CN110090216B - Application of indole alkaloid compound and derivatives or salts thereof in products for preventing and treating diabetic nephropathy - Google Patents

Application of indole alkaloid compound and derivatives or salts thereof in products for preventing and treating diabetic nephropathy Download PDF

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CN110090216B
CN110090216B CN201910350483.0A CN201910350483A CN110090216B CN 110090216 B CN110090216 B CN 110090216B CN 201910350483 A CN201910350483 A CN 201910350483A CN 110090216 B CN110090216 B CN 110090216B
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leuconolam
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王志伟
闫慧娇
穆岩
林云良
耿岩玲
刘伟
王晓
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Shandong Analysis and Test Center
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    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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Abstract

The invention provides an application of indole alkaloid compounds and derivatives or salts thereof in preparing products for treating diabetic nephropathy. The indole alkaloid compound has a structure shown in a formula (I) or a formula (I):
Figure DDA0002043766370000011
wherein R is1Is selected from hydrogen or COOR ', wherein R' is selected from C1‑10Alkyl radical, C2‑10Alkenyl and C2‑10An alkynyl group; r2Selected from hydrogen, hydroxy, wherein the hydroxy group may be replaced by C1‑10Alkoxy radical, C2‑10Alkenyloxy radical, C2‑10Alkynyloxy and halogen atoms; n is an integer of 1 to 4; r3、R4、R6、R7And R8Each independently selected from hydrogen, hydroxy, carbonyl, C1‑10Alkoxy radical, C2‑10Alkenyloxy radical, C2‑10Alkynyloxy and a halogen atom; r5Selected from hydrogen, hydroxy, C1‑10Alkoxy radical, C2‑10Alkenyloxy radical、C2‑10Alkynyloxy and a halogen atom.

Description

Application of indole alkaloid compound and derivatives or salts thereof in products for preventing and treating diabetic nephropathy
Technical Field
The invention relates to the technical field of medicaments, in particular to an application of indole alkaloid compounds and derivatives or salts thereof in preparing products for treating diabetic nephropathy.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Diabetic Nephropathy (DN) is the most common microvascular complication of diabetic complications, with an incidence of 20% to 40% in diabetic patients, and has been one of the leading causes of end-stage renal disease and mortality. The major pathological changes associated with DN include mesangial expansion, podocyte loss, increased basement membrane thickness, glomerular and tubular cell damage, leading to glomerular sclerosis and interstitial fibrosis (Hovind P, Rossing P, Tarnow L, Smidt UM and Parving HH: Progression of metabolic neuropathology. kidney int.59: 702-709.2001; Parving HH: metabolic neuropathology: prediction and treatment. kidney int.60: 2041-2055.2001.). Hyperglycemia is a key to renal cell injury and overproduction of extracellular matrix in DN (Kanwar YS, Wada J, Sun L, Xie P, Wallner EI, Chen S, Chugh S and Danesh FR: diabetes neuropathology: Mechanisms of renal disease promotion. exp Biol Med (Maywood): 233: 4-11.2008.; Ban CR and twist SM: diabetes in diabetes compositions: nutritional Mechanisms and circulatory markers. Vasc Health skin Manual.4: 575-596.2008.). Podocytes are terminally differentiated cells present on the outer surface of the glomerular basement membrane that maintain the structure and function of the glomerular filtration barrier. Previous studies have shown that podocyte damage is associated with The generation and development of DN (Wiggins RC: The specificity of podocytopathies: A differentiation view of macromolecular diseases. kidney int.71: 1205-1214.2007.). Furthermore, a reduction in The number of glomerular podocytes is The strongest predictor of DN progression (Drummond K and Mauer M; International diagnostic New photopath Study Group: The early natural history of neuropath in type 1diabetes: II. early real recombinant genes in type 1 diabetes.51: 1580-1587.2002.; Pagtalan ME, Miller PL, Jumping-Eagle S, Nelson RG, Myers BD, Rennke HG, Coplon, Sun L and Meyer TW: Podocyte and pro-constructive viral expression in type II diabetes.J. Clin-348.1997). It has been found that changes in the glomerular filtration barrier, particularly in the damage of podocytes due to high sugar, play a critical role in the pathological changes in diabetic nephropathy.
Astragaloside IV (AS-IV) is a saponin isolated from Astragalus membranaceus (Astragalus membranaceus), which has various pharmacological activities. The results from Molecular Medicine Reports,2016,13:5149-5156 indicate that AS-IV can prevent hyperglycemia-induced podocyte apoptosis by down-regulating TRPC6, which is likely mediated through the calcineurin/NFAT signaling pathway.
