the grass carp for three times, wherein the feeding amount of each time is 0.5% -5% of the weight of the grass carp, and the interval time of each time is 4-8 h.
10. Use of a silibinin derivative according to any one of claims 1 to 3 in a feed additive or feed.
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