CN106397140A - Poly-bibenzyl type compound and preparation method and purpose thereof - Google Patents
Poly-bibenzyl type compound and preparation method and purpose thereof Download PDFInfo
- Publication number
- CN106397140A CN106397140A CN201610771277.3A CN201610771277A CN106397140A CN 106397140 A CN106397140 A CN 106397140A CN 201610771277 A CN201610771277 A CN 201610771277A CN 106397140 A CN106397140 A CN 106397140A
- Authority
- CN
- China
- Prior art keywords
- compound
- eluent
- pharmaceutically acceptable
- solvate
- bibenzyl
- 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.)
- Granted
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- 150000001875 compounds Chemical class 0.000 claims abstract description 58
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- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
- 238000005570 heteronuclear single quantum coherence Methods 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 201000006894 monocytic leukemia Diseases 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000001269 time-of-flight mass spectrometry Methods 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/34—Separation; Purification; Stabilisation; Use of additives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a compound as shown in formula (I) or a pharmaceutically acceptable salt, a crystal type and a solvate thereof. R1, R2, R3, R4, R5, R6, R7 and R8 are respectively selected from H, hydroxyls, sulfydryls, C1 to C4 alkyls or C1 to C4 alkoxys. Compared with the existing bibenzyl type compound, a poly-bibenzyl type compound has the advantages that the structure is quite different; the poly-bibenzyl type compound has a new medicine effect, i.e., has a good inhibiting function on tumor cells, particularly, the inhibiting function on lung cancer cells, and the obvious inhibiting activity on the proliferation of acute leukemia cells is realized; a preparation method of the poly-bibenzyl type compound is simple and convenient, the reaction condition is mild, the operation and control are convenient, the energy consumption is low, the yield is high, the cost is low, and the poly-bibenzyl type compound is very suitable for industrialized production. (The formula (1) is shown in the description.).
Description
Technical Field
The invention relates to a polybibenzyl compound and a preparation method and application thereof.
Background
The prior literature reports that bibenzyl compounds have the drug effect and the application of inhibiting passive skin allergic reaction (passive cutaneous anaphylaxis) and beta-hexosaminidase released by RBL-2H3 cells (basophilic leukemia cells) (see: Matsuda H et al. antibacterial phenyl anthracenes and … Planta Med 2004; 70: 847-855):
at present, no research report of the polybibenzyl compound shown in the formula I is found, and no research report of the polybibenzyl compound shown in the formula I used for preparing antitumor drugs is found.
Disclosure of Invention
The invention aims to provide a novel polybibenzyl compound with different structures and medicinal values: a compound of formula I.
The invention provides a compound shown as a formula I or pharmaceutically acceptable salt, crystal form and solvate thereof:
wherein,
R1、R2、R3、R4、R5、R6、R7、R8each independently selected from H, hydroxyl, sulfydryl and C1~C4Alkyl or C1~C4An alkoxy group.
Further, R1、R3、R5、R8Are each independently selected from C1~C4Alkyl or C1~C4An alkoxy group; r2、R4、R6、R7Each independently selected from H, hydroxy or mercapto.
Further, R1、R3、R5、R8Each independently selected from methoxy, ethoxy, n-propoxy or isopropoxy; r2、R4、R6、R7Each independently selected from hydroxyl or thiol.
Further, the compound is
The invention provides a method for preparing a compound Y, which comprises the following steps:
i. extracting rhizoma Bletillae with ethanol to obtain ethanol extractive solution;
ii. Taking the ethanol extract, and concentrating to obtain a fluid extract;
iii, dispersing the fluid extract with water, sequentially extracting with ethyl acetate and n-butanol, combining ethyl acetate parts, and recovering the solvent to obtain an ethyl acetate extract;
iv, taking the ethyl acetate extract, and performing gradient elution by adopting silica gel column chromatography by sequentially using petroleum ether-acetone as an eluent at a ratio of 100:1, 50:1 and 30:1 to obtain an eluent Fr.16 when the petroleum ether-acetone is 30: 1;
v, performing gradient elution on reverse-phase polystyrene resin columns on Fr.16 by using ethanol-water of 10:90, 30:70, 50:50, 70:30, 90:10 and 100:0 as eluent in sequence to obtain Fr.16-j when the ethanol-water of 100: 0;
vi, subjecting the Fr.16-j to a sephadex chromatographic column, and sequentially eluting by using dichloromethane-methanol (1: 1) as an eluent, wherein the eluent has the volume of 0.8 time of the column volume and 2.2 times of the column volume to obtain Fr.16-j-1 and Fr.16-j-2 respectively;
vii and Fr.16-j-2, eluting with silica gel column chromatography sequentially with dichloromethane-methanol (1: 0), 200:1 and 100:1 as eluent for 3 column volumes respectively, recovering solvent, and collecting Fr.16-j-2c when dichloromethane-methanol (100: 1);
viii. fr.16-j-2c by preparative thin layer chromatography using dichloromethane-acetone 20:1 as developing solvent, RfSamples were obtained and then separated by reverse phase high performance liquid chromatography eluting with methanol-water 78:22 as eluent, detection was performed at 210nm wavelength and fractions collected for 28min to give compound Y.