The inventor finds that the glucocorticoid and the immunosuppressant which are mainly applied to the treatment of the diabetic nephropathy clinically at present have significant curative effect but have large side effect after long-term use.
Disclosure of Invention
The invention aims to provide application of indole alkaloid compounds and derivatives or salts thereof in preparation of products for treating diabetic nephropathy. The indole alkaloid compound has a structure shown in a formula (I) or a formula (I):
Figure GDA0002990281890000021
wherein R is1Is selected from hydrogen or COOR ', wherein R' is selected from C1-10Alkyl radical, C2-10Alkenyl and C2-10An alkynyl group;
R2selected from hydrogen, hydroxy, wherein the hydroxy group may be replaced by C1-10Alkoxy radical, C2-10Alkenyloxy radical, C2-10Alkynyloxy and halogen atoms; n is an integer of 1 to 4;
R3、R4、R6、R7and R8Each independently selected from hydrogen, hydroxy, carbonyl, C1-10Alkoxy radical, C2-10Alkenyloxy radical, C2-10Alkynyloxy and a halogen atom;
R5selected from hydrogen, hydroxy, C1-10Alkoxy radical, C2-10Alkenyloxy radical, C2-10Alkynyloxy and a halogen atom.
The halogen atom is preferably fluorine, chlorine, bromine or iodine.
Specifically, the invention is realized by the following technical scheme:
in a first aspect of the invention, the invention provides the use of an indole alkaloid compound or a derivative or pharmaceutically acceptable salt thereof, having a structure according to formula (I) or formula (II):
Figure GDA0002990281890000031
wherein R is1Is selected from hydrogen or COOR ', wherein R' is selected from C1-10Alkyl radical, C2-10Alkenyl and C2-10An alkynyl group;
R2selected from hydrogen, hydroxy, wherein the hydroxy group may be replaced by C1-10Alkoxy radical, C2-10Alkenyloxy radical, C2-10Alkynyloxy and halogen atoms; n is an integer of 1 to 4;
R3、R4、R6、R7and R8Each independently selected from hydrogen, hydroxy, carbonyl, C1-10Alkoxy radical, C2-10Alkenyloxy radical, C2-10Alkynyl radicalOxy and halogen atoms;
R5selected from hydrogen, hydroxy, C1-10Alkoxy radical, C2-10Alkenyloxy radical, C2-10Alkynyloxy and a halogen atom.
The halogen atom in the present invention is preferably fluorine, chlorine, bromine or iodine.
In the present specification, the term "alkyl" refers to a straight or branched hydrocarbon group, preferably having 1 to 10 carbon atoms, more preferably having 1 to 6 carbons, and still more preferably having 1 to 4 carbons. Representative groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, and the like;
the term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group having at least one carbon-carbon double bond, preferably having 2 to 10 carbon atoms, more preferably having 2 to 6 carbons, and more preferably having 2 to 4 carbons. Representative examples include ethenyl, propenyl, allyl, butenyl, pentadienyl and the like.
The term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group having at least one carbon-carbon triple bond, preferably having 2 to 10 carbon atoms, more preferably having 2 to 6 carbons, and more preferably having 2 to 4 carbons. Representative examples are ethynyl, propynyl, butynyl and the like.
The term "oxo" refers to the group-C ═ O.
In some embodiments of the invention, the compound of formula (I) or formula (II) is selected from the following structures:
Figure GDA0002990281890000041
a more preferred compound of formula (I) in the present invention is Kopsinine, which has the structure shown in formula (I'):
Figure GDA0002990281890000042
also, a more preferred compound of formula (II) of the present invention is leuconolam, which has the structure shown in formula (II'):
Figure GDA0002990281890000043
in the present invention, the term "pharmaceutically acceptable salt" refers to non-toxic acid addition salts derived from inorganic and organic acids. Although reference is made herein to "a compound of formula (I)" or "a compound of formula (I ')" or "a compound of formula (II)" or "kopsin" or "leuconolam" and "a pharmaceutically acceptable salt thereof", unless otherwise indicated by context, the terms "a compound of formula (I)" or "a compound of formula (I ')" or "a compound of formula (II)" or "Kopsinine" or "leuconolam" are to be understood as including the compounds themselves as well as pharmaceutically acceptable salts, since for the sake of brevity the term "a compound of formula (I)" or "a compound of formula (I ')" or "a compound of formula (II)" or "kopsin" or "leuconolam" may be used alone.
Acids commonly used to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like, and organic acids such as tartaric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, oxalic acid and the like. Base addition salts include the following salts: derived from inorganic bases such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Thus, such bases useful in preparing the salts of the present invention include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium salt form and the sodium salt form are particularly preferred.
