CN107955060B - Limonin compound and its dimer - Google Patents
Limonin compound and its dimer Download PDFInfo
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- CN107955060B CN107955060B CN201610975533.0A CN201610975533A CN107955060B CN 107955060 B CN107955060 B CN 107955060B CN 201610975533 A CN201610975533 A CN 201610975533A CN 107955060 B CN107955060 B CN 107955060B
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
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Abstract
The present invention relates to a kind of limonin compound and its dimers.Specifically, the present invention discloses a kind of structure limonin compound as shown in formula (I) and structure limonin dimer as shown in (IIa) or (IIb), and the definition of each group is detailed in specification in formula.The invention also discloses their preparation method and purposes.
Description
Technical field
The invention belongs to natural product fields.In particular it relates to a kind of limonin compound and its dimer,
Further relate to preparation method and application.
Background technique
Mangrove is a kind of salt-tolerant plant group for being grown in the torrid zone, subtropical zone ocean intertidal zone.The existing mangrove in the whole world
84 kinds of plant, true mangrove and semi-ma ngrove two major classes can be divided into.Wherein 70 kinds of true mangrove plants, 14 kinds of mangrove associates [1].The whole world
The mangrove for belonging to Meliaceae only has the category of true mangrove plants xylocarpus granatum one.According to the literature, Xylocarpus Koenig mangrove is main
Secondary metabolite is limonin.Limonin is a kind of highly oxidized four drops triterpene compound, is primarily present in chinaberry
In the plants such as section, Rutaceae, Simarubaceae and Cneoraceae.Such compound is by with 4,4,8- trimethyl -17- furans steroidal
The precursor of skeleton is derived by a series of oxidation rearrangement.Limonin mainly have food refusal, desinsection, antibacterial, antimalarial and
The multiple biological activities such as anticancer.
Limonoid is highly oxidized terpenoid, and it is changeable that structure is complicated, passes through the side of organic synthesis
Method obtain it is very difficult, therefore, it is now discovered that limonin compound be mostly natural products.Meanwhile limonoid
Separation identification work starting it is also later, from nineteen sixty, David A.H.Taylor et al. is to Angola Africa chinaberry
The research of the limonoid of (Entandrophragma angolense C.DC) rises, and people are to Meliaceae plant origin
The research of limonin just start to rise.The same with most of secondary metabolites, limonin content in plant is usual
It is lower, it to obtain largely, while the limonin compound for having preferable bioactivity need to largely be paid.
Summary of the invention
The object of the present invention is to provide a kind of limonin compound, and its preparation method and application.
It is a further object of the present invention to provide a kind of limonin dimer, and its preparation method and application.
First aspect present invention provides a kind of limonin compound, shown in structure such as formula (I)：
In formula, R1、R2It is each independently hydrogen, C1-C10 alkyl acyl, C1-C10 alkyl, unsubstituted or substituted C6-
C10 aryl, the substituent group are selected from the group：C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkyl acyl, C2-C5 alkenylacyl, not
Substituted benzoyl and by selected from chlorine, bromine, trifluoromethyl substituent group replaced benzoyl.
In another preferred example, R1、R2Be each independently hydrogen, C1-C6 alkyl acyl, C1-C6 alkyl, it is unsubstituted or
Substituted phenyl.
In another preferred example, R1、R2It is each independently isobutyryl.
Second aspect of the present invention provides the preparation method of compound described in first aspect present invention, including step：From
It is extracted in the seed of mangrove Xylocarpus moluccensis and obtains the compound.
Third aspect present invention provides a kind of limonin dimer, and structure such as formula (IIa) or (IIb) are shown：
In various, R1、R2It is each independently hydrogen, C1-C10 alkyl acyl, C1-C10 alkyl, unsubstituted or substituted
C6-C10 aryl, the substituent group are selected from the group：C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkyl acyl, C2-C5 alkenyl acyl
Base, unsubstituted benzoyl and by selected from chlorine, bromine, trifluoromethyl substituent group replaced benzoyl.
In another preferred example, R1、R2Be each independently hydrogen, C1-C6 alkyl acyl, C1-C6 alkyl, it is unsubstituted or
Substituted phenyl.
In another preferred example, R1、R2It is each independently isobutyryl.