Further, in the above-mentioned case,
in the step iv, the amount of the ethyl acetate extract is 155-165 g, and the conditions of gradient elution are as follows:
in the step v, the amount of Fr.16 is 15-20 g, and gradient elution conditions are as follows:
the invention also provides application of the compound or pharmaceutically acceptable salts, crystal forms and solvates thereof in preparing medicaments for treating and/or preventing tumors.
Further, the tumor is lung cancer and/or acute leukemia.
The invention also provides a pharmaceutical composition for treating and/or preventing tumors, which is a preparation prepared by taking the compound or pharmaceutically acceptable salts, crystal forms and solvates thereof as active ingredients and adding pharmaceutically common auxiliary materials.
Further, the tumor is lung cancer and/or acute leukemia.
Compared with the existing bibenzyl compounds, the poly-bibenzyl compound has great difference in structure; in addition, the polybibenzyl compound has a new drug effect: the polybibenzyl compound has good inhibition effect on tumor cells, particularly on lung cancer cells, and has obvious inhibition activity on the proliferation of acute monoleukemia cells; meanwhile, the preparation method of the polybibenzyl compound is simple and convenient, mild in reaction conditions, convenient to operate and control, low in energy consumption, high in yield, low in cost and very suitable for industrial production.
The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix Ca~CbAlkyl means any alkyl group containing "a" to "b" carbon atoms. Thus, for example, C1~C4The alkyl group means an alkyl group containing 1 to 4 carbon atoms, in other words, C1~C4Alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, as well as zwitterionic (inner) salts, and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound or a stereoisomer thereof may be obtained by appropriately (e.g., equivalently) mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The pharmaceutically acceptable auxiliary material of the invention refers to a substance contained in a dosage form except for an active ingredient.
The pharmaceutically acceptable auxiliary components have certain physiological activity, but the addition of the components does not change the dominant position of the pharmaceutical composition in the disease treatment process, but only plays auxiliary effects, and the auxiliary effects are only the utilization of the known activity of the components and are auxiliary treatment modes which are commonly used in the field of medicine. If the auxiliary components are used together with the pharmaceutical composition of the present invention, the protection scope of the present invention still remains.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 shows the HR-ESI-MS spectrum of Compound Y obtained in example 1 of the present invention.
FIG. 2 shows the preparation of Compound Y obtained in example 1 of the present invention1H NMR spectrum.
FIG. 3 shows the preparation of Compound Y according to example 1 of the present invention13C NMR spectrum.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
Experimental materials:
(ii) reagent
Column chromatography silica gel of 200-300 mesh (reagent grade) purchased from Qingdao ocean silica gel desiccant factory;
thin layer chromatography silica gel G, GF254 and H (chemically pure), purchased from Qingdao ocean silica gel desiccant factory;
MCI gel CHP 20P, 75-150 μm, is a reversed-phase polystyrene-type resin, and is purchased from Mitsubishi chemical corporation of Japan;
sephadex LH-20 sepharose, available from Amersham, Sweden;
a GF254 silica gel preparation thin layer purchased from Yangtze river friend silica gel development Co., Ltd;
95% ethanol (Chengdu Kelong chemical reagent factory);
methanol (Chengdu Kelong chemical reagent plant);
dichloromethane (chengdong chemical reagent plant);
dimethyl sulfoxide (chengdu corson chemical reagent factory);
dimethylsulfoxide (chromatographic grade) (Sigma company);
IMDM (produced by Gibco corporation);
1640 medium, fetal bovine serum (Hyclone);
trypsin (Gibco);
MTT (Amresco corporation);
all other reagents used were analytical grade.
Second experiment instrument
Waters Synapt G2HDMS high resolution time-of-flight mass spectrometry (Waters, usa);
Bruker-AV-600 NMR spectrometer (Bruker, Switzerland);
BP211D one tenth ten million electronic balance (Sartorius, switzerland);
r-210 rotary evaporator (BUCHI, Switzerland);
model DZG-6050 vacuum drying oven (shanghai semen);
microplate reader (Thermo 3001, Thermo Fisher Scientific);
an electronic balance (model ESJ120-4, shenyang dragon electronic weighing instrument ltd);
ultra clean bench (MCV-B161F (T), SANYO, Japan);
microscope (Primo Vert, AxioCam ERc 5s, ZEISS);
CO2incubator (HH.CP-T, Shanghai Zixin scientific instruments Co., Ltd.).