It will be appreciated that the particular counter ion that forms part of any salt of the invention is not critical, so long as the salt as a whole is pharmacologically acceptable and the counter ion does not impart undesirable properties to the salt as a whole.
Also, the present invention provides derivatives of indole alkaloid compounds, optionally, kopsine or leuconolam may be structurally modified and derivatized, such as by introducing various substituent groups on the indole ring, or by changing and modifying substituents on other rings. The substituents and substitution conditions are as defined above, and those skilled in the art can select appropriate synthesis or modification methods according to the target structure and optional groups.
For example, references J.Nat.Prod.2017,80,4, 864-Asca 871 or J.org.chem.2019,84(2) 1111-Asca 1116; derivatives of Kopsine can be prepared from org.Lett,2013,15(4):868-870 or Bioorganic and Medicinal Chemistry Letters 1998vol.8#19p.2769-2772 or Phytochemistry 1999vol.50#1 p.75-79. The documents are incorporated herein by reference in their entirety.
For example, the references Journal of the American Chemical Society2015vol.137#20p.6712-6724 or Low, Y.Y., Hong, F.J., Lim, K.H., Thomas, N.F., & Kam, T.S. (2014.) Transformations of the 2,7-seco asperma alkloid structures, structure repetition of epi-structures, and partial syntheses of leucoxenes and leucocyanides a and f.journal of Natural Products,77(2),327 and 338. derivatives of leuconoloma can be prepared. The documents are incorporated herein by reference in their entirety.
For example, the following compounds may be prepared or purchased:
Figure GDA0002990281890000061
the above compounds are all known compounds, and corresponding compound information can be found in pubchem, such as 11-Hydroxykopsilangine, the pubchem CID of which is 44326385.
In an embodiment of the invention, the compounds of the invention are subjected to multiple rounds of activity screening, and during the screening process, it is found that all other substituents are H, R1is-COOCH3However, these compounds (e.g. pleiocarpine, which has a pubchem CID of 101650372) are less active and are screened out during the primary screening of the activity of the present invention, and are therefore excluded from the scope of the present invention.
In addition, in another embodimentIn some embodiments, when n is 1, R2Is methoxy at the C-12 position, with R1is-COOCH3When R is5When the other substituent is H for-OH, these compounds (e.g., (-) -N-methoxybutyryl-12-methoxykopsin, Feng XZ, Kan C, Potier P, et al monomer induced alkali from Kopsia of fisinalis [ J.]EC of plantas Medica,1983,48(8):280-50Values often higher than 30. mu.M, and these compounds are also excluded from the scope of protection of the present invention. The documents are incorporated herein by reference in their entirety.
For example, substituents on the indole ring can be introduced by, for example, the method of chinese patent CN 101108859A. Which is incorporated herein by reference in its entirety.
For example, the ethyl group on the indole ring can be introduced by, for example, the method of Jacquesy, j. -c. (j. fluor. chem.2006,127, 1484-1487). Which is incorporated herein by reference in its entirety.
For example, the substituent on the indole ring N can be introduced by, for example, the method of Kuboyama et al (Proc. Nat. Acad. Sci. USA,2004,101(33), 11966-11970). Which is incorporated herein by reference in its entirety. For example, Kopsinine or Leuconolam is dissolved in acetic anhydride: formic acid (11: 5) is stirred to react for 1.5 hours, then ammonia is used for stopping the reaction, dichloromethane is used for extraction, the solvent is recovered, and the crude product is purified to obtain the derivative acylated on N.
For example, kopsine and leuconolam are respectively dissolved in a mixed solvent of anhydrous dichloromethane and trifluoroacetic acid at a proper temperature (-20-30 ℃), and react with NBS to respectively obtain 10 '-bromo kopsine and 10' -bromo leuconolam, and then the 10 '-bromo kopsine and 10' -bromo leuconolam are respectively dissolved in water and heated to 75 ℃ under the catalysis of transition metal to respectively obtain 10 '-hydroxy kopsine and 10' -hydroxy leuconolam.
In some embodiments of the invention, the disease associated with high sugar-induced podocyte damage is diabetic nephropathy.
The product of the invention comprises a medicine, a food or a health product.
In a second aspect of the present invention, there is provided a composition for treating a disease associated with high-sugar podocyte damage, in which the indole alkaloid compound or its derivative or its pharmaceutically acceptable salt described in the above first aspect may be administered to a subject in the form of a pharmaceutical composition. The pharmaceutical composition of the present invention comprises the indole alkaloid compound or its derivative or its pharmaceutically acceptable salt described above in the first aspect of the present invention and a pharmaceutically acceptable carrier or excipient.