Fourth aspect present invention provides the preparation method of limonin dimer described in third aspect present invention, including
Step：In atent solvent, in the presence of an oxidizer, compound (I) is subjected to polymerization reaction, to form compound (IIa)
With compound (IIb)；
In various, R1、R2It is as defined above.
In another preferred example, the atent solvent is selected from the group：CH2Cl2、CH3CN, MeOH, EtOH, CHCl3、
CH3COCH3、AcOH、CH3COOCH2CH3、H2O, DMSO, and combinations thereof.
In another preferred example, the oxidant is selected from the group：MnO2、Ag2O、FeCl3·6H2O, cerous nitrate (IV) ammonium
(CAN) and the chloro- 5,6- dicyano benzoquinone (DDQ) of 2,3- bis-；And/or the equivalent proportion of the oxidant and compound (I) is 1：1
~1：2 (preferably, be 1：1~1：1.2).
In another preferred example, the temperature of the polymerization reaction is room temperature；And/or the time of the polymerization reaction is 1-12
Hour is (preferably, be 2-6 hours；More preferably, it is 3-4 hours).
Fifth aspect present invention provides limonin compound described in first aspect present invention or third party of the present invention
The purposes of limonin dimer described in face is used to prepare treating cancer or inhibits the pharmaceutical composition of cancer cell growth.
In another preferred example, the cancer is selected from the group：Melanoma, gastric cancer, colorectal cancer, lung cancer, breast cancer,
And combinations thereof.
In another preferred example, the cancer cell is selected from the group：A375,AGS,HCT-8,HCT-8/T,A549,MDA-
MB-231, SKBR3, MB453, MCF-7, MCF-7/ADR, and combinations thereof.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Detailed description of the invention
Fig. 1 is the HR-ESI of compound 1.
Fig. 2A is the HNMR (deuterated chloroform, 400MHz) of compound 1.
Fig. 2 B is the HNMR (deuterated DMSO, 400MHz) of compound 1.
Fig. 3 A is the CNMR (deuterated chloroform, 100MHz) of compound 1.
Fig. 3 B is the CNMR (deuterated DMSO, 100MHz) of compound 1.
Fig. 4 is the HR-ESI of compound 2a.
Fig. 5 is the HNMR (deuterated chloroform, 400MHz) of compound 2a.
Fig. 6 is the CNMR (deuterated chloroform, 100MHz) of compound 2a.
Fig. 7 is the HR-ESI of compound 2b.
Fig. 8 is the HNMR (deuterated chloroform, 400MHz) of compound 2b.
Fig. 9 is the CNMR (deuterated chloroform, 100MHz) of compound 2b.
Figure 10 is the HMBC (deuterated DMSO, 400MHz) of compound 1.
Figure 11 is the HMBC (deuterated chloroform, 400MHz) of compound 1.
Figure 12 is the HMBC (deuterated chloroform, 400MHz) of compound 2a.
Figure 13 is the HMBC (deuterated chloroform, 400MHz) of compound 2b.
Specific embodiment
The present inventor extracts from mangrove a kind of with high anti-cancer after extensive and in-depth study, unexpectedly
Active limonin compound, and further by artificial synthesized method be made it is a kind of with specific rotating configurations and
With the active limonin dimer of high anti-cancer.On this basis, inventor completes the present invention.
Term
As used herein, term " C1-C10 alkyl " refers to the alkyl of branch or straight chain with 1-10 carbon atom, art
Language " C1-C6 alkyl " refers to that the alkyl of branch or straight chain with 1-6 carbon atom, term " C1-C5 alkyl " refer to 1-5
The branch of a carbon atom or the alkyl of straight chain.Specific example may include methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl
The similar group such as base, amyl, hexyl.
As used herein, term " C6-C10 aryl " refers to that the aryl with 6-10 carbon atom, specific example can wrap
Include the similar group such as phenyl, naphthalene.
As used herein, term " C2-C5 alkenyl " refers to the alkenyl of branch or straight chain with 2-5 carbon atom, specifically
Example can be the similar group such as vinyl, acrylic, cyclobutenyl, methylpropenyl, isopentene group.
As used herein, term " C2-C5 alkyl acyl " refers to the alkyl acyl of branch or straight chain with 2-5 carbon atom
Base, specific example can be the similar group such as acetyl group, propiono, bytyry, isobutyryl.