③ cells
The lung cancer cell A549 and the human acute lymphoblastic monocytic leukemia cell MV4-11 are both from American ATCC company.
Example 1 extraction and structural identification of Polybibenzyl Compounds of the invention
(1) Extracting medicinal materials:
extracting dried rhizoma Bletillae coarse powder (3kg) with 95% ethanol under reflux for 3 times (30L × 3), each time for 2 hr;
(2) separation and purification of components:
firstly, concentrating and drying the ethanol extract (90L) under reduced pressure to obtain 510g of semisolid fluid extract;
dispersing the semi-solid fluid extract (500g) with water (5L), sequentially extracting with ethyl acetate (20L) and n-butanol (20L), combining ethyl acetate parts, and recovering the solvent under reduced pressure to obtain 160g of ethyl acetate extract;
③ separating the ethyl acetate extract (160g) by silica gel column chromatography, and purifying by using petroleum ether: gradient elution is carried out on acetone, and the eluent is detected by thin layer chromatography to obtain petroleum ether: eluent fr.16 when acetone is 30: 1;
the conditions for gradient elution were as follows:
processing the Fr.16 component (18g) by MCI, performing gradient elution by using 10-100% v/v ethanol water, and detecting by combining thin-layer chromatography to respectively obtain 10 components Fr.16-a-Fr.16-j;
the conditions for gradient elution were as follows:
fifthly, enabling the Fr.16-j component (3.0g) to pass through a gel LH-20 chromatographic column, eluting by using dichloromethane-methanol (1: 1) as an eluent, and sequentially collecting the Fr.16-j-1, Fr.16-j-2 and Fr.16-j-3 when the elution is 0.8 times of the column volume, 2.2 times of the column volume and 3 times of the column volume, wherein the Fr.16-j-2 component is a concentrated part of the bibenzyl compound;
sixthly, subjecting the Fr.16-j-2 component (1.8g) to silica gel column chromatography, and respectively performing column chromatography by using dichloromethane-methanol: 0. 200: 1. 100, and (2) a step of: 1. 50:1, eluting 3 column volumes by eluent with each proportion, recovering the solvent under reduced pressure, collecting 100:1 elution site Fr.16-j-2 c;
⑦, Fr.16-j-2c fraction (390mg) to prepare thin layer chromatography (developing solvent dichloromethane-acetone ═ 20:1, Rf0.60), separating by reverse phase high performance liquid chromatography, eluting with 78% methanol-water, and detecting at 210nm wavelengthMeasuring and collecting a chromatographic peak eluted for 28min to obtain a compound Y of the invention;
when the thin-layer chromatography is used for color development, 10% sulfuric acid ethanol test solution is sprayed, and yellow, orange to reddish spots are developed for 3min at 105 ℃, so that the method can be used for tracking and detecting bibenzyl;
the compound Y of the invention has the formula C46H46O8High resolution mass spectrometry data: HR-ESI-MS M/z 725.3094[ M-H ]]-(C46H45O8Calculated of 725.3114), unsaturation was 24;
nuclear magnetic resonance hydrogen spectrum of the compound (1H-NMR) and nuclear magnetic resonance carbon Spectroscopy (C13C-NMR) was measured by Bruker-AV-600 NMR, and the data are shown in Table 1;
TABLE 1 preparation of Compound Y of the invention1H NMR (600MHz) and13C NMR(150MHz)in CD3COCD3data of (2)
According to the above-mentioned spectral data, the two-dimensional nuclear magnetic resonance data of HSQC, COSY and HMBC are combined to determine that the compound Y of the invention is 3,3 ' -bis (p-hydroxybenzyl) -4,6 ' -dimethoxy-2, 2 ' -bis (3-methoxyphenethyl) - (1,1 ' -biphenyl) -6,4 ' -diol, and the structure is as follows:
example 2 anti-Lung cancer A549 Activity assay of Polybibenzyl Compounds of the invention
(ii) inoculation of cells
Digesting the cells in logarithmic growth phase with 0.25% pancreatin, preparing single cell suspension by using cell culture medium containing 10% FBS, counting by using cell counting plate, inoculating A549 tumor cells in good state into 96-well plate to make cell density be 4 × 103Each well was filled with 100. mu.L of cell suspension, incubated at 37 ℃ with 5% CO2Culturing in an incubator for 24 h.