The pharmaceutical compositions of the present invention are generally safe, non-toxic and biologically desirable, and therefore the pharmaceutically acceptable carriers or excipients of the present invention are non-toxic and safe, as well as combinations thereof with the compounds of the present invention. The pharmaceutically acceptable carriers and excipients of the present invention are generally well known to those skilled in the art or can be determined by those skilled in the art in view of the actual circumstances. Examples of suitable carriers and excipients include glucose, water, glycerol, ethanol, propylene glycol, corn starch, gelatin, lactose, sucrose, alginic acid, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, croscarmellose sodium and sodium starch glycolate and the like polysorbate 80, polyethylene glycol 300, polyethylene glycol 400, cyclodextrins or derivatives thereof such as ((2-hydroxypropyl) -cyclodextrin) and (2-hydroxyethyl) -cyclodextrin, which are also known as HPCD, pegylated castor oil, poloxamers such as poloxamer 407 or 188; hydrophilic carriers, hydrophobic carriers, or combinations thereof, and the like. Hydrophobic carriers include, for example, fat emulsions, lipids, pegylated phospholipids, biocompatible polymers, lipid spheres, liposomes, vesicles, polymer matrices, particles, and the like. Furthermore, one skilled in the art will appreciate that diluents are included within the term carrier and excipient.
The carrier may be present in the pharmaceutical composition in an amount of 1% to 98% by weight, usually about 80% by weight. For convenience, the local anesthetic, preservative, buffer, etc. may be dissolved directly in the vehicle.
In a third aspect of the present invention, the present invention also provides a pharmaceutical preparation for treating diseases associated with high-sugar podocyte injury, comprising the indole alkaloid compound or derivative or the pharmaceutically acceptable salt thereof according to the first aspect of the present invention, or the pharmaceutical composition according to the second aspect of the present invention, and at least one pharmaceutically acceptable adjuvant.
The pharmaceutically acceptable excipients include, but are not limited to, excipients, carriers, and the like. One skilled in the art can select the appropriate excipient for various purposes. For example, depending on the nature of the drug or the mode of administration, commonly used excipients such as solvents, solubilizers, surfactants, preservatives, fillers, emulsifiers, binders, disintegrants, stabilizers, flavors, antioxidants, colorants, diluents, pH adjusters, pressure adjusters, and the like, or combinations of two or more of these, and the like.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form. The administration form may be a conventional form such as a liquid form such as an emulsion form, a colloid form, a true solution form, a microparticle form, a racemic form; such as other conventional machine types such as tablets, capsules, dripping pills, aerosols, pills, oral liquids, powders, injections, solutions, suspensions, emulsions, granules, clathrates, landfills, and the like. These preparations can be prepared according to the conventional preparation methods in the art, such as mixing, granulating, tabletting, filling, dissolving or suspending dispersion, and the like.
Where a carrier is included in a pharmaceutical composition or formulation of the invention, the carrier may be present in the pharmaceutical composition in an amount of from 1% to 98% by weight, typically about 80% by weight. For convenience, the local anesthetic, preservative, buffer, etc. may be dissolved directly in the vehicle.
The oral liquid can be made into suspension, solution, emulsion, syrup, or dried product, and is supplemented with suitable solvent or other suitable medium before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, or non-aqueous vehicles, which may include edible oils, preservatives. Flavoring or coloring agents may be added if desired. Oral tablets and capsules may contain compatible excipients such as binders, fillers, disintegrants or acceptable wetting agents. The tablets may be coated by methods known in the art of pharmacy.
For example, in some embodiments of the present invention, a method for preparing an injection solution containing kopsine or leuconolam or a salt thereof as an active ingredient is provided, for example, an injection solution can be prepared by dissolving the active ingredient in water for injection, fine-filtering, filling, and sterilizing according to a conventional preparation method for an injection solution in the art.
For example, in some embodiments of the invention, a powder for injection is provided having kopsin or leuconolam, for example, or a salt thereof, as the active ingredient, for example, by dissolving the active ingredient in sterile water for injection, stirring for dissolution, filtering through a sterile suction funnel, sterile fine filtering, dispensing into ampoules, and freeze-drying at low temperature to form a sterile, melt-sealed powder for injection.
For example, in some embodiments of the present invention, a tablet comprising kopsine or leuconolam or a salt thereof as an active ingredient is prepared by mixing 80-99% of a total amount of a filler (e.g., starch), a disintegrant (e.g., 1-6% sodium carboxymethyl starch), and a binder (e.g., 50-70% sucrose solution) uniformly according to conventional tablet preparation methods, granulating, and tabletting.
Furthermore, in some embodiments of the present invention, the composition of the present invention also comprises a plant extract comprising a compound of formula (I ') or formula (II') as described herein. The plant can be, for example, Yunnan patchouli, and the extract part is the branch, leaf or rhizome of the Yunnan patchouli.