As used herein, term " C2-C5 alkenylacyl " refers to the alkenyl acyl of branch or straight chain with 2-5 carbon atom
Base, specific example can be the similar group such as methylacryloyl, crotonyl；
As used herein, described " by benzoyl replaced the substituent group of chlorine, bromine, trifluoromethyl is selected from " can be
2 '-chlorobenzene formacyls, 2 '-benzoyl bromides, 2 '-trifluoromethylbenzoyl, 4 '-chlorobenzene formacyls, 4 '-benzoyl bromides,
4 '-trifluoromethylbenzoyl.
Limonin compound and preparation method thereof
Limonin compound of the invention, shown in structure such as formula (I)：
In formula, R1、R2It is each independently hydrogen, C1-C10 alkyl acyl, C1-C10 alkyl, unsubstituted or substituted C6-
C10 aryl, the substituent group are selected from the group：C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkyl acyl, C2-C5 alkenylacyl, not
Substituted benzoyl and by selected from chlorine, bromine, trifluoromethyl substituent group replaced benzoyl.
In another preferred example, R1、R2Be each independently hydrogen, C1-C6 alkyl acyl, C1-C6 alkyl, it is unsubstituted or
Substituted phenyl.
In another preferred example, R1、R2It is each independently isobutyryl.
In another preferred example, the substituent group is selected from the group：Methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl
Base, isopentene group, acetyl group, propiono, bytyry, isobutyryl, methylacryloyl, crotonyl, benzoyl, 2 '-
Chlorobenzene formacyl, 2 '-benzoyl bromides, 2 '-trifluoromethylbenzoyl, 4 '-chlorobenzene formacyls, 4 '-benzoyl bromides, 4 '-
Trifluoromethylbenzoyl.
The compound can be prepared by following methods.
E.g., including step：It is extracted from the seed of mangrove Xylocarpus moluccensis and obtains describedization
Close object.
Specifically, for example including step：
(1) use ethyl alcohol (such as 95% in the seed of mangrove Xylocarpus moluccensis (preferably drying)
Ethyl alcohol) it impregnated, extracted, extracting solution merges and is concentrated, to obtain the first coarse extract；
(2) it after mixing the first coarse extract and water, is extracted with ethyl acetate, organic phase merges and is concentrated, to obtain the
Two coarse extracts；
(3) silica gel (preferably 100-200 mesh) second coarse extract of column chromatographic isolation and purification is used, the compound is obtained.
In step (1), the immersion, extraction carry out at room temperature.
It is described to impregnate each 20-60 hours (preferably 24-50 hours in step (1)；It is more preferably 48 hours).
It is described to impregnate, extract progress 3-8 times (preferably 4-6 times) in step (1).
In step (2), the extraction carries out 3-8 times (preferably 4-6 times).
In step (3), the column chromatography chloroform-methanol system gradient elution；Preferably, the gradient is 100:0-
5:1 (chloroform:Methanol).
The compound may also pass through recrystallization.For example, with acetone and recrystallizing methanol.Wherein, acetone and methanol
Usage ratio is 2：1.
Limonin dimer and preparation method thereof
Limonin dimer of the invention, structure such as formula (IIa) or (IIb) are shown：
In various, R1、R2It is as defined above.
The limonin dimer can be prepared via a method which to obtain,
E.g., including step：In atent solvent, in the presence of an oxidizer, compound (I) is subjected to polymerization reaction, from
And form compound (IIa) and compound (IIb).
The atent solvent can be selected from the following group：CH2Cl2、CH3CN, MeOH, EtOH, CHCl3、CH3COCH3、AcOH、
CH3COOCH2CH3、H2O, DMSO, and combinations thereof.
The oxidant can be selected from the following group：MnO2、Ag2O、FeCl3·6H2O, cerous nitrate (IV) ammonium (CAN) and 2,3- bis-
Chloro- 5,6- dicyano benzoquinone (DDQ).
The equivalent proportion of the oxidant and compound (I) is 1：1~1：2 (preferably, be 1：1~1：1.2).
The temperature of the polymerization reaction is room temperature.
The time of the polymerization reaction is 1-12 hours (preferably, being 2-6 hours；More preferably, it is 3-4 hours).
The polymerization reaction can carry out under nitrogen protection, can also not have to nitrogen protection.
The polymerization reaction can also carry out in the presence of auxiliary agent (such as TFA), naturally it is also possible to not add auxiliary agent.