② treatment with drugs
Starting from 10. mu.g/mL of each sample, the samples were diluted with a gradient of medium, 2-fold diluted, 5 drug concentrations were set, and duplicate wells were tested for each concentration. The drug is added into each hole at the concentration of 10, 5, 2.5, 1.25 and 0.625 mug/mL for 100 muL, each concentration is provided with 3 multiple holes, and the steps are repeated for 3 times. The negative control group is a culture medium solution containing a proper amount of DMSO, and the blank control group is a culture medium and a solvent which do not contain cells. The 96-well plate was returned to the incubator and exposed for 72h at 37 ℃.
③ color development and IC50Is calculated by
After 72h, 20. mu.L of MTT solution (5g/L) was added to each well in the dark, incubation was continued for 4h, the supernatant was discarded, 150. mu.L of DMSO was added to each well, the mixture was placed on a shaker and shaken at a slow speed for 10min to dissolve formazan sufficiently, and then OD at a wavelength of 570nm was measured using a microplate reader.
IC by using improved Kouya method50=log-1[Xm-i(∑P-0.5)]A calculation was performed wherein Xm: a designed logarithm of maximum concentration; i: log of each concentration multiple concentration; e, sigma P: sum of growth inhibition rates of each group; 0.5: an empirical constant. By repeating the experiment three times, 3 ICs were calculated50The values (two decimal places were retained) were averaged to obtain the IC of the compound Y obtained in example 1 of the present invention50The value was 0.9. mu.M.
The results show that the polybibenzyl compound has obvious inhibitory activity on the proliferation of lung cancer cells, can be used for treating and/or preventing lung cancer, and has good clinical application prospect.
Example 3 Activity assay of Polybibenzyl Compounds of the invention against acute monocytic leukemia MV4-11
(ii) inoculation of cells
Digesting cells in logarithmic growth phase by 0.25% pancreatin, preparing single cell suspension by using cell culture medium containing 10% FBS, counting by using cell counting plate, inoculating MV4-11 cells in good state into 96-well plate, and making cell density be 2 × 104Each well was filled with 100. mu.L of cell suspension, incubated at 37 ℃ with 5% CO2Culturing in an incubator for 24 h.
② treatment with drugs
Starting from 20. mu.g/mL of each sample, the samples were diluted with a gradient of medium, 2-fold diluted, 5 drug concentrations were set, and duplicate wells were tested for each concentration. The drug is added into each hole with the concentration of 20, 10, 5, 2.5 and 1.25 mug/mL for 100 mug L, each concentration is provided with 3 multiple holes, and the steps are repeated for 3 times. The negative control group is a culture medium solution containing a proper amount of DMSO, and the blank control group is a culture medium and a solvent which do not contain cells. The 96-well plate was returned to the incubator and exposed for 72h at 37 ℃.
③ color development and IC50Is calculated by
After 72h, 20. mu.L of MTT solution (5g/L) was added to each well in the dark, incubation was continued for 4h, the supernatant was discarded, 150. mu.L of DMSO was added to each well, the mixture was placed on a shaker and shaken at a slow speed for 10min to dissolve formazan sufficiently, and then OD at a wavelength of 570nm was measured using a microplate reader.
IC by using improved Kouya method50=log-1[Xm-i(∑P-0.5)]A calculation was performed wherein Xm: a designed logarithm of maximum concentration; i: log of each concentration multiple concentration; e, sigma P: sum of growth inhibition rates of each group; 0.5: an empirical constant. By repeating the experiment three times, 3 ICs were calculated50The values (two decimal places were retained) were averaged to obtain I of the compound Y obtained in example 1 of the present inventionC50The value was 13.2. mu.M.
The results show that the polybibenzyl compound has obvious inhibitory activity on the proliferation of acute single leukemia cells, can be used for treating and/or preventing acute leukemia, and has good clinical application prospect.
In conclusion, the polybibenzyl compound of the present invention has a great difference in structure compared to the existing bibenzyl compounds; in addition, the polybibenzyl compound has a new drug effect: the polybibenzyl compound has good inhibition effect on tumor cells, particularly on lung cancer cells, and has obvious inhibition activity on the proliferation of acute monoleukemia cells; meanwhile, the preparation method of the polybibenzyl compound is simple and convenient, mild in reaction conditions, convenient to operate and control, low in energy consumption, high in yield, low in cost and very suitable for industrial production.
Claims (10)
1. A compound represented by formula I or a pharmaceutically acceptable salt, crystal form, solvate thereof:
wherein,
R1、R2、R3、R4、R5、R6、R7、R8each independently selected from H, hydroxyl, sulfydryl and C1~C4Alkyl or C1~C4An alkoxy group.