In some embodiments of the invention, the activity of the extract comprising the compounds of formula (I ') and/or formula (II') extracted from patchouli leaves is better than that of the extract extracted from patchouli rhizomes.
The invention also provides a preparation method of the compound shown in the formula (I ') or the formula (II'), and the compound shown in the formula (I ') or the formula (II') is extracted and separated from the plant patchouli.
In some embodiments of the present invention, the preparation method comprises extracting a plant material of patchouli with water or an organic solvent 1 to obtain an extract, and subjecting the extract to an extraction treatment to obtain an alkaloid containing the compound of formula (I ') or formula (II').
Yunnan stamen (Latin's name: Kopsia officinalis) is a plant of genus pistil of Apocynaceae, mainly produced in southern Yunnan, and is grown in mountain sparse forest with elevation of 500-. The flowering period is 4-9 months, and the fruit period is 9-12 months. The bark of Yunnan folk is decocted with water to treat edema; the fruits and leaves have the effects of diminishing inflammation, relieving pain, relaxing tendons and activating collaterals, and can be used for treating pharyngolaryngitis, tonsillitis, rheumatic bone pain, limb numbness and other diseases.
In one or more embodiments, the extraction of the present invention is heat reflux extraction or leaching.
In one or more embodiments, the extraction treatment comprises acidifying the extract by suspension in water, extracting with organic solvent 2, then basifying the aqueous layer, and then extracting with organic solvent 3, preferably, the organic solvent may be concentrated after extraction.
In the present invention, the extract or alkaloid containing the compound of formula (I ') or formula (II') is further separated and purified to obtain the compound of formula (I ') or formula (II').
The separation and purification method of the invention is a column chromatography and/or a preparation liquid phase method; such as silica gel column chromatography, C18 column chromatography, ion exchange resin column chromatography, Sephadex column chromatography, C18 reversed phase preparation liquid phase, etc.
In some embodiments of the invention, the method of making comprises: extracting Cistus plant material with water or organic solvent 1, suspending the extract with water, extracting with organic solvent 2 under acidic condition, extracting the residual water layer with organic solvent 3 under alkaline condition, concentrating the organic solvent, enriching to obtain alkaloid containing compound of formula (I ') or formula (II'), and further performing column chromatography and/or preparative liquid chromatography to obtain compound of formula (I ') or formula (II').
In one or more embodiments, the organic solvent 1 is selected from C1-6Alcohol, C3-6Ketones, C2-6Ether, C2-6Esters or C1-6A halogenated hydrocarbon; ratio ofSuch as, the C3-6The ketone is selected from one or more of acetone, methyl ethyl ketone and methyl isobutyl ketone; for example, preferably, said C2-6The ether is selected from one or more of methyl ether and ethyl ether; for example, the C2-6The ester is selected from one or more of ethyl formate, ethyl acetate and ethyl propionate; for example, the C1-6The halogenated hydrocarbon is selected from one or more of dichloromethane, trichloromethane and dichloroethane.
In some embodiments of the invention, the organic solvent 1 is selected from C1-6Alcohols, such as ethanol.
In some embodiments of the invention, the organic solvent 2 is selected from C2-6Esters and/or C1-6A halogenated hydrocarbon; such as ethyl acetate and/or dichloromethane.
In some embodiments of the invention, the organic solvent 3 is selected from C1-6A halogenated hydrocarbon; such as methylene chloride.
In some embodiments of the invention, the acidic conditions in the acid-base extraction treatment are a pH of 2.0 to 3.0; for example, the pH is adjusted to 2.0-3.0 with 10% HCl.
In some embodiments of the invention, the basic conditions in the acid-base extraction treatment are a pH of 9.0 to 11.0; for example, the pH is adjusted to 9.0-11.0 with 10% NaOH.
In some embodiments of the invention, the eluent for the column chromatography is chloroform/methanol, petroleum ether/acetone. Preferably, the volume ratio of chloroform/methanol is 200:1-1: 1; for example, in elution, chloroform/methanol was used at a ratio of 200:1, 100:1, 70:1, 30:1, 15:1, 10:1, 8:1, 4:1, 1: 1.
In some embodiments of the invention, the method of making comprises: heating and refluxing air-dried patchouli branches and leaves by using an organic solvent 1 for 1-4 times, recovering the solvent until the solvent is tasteless, adding water for suspension, extracting by using an organic solvent 2 for 1-3 times under an acidic condition, extracting a water layer for 3 times by using dichloromethane under an alkaline condition, concentrating the organic solvent to obtain total alkaloids, then carrying out column chromatography, eluting by using chloroform/methanol 200:1, 100:1, 70:1, 30:1, 15:1, 10:1, 8:1, 4:1, 1:1, and dividing into 11 sections (C1-C8), eluting by using 45% petroleum ether/acetone in an S5 section, and preparing a liquid phase by C18 reverse phase to obtain Kopsinine; the S8 stage was eluted with 50% petroleum ether/acetone and the liquid phase was prepared by C18 reverse phase to give leuconolam.