Active constituent
As used herein, term " the compounds of this invention " refers to formula (I), formula (IIa) or (IIb) compound represented.
Pharmaceutical composition and method of administration
Since the compounds of this invention with excellent anticancer activity, the compounds of this invention and contains chemical combination of the present invention
Object is that the pharmaceutical composition of main active can be used for inhibiting cancer cell growth and for treating, preventing and alleviating cancer
Disease.The cancer is selected from the group：Melanoma, gastric cancer, colorectal cancer, lung cancer, breast cancer or combinations thereof.The cancer cell
It is selected from the group：A375, AGS, HCT-8, HCT-8/T, A549, MDA-MB-231, SKBR3, MB453, MCF-7, MCF-7/ADR,
Or combinations thereof.
Pharmaceutical composition of the invention is comprising the compounds of this invention within the scope of safe and effective amount and can pharmacologically receive
Excipient or carrier.Wherein " safe and effective amount " refers to：The amount of compound is enough to be obviously improved the state of an illness, and is unlikely to generate
Serious side effect.In general, pharmaceutical composition, which contains 0.5-2000mg the compounds of this invention/agent, more preferably contains 1-500mg
The compounds of this invention/agent.Preferably, described is " one " for a capsule or tablet.
" pharmaceutically acceptable carrier " refers to：One or more biocompatible solids or liquid filler or jello
Matter, they are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as combines
In object each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the drug effect of compound.Medicine
Acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, fibre on
Tie up plain acetic acid esters etc.), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame
Sesame oil, peanut oil, olive oil etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite), emulsifier (such as)、
Wetting agent (such as lauryl sodium sulfate), colorant, flavoring agent, stabilizer, antioxidant, preservative, apirogen water.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representative method of application includes
(but being not limited to)：Oral, duodenum, rectum, parenteral (intravenous, intramuscular or subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations
In type, reactive compound is mixed at least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with
Following compositions mixing：(a) filler or expanding material, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) it bonds
Agent, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizer, example
Such as, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates,
And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti
Pure and mild glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, talcum, calcium stearate, tristearin
Or mixtures thereof sour magnesium, solid polyethylene glycol, lauryl sodium sulfate,.In capsule, tablet and pill, dosage form also may include
Buffer.
Coating and shell material preparation can be used in solid dosage forms such as tablet, sugar-pill, capsule, pill and granule, such as casing and
Other materials well known in the art.They may include opacifying agent, also, reactive compound or compound in this composition
Release can discharge in certain a part in the digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material
And wax material.When necessary, reactive compound can also be with one of above-mentioned excipient or a variety of formation microencapsulation forms.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture.
In addition to active compounds, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase
Solvent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethyl formyl
The mixture of amine and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances
Deng.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste
Agent, corrigent and fragrance.
In addition to active compounds, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene
Sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
The dosage form of the compounds of this invention for local administration includes ointment, powder, patch, stock solution and inhalant.
Active constituent aseptically with physiologically acceptable carrier and any preservative, buffer, or when necessary may need
Propellant be mixed together.
The compounds of this invention can be administered alone, or be administered in combination with other pharmaceutically acceptable compounds.
It is the mammal that the compounds of this invention of safe and effective amount is applicable to treatment when using pharmaceutical composition
(such as people), wherein dosage is the effective dosage pharmaceutically thought when application, for the people of 60kg weight, day is to medicament
Amount is usually 0.5~2000mg, preferably 1~500mg.Certainly, specific dosage is also contemplated that administration route, patient health situation etc.
Factor, within the scope of these are all skilled practitioners technical ability.
Advantages of the present invention mainly includes：
1. the present invention provides a kind of limonin compound, with good anticancer activity.
2. the present invention provides the isolation and purification method of above-mentioned limonin compound, this method is easy to operate and product
High income.
2. the present invention further synthesize by above-mentioned limonin compound obtained it is a kind of active with high anti-cancer
Limonin dimer.
Below with reference to specific implementation, the present invention is further explained.It should be understood that these embodiments be merely to illustrate the present invention and
It is not used in and limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition,
Or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.The present invention is implemented
Raw materials used or instrument in example, if not it illustrates, it is commercially available.