2. The compound according to claim 1, or a pharmaceutically acceptable salt, crystalline form, solvate thereof, wherein: r1、R3、R5、R8Are each independently selected from C1~C4Alkyl or C1~C4An alkoxy group; r2、R4、R6、R7Each independently selected from H, hydroxy or mercapto.
3. The compound according to claim 2, or a pharmaceutically acceptable salt, crystalline form, solvate thereof, wherein: r1、R3、R5、R8Each independently selected from methoxy, ethoxy, n-propoxy or isopropoxy; r2、R4、R6、R7Each independently selected from hydroxyl or thiol.
4. The compound according to claim 3, or a pharmaceutically acceptable salt, crystalline form, solvate thereof, wherein: the compound is
5. A process for preparing compound Y, characterized in that: it comprises the following steps:
i. extracting rhizoma Bletillae with ethanol to obtain ethanol extractive solution;
ii. Taking the ethanol extract, and concentrating to obtain a fluid extract;
iii, dispersing the fluid extract with water, sequentially extracting with ethyl acetate and n-butanol, combining ethyl acetate parts, and recovering the solvent to obtain an ethyl acetate extract;
iv, taking the ethyl acetate extract, and performing gradient elution by adopting silica gel column chromatography by sequentially using petroleum ether-acetone as an eluent at a ratio of 100:1, 50:1 and 30:1 to obtain an eluent Fr.16 when the petroleum ether-acetone is 30: 1;
v, performing gradient elution on reverse-phase polystyrene resin columns on Fr.16 by using ethanol-water of 10:90, 30:70, 50:50, 70:30, 90:10 and 100:0 as eluent in sequence to obtain Fr.16-j when the ethanol-water of 100: 0;
vi, subjecting the Fr.16-j to a sephadex chromatographic column, and sequentially eluting by using dichloromethane-methanol (1: 1) as an eluent, wherein the eluent has the volume of 0.8 time of the column volume and 2.2 times of the column volume to obtain Fr.16-j-1 and Fr.16-j-2 respectively;
vii and Fr.16-j-2, eluting with silica gel column chromatography sequentially with dichloromethane-methanol (1: 0), 200:1 and 100:1 as eluent for 3 column volumes respectively, recovering solvent, and collecting Fr.16-j-2c when dichloromethane-methanol (100: 1);
viii, fr.16-j-2c by preparative thin layer chromatography using dichloromethane-acetone 20:1 as developing agent, RfSamples were obtained and then separated by reverse phase high performance liquid chromatography eluting with methanol-water 78:22 as eluent, detection was performed at 210nm wavelength and fractions collected for 28min to give compound Y.
6. The process for preparing compound Y according to claim 5, wherein:
in the step iv, the amount of the ethyl acetate extract is 155-165 g, and the conditions of gradient elution are as follows:
in the step v, the amount of Fr.16 is 15-20 g, and gradient elution conditions are as follows:
7. use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, crystal form or solvate thereof in the preparation of a medicament for the treatment and/or prevention of a tumour.
8. Use according to claim 7, characterized in that: the tumor is lung cancer and/or acute leukemia.
9. A pharmaceutical composition for treating and/or preventing tumors, which is characterized in that: the compound or pharmaceutically acceptable salt, crystal form and solvate thereof according to any one of claims 1 to 4 are used as an active ingredient, and are added with pharmaceutically common auxiliary materials to prepare the preparation.
10. The pharmaceutical composition of claim 9, wherein: the tumor is lung cancer and/or acute leukemia.
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CN103933350A (en) * | 2012-12-31 | 2014-07-23 | 成都中医药大学 | Use of rhizoma bletillae ethyl acetate extract |
CN105001064A (en) * | 2015-07-10 | 2015-10-28 | 浙江中医药大学 | Bletilla striata fibrous root blestriarene A and preparation method and application thereof |
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CN103933350A (en) * | 2012-12-31 | 2014-07-23 | 成都中医药大学 | Use of rhizoma bletillae ethyl acetate extract |
CN105001064A (en) * | 2015-07-10 | 2015-10-28 | 浙江中医药大学 | Bletilla striata fibrous root blestriarene A and preparation method and application thereof |
Non-Patent Citations (2)
Title |
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JIA-QUAN FENG等: "Novel Bibenzyl Derivatives from the Tubers of Bletilla striata", 《HELVETICA CHIMICA ACTA》 * |
仰莲等: "白及的化学成分及生物活性研究进展", 《中药与临床》 * |
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