In some embodiments of the invention, the method of making comprises: taking 11.3kg of air-dried branches and leaves (or roots) of the patchouli, heating and refluxing for 4 times by using 95% ethanol, recovering a solvent until no alcohol smell exists, adding water for suspension, adjusting the pH value to 2 by using 10% HCl, extracting for 3 times by using dichloromethane, adjusting the pH value of a water layer to 10 by using 10% NaOH, extracting for 3 times by using dichloromethane, recovering dichloromethane to obtain total alkaloids, mixing samples by using silica gel, performing column chromatography by using 150g of 200-mesh and 300-mesh silica gel, eluting by using chloroform/methanol 200:1, 100:1, 70:1, 30:1, 15:1, 10:1, 8:1, 4:1, 1:1, dividing into 11 sections (C1-C8 sections), eluting by using 45% petroleum ether/acetone in an S5 section, and preparing a liquid phase by using C18 reverse phase to obtain Kopsine. The S8 stage was eluted with 50% petroleum ether/acetone and the liquid phase was prepared by C18 reverse phase to give leuconolam.
The use of the extract obtained before separation and purification in the above embodiment of the present invention for the preparation of a product for preventing and/or treating a disease associated with high-sugar podocyte damage. And a composition or preparation for preventing and/or treating a disease associated with podocyte damage caused by high sugar, which contains the extract liquid obtained in the above embodiment, also belong to the scope of the present invention.
The compounds of the present invention, kopsin, leuconolam, and analogs thereof, and pharmaceutically acceptable salts thereof, may be administered orally or parenterally, and the dosage of administration varies depending on the drug, and is preferably 1 to 1000mg per day for adults.
In one or more embodiments of the present invention, the indole alkaloid compounds of formula (I) and formula (II) of the present invention have a better activity for antagonizing podocyte damage caused by hyperglycemia, and half the effective amount (EC)50) Is between 3.0 and 25.0 mu M, especially between 3.0 and 5.0 mu M, and has the potential of developing drugs for preventing or treating diabetic nephropathy. For example, Kopsine and Leuconolam antagonize the activity EC of immortalized mouse podocyte damage caused by high sugar503.03 and 3.76 mu M respectively, and the treatment effect is obviously better than that of positive drug astragaloside IV (EC)50＝15.41μM)。
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the application and, together with the description, serve to explain the application and are not intended to limit the application. Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 is a hydrogen spectrum of Kopsine.
FIG. 2 is a carbon spectrum of Kopsine.
FIG. 3 is a hydrogen spectrum of Leuconolam.
FIG. 4 is a carbon spectrum of Leuconolam.
FIG. 5 shows the EC of Kopsine in the experimental examples50A graph of (a).
FIG. 6 shows EC of leuconolam in the experimental example50A graph of (a).
FIG. 7 shows EC of astragaloside IV in experimental example50A graph of (a).
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Example 1
Taking 11.3kg of air-dried patchouli branches and leaves, heating and refluxing for 4 times by using 95% ethanol, recovering a solvent until no alcohol smell exists, adding water for suspension, adjusting the pH value to 2 by using 10% HCl, extracting for 3 times by using dichloromethane, adjusting the pH value of a water layer to 10 by using 10% NaOH, extracting for 3 times by using dichloromethane, recovering dichloromethane to obtain total alkaloids, then mixing samples by using silica gel, performing column chromatography by using 150g of 200-mesh and 300-mesh silica gel, eluting by using chloroform/methanol 200:1, 100:1, 70:1, 30:1, 15:1, 10:1, 8:1, 4:1, 1:1, dividing into 11 sections (C1-C8 sections), eluting by using 45% petroleum ether/acetone in an S5 section, and preparing a liquid phase by using C18 reverse phase to obtain Kopsine. The S8 stage was eluted with 50% petroleum ether/acetone and the liquid phase was prepared by C18 reverse phase to give leuconolam. The chemical structural formula of Kopsinine is:
Figure GDA0002990281890000121
molecular weight 338.4, formula C21H26N2O2(ii) a A white powder; is easily soluble in chloroform, dichloromethane, acetone, and methanol.
The structural formula of Kopsinine is determined by its mass spectrum, nuclear magnetic resonance spectrum.
Furthermore, Kopsine can also be prepared in Linde, H.H. (1970) [ analogs from structural australis (f.mueller) pierre (apocynaceae) and nanoparticles on the structure of reframine and pyrifoline.
Mass spectral data for kopsine: ESI-MS (m/z): 339.2[ M + H]+；
Of Kopsine1H NMR and13the C NMR data are shown in Table 1, FIG. 1 and FIG. 2.
The analysis of the data confirms the chemical structure of kopsine.
TABLE 1 of Kopsine1H NMR and13c NMR data (CDCl)3Showing an overlapping signal)
Figure GDA0002990281890000131
Figure GDA0002990281890000141
The chemical structural formula of leuconolam is
Figure GDA0002990281890000142
Molecular weight 326.4, formula C19H22N2O3(ii) a A white powder; is easily soluble in chloroform, dichloromethane, acetone, and methanol.
The structural formula of leuconolam is determined by its mass spectrum, nuclear magnetic resonance spectrum.
Furthermore, leuconolam can also be prepared by the Journal of the American Chemical society2015vol.137#20p.6712-6724 or Low, Y.Y., Hong, F.J., Lim, K.H., Thomas, N.F., & Kam, T.S. (2014.) Transformations of the 2,7-seco asperma alkaloid leucolam, structure review of epi-leucolam, and partial syntheses of leucooxins and leucogens a f.journal of Natural Products,77(2), 327; 338).
Mass spectral data of Leuconolam: ESI-MS (m/z): 328.2[ M + H ]]+；
Leuconolam' s1H NMR and13the C NMR data are shown in Table 2, FIG. 3 and FIG. 4.
The analysis of the data confirms that the chemical structure of leuconolam is shown as the formula (II).
TABLE 2 Leuconolam1H NMR and13c NMR data (CDCl)3Showing an overlapping signal)
Figure GDA0002990281890000151
Example 2
Kopsin and leuconolam hydrochloride were obtained as described in example 1, and a 4% hydrochloric acid solution at pH 4 was added, filtered and dried to obtain kopsin hydrochloride and leuconolam hydrochloride, respectively.
Example 3
Kopsin and leuconolam were obtained as described in example 1, and a 4% ethanol solution of sulfuric acid was added thereto, respectively, at a pH of 4, followed by filtration and drying to obtain Kopsinine sulfate and leuconolam sulfate, respectively.
Example 4
Kopsin and leuconolam were obtained as described in example 1, and a 4% phosphoric acid solution was added to each of them at a pH of 4, followed by filtration and drying to obtain kopsin phosphate and leuconolam phosphate, respectively.
Example 5
Kopsine and leuconolam were obtained as described in example 1, and a 4% citric acid solution was added to each of them at pH 4, followed by filtration and drying to obtain Kopsine citrate and leuconolam citrate, respectively.
Example 6
Kopsin and leuconolam were obtained as described in example 1, and a 4% tartaric acid solution was added, respectively, at a pH of 4, filtered and dried to obtain kopsin tartrate and leuconolam tartrate, respectively.
Example 7
Kopsin and leuconolam were obtained as described in example 1, and a 4% formic acid solution was added, respectively, at a pH of 4, filtered and dried to obtain kopsin formate and leuconolam formate, respectively.
Example 8
Kopsin and leuconolam were obtained as described in example 1, and a 4% oxalic acid solution was added thereto, respectively, at a pH of 4, filtered, and dried to obtain kopsin and leuconolam oxalate, respectively.
Example 9
Kopsine and leuconolam (prepared by the method of example 1) are dissolved in a mixed solvent of anhydrous dichloromethane and trifluoroacetic acid at a proper temperature (-20-30 ℃), and react with NBS to obtain 10 '-bromo Kopsine and 10' -bromo leuconolam respectively, and then the 10 '-bromo Kopsine and 10' -bromo leuconolam are dissolved in water respectively and are heated to 75 ℃ under the catalysis of transition metal to react to obtain 10 '-hydroxy Kopsine and 10' -hydroxy leuconolam respectively.
Examples of the experiments
The experiment proves that the inventionThe indole alkaloid compound shown in formula (I) or formula (II) has good activity for antagonizing podocyte injury caused by high sugar, and half effective dose (EC)50) Is between 3.0 and 25.0 mu M, especially can be as low as 3.0 to 5.0 mu M, and has the potential of developing drugs for preventing or treating diabetic nephropathy.
The test methods and results are as follows:
the first, material and method:
(1) experimental Material
Cell lines: immortalized mouse podocytes (MPC5, source ATCC).
Reagent testing: RPMI 1640 medium (Gibco, lot # 991030); trypsin (Amresco, batch No. 27250018); FBS (Thermo Fisher, batch: NVM 0344); MTT (Ameresco, batch No. M21128); DMSO (Solarbio, batch number: 302A 034); penicillin (Solarbio, batch No. 119A 031); streptomycin (Solarbio, batch No.: 423A054) Na2HPO4·12H2O (Nanjing chemical Co., Ltd., lot No. 090902); KH (Perkin Elmer)2PO4(Nanjing chemical Co., Ltd., batch No. 090922); NaCl (Nanjing chemical Co., Ltd., lot No. 09060310494); KCl (Nanjing chemical Co., Ltd., batch No.: 060960239).
Instruments and consumables:
Figure GDA0002990281890000171
cell type 150 Cell incubator (Thermo Electron Corporation, USA); RT-6000 type enzyme labeling instrument (Shenzhen Redu Life technologies, Ltd.); clean bench (suzhou encorin clean-up facilities ltd); COIC XDS-1B type inverted optical microscope (Chongqing photoelectric Instrument Co., Ltd.); a ten thousandth electronic balance model BS124S (Sartorius, USA); model YXQ-SG 41-280 autoclave (Shanghai Hualin medical nuclear instruments Co., Ltd.); model 79-1 magnetic stirrers (Shenzhen China Instrument Co., Ltd.); 0412-1 type centrifuge (Shanghai medical devices, Inc.); micropipettes (Thermo Electron Corporation, USA); 96-well cell culture plates (Caster Co.).
(2) Experimental methods
Placing the 96-well plate inoculated with the MCP5 cellsAt 5% CO2Culturing in a constant temperature incubator at 33 ℃ by using RPMI-1640 medium (containing 10% FBS and 10U/ml IFN gamma). When the cells grew to 90% confluence, the cells were differentiated by culturing in RPMI-1640 medium containing 10% FBS (without IFN. gamma.) for 10 days. The differentiated cells were used in subsequent experiments.
The differentiated cells were divided into the following three groups:
blank control group: culturing in RPMI-1640 culture medium with glucose concentration of 5.5 mmol/L;
model control group: culturing in RPMI-1640 culture medium with glucose concentration of 33 mmol/L;
administration group: the liquid medicines with different concentrations are administered while culturing in RPMI-1640 medium with glucose concentration of 33 mmol/L.
The reagent comprises the following components: kopsine, leuconolam and 11-Hydroxykopsilongine (pubchem CID 44326385, prepared according to J.Nat.Prod.2017,80,4,864-871 or Bioorganic and Medicinal Chemistry Letters 1998vol.8#19p.2769-2772 or Phytochemistry vol 1999.50 #1 p.75-79) prepared in example 1.
Culturing for 48h, taking out the drug-containing culture solution, adding fresh culture medium 180 μ L into each well, adding 20 μ L MTT 5mg/mL, culturing for 4h, removing the liquid in each well, adding 200 μ L DMSO into each well, shaking for 10min, detecting the absorbance value of each well at 492nm, calculating cell activity, and calculating EC of the compound50The value is obtained.
Note: EC (EC)50The half effective concentration (concentration for 50% effect) refers to a concentration that is effective in 50% of individuals.
Secondly, the result is:
EC with positive control drug of astragaloside5015.41 μ M; kopsine, leuconolam, 11-hydroxykopsilangine antagonize the activity EC of pedal cell damage in immortalized mice caused by high sugar50Respectively 3.03, 3.76 and 24.53 mu M, wherein the effects of Kopsine and leuconolam are obviously better than those of positive control drug astragaloside. As shown in fig. 5-7.
Thirdly, conclusion:
under the experimental conditions, the compounds Kopsine and Leuconolam show obvious activity of antagonizing podocyte injury caused by high sugar, and have the potential of being developed into medicaments for preventing or treating diabetic nephropathy.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (7)

1. Use of an indole alkaloid compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of diabetic nephropathy due to high sugar, said indole alkaloid compound having a structure represented by formula (I ') or formula (II'):
Figure FDA0003061904710000011
2. the use according to claim 1, characterized in that said pharmaceutically acceptable salt is a non-toxic acid addition salt derived from inorganic and organic acids.
3. Use according to claim 2, characterized in that the mineral acid is selected from the group consisting of carbonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid.
4. Use according to claim 2, characterized in that the organic acid is selected from tartaric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, succinic acid, citric acid, benzoic acid, acetic acid and oxalic acid.
5. The use according to claim 1, wherein the pharmaceutical product for the prophylaxis and/or treatment of diabetic nephropathy due to high sugar comprises a pharmaceutically acceptable carrier or excipient.
6. The use according to claim 1, wherein the medicament for preventing and/or treating diabetic nephropathy due to hyperglycemia comprises a plant extract containing the compound of formula (I ') or formula (II').
7. Use according to claim 6, wherein the plant is patchouli.
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