The preparation of 1 compound 1 of embodiment
1 instrument and material
Half preparative high-performance liquid chromatographic instrument (Waters, US) of Waters 2535Q, 2489 binary channels of Waters are purple
Outer visible light detector (Waters, US), III 400 type nuclear magnetic resonance chemical analyser (Switzerland Bruker of Bruker AVANCE
Company), amaZon SL ion trap electrospray mass spectrometer (German Bruker Daltonics company).Purification on normal-phase silica gel (100~200
Mesh) it is Haiyang Chemical Plant, Qingdao's product, reverse phase silica gel (C18) is Japan's YMC Products, and acetonitrile, methanol are chromatographically pure (Germany
Merck company), other reagents are that analysis is pure.
The seed of mangrove Xylocarpus moluccensis (X.moluccensis) is collected in in August, 2009
India An Delabang Godavari Mangrove Wetlands.By Tirumani Satyanandamurty (Government Degree
College at Amadala valasa, Srikakulam District, Andhra Pradesh, India) identification.
2 experimental sections
Dry X.moluccensis seed 6.0kg, after crushing with 95% ethyl alcohol extract at room temperature five times (5 ×
20L), it impregnates 48 hours every time.Extracting solution merging is concentrated under reduced pressure to give coarse extract 1100.0g.Coarse extract adds water to be suspended, and then uses
Ethyl acetate extracts five times, and ethyl acetate extraction part 520.0g is concentrated under reduced pressure to obtain.
Acetic acid ethyl ester extract (320.0g) is chromatographed through positive silica gel (100-200 mesh) column, chloroform-methanol system gradient
(100:0-5:1) it elutes, 262 fractions is obtained.Fraction 12-21 merges (63.8g), through acetone/methanol (2:1) it crystallizes to change
It closes object 1 (1.9g).HR-ESI, HNMR, CNMR data of compound 1 are respectively as shown in Fig. 1-Fig. 3 B；HMBC data such as Figure 10-figure
Shown in 11.
1. compound 1 of table1H (400MHz) with13C NMR (100MHz) data (δ：ppm,J：Hz)
aDMSO-d6；bCDCl3；cThe signal of overlapping accumulation is confirmed by HMBC spectrogram.
The preparation of 2 compound of embodiment, 1 dimer
1 experimental section
DDQ (80.9mg, 0.36mmol) is added to the methanol solution (80mL) of compound 1 (197mg, 0.30mmol).Instead
Answer mixture that 3.5h is stirred at room temperature.Then, concentrated reaction mixture and purified with preparative HPLC (YMC-Pack 250 ×
10mm i.d.), obtain product 2a (58.6mg, MeCN/H2O,70:30),2b(18.9mg,MeCN/H2O,80:20, and contain
0.3%AcOH).
In formula, R is isobutyryl.
HR-ESI, HNMR, CNMR data of compound 2a and 2b are respectively as shown in Fig. 4-Fig. 9；HMBC data such as Figure 12-figure
Shown in 13.
Table 2. compound 2a's and 2b1H NMR (400MHz) and13C NMR(100MHz)(δ：Ppm, J：Hz), solvent：
CDCl3
aOverlapped signal is identified by HMBC.
bProduct 2a is the dimer of (M)-conformation, and product 2b is the isomers of (P)-conformation.Rotational conformations pass through circular dichroism
(ECD) measurement is composed, is compared with known determining conformational analogs and quantum chemistry calculation confirms.
2 discuss part
The different oxidants of the cross-coupling for compound 1, including AgO/HNO are investigated3、Mn(OAc)3、MnO2、
Ag2O, metachloroperbenzoic acid (mCPBA), FeCl3·6H2O, cerous nitrate (IV) ammonium (CAN) and the chloro- 5,6- dicyan of 2,3- bis-
Base benzoquinones (DDQ).Available product 2a when having been surprisingly found that DDQ as oxidative coupling reagent, and this method obtains simultaneously
(M)-conformation dimeric structure product 2a and (P)-conformation isomer products 2b.And strong oxidizer FeCl3·6H2O、Ag2O and
CAN is unable to get result of the compound 2a and 2b as primary product.As for other three kinds of oxidants, AgO/HNO3、Mn(OAc)3
It does not react with mCPBA.
In addition the solvent of the oxidation cross-coupling of compound 1 of the DDQ as oxidative coupling reagent when has been investigated.As a result it sends out
It is existing：When solvent is 1,4- dioxane, acetone, DMSO, CH3NO2Or when AcOH, it is unable to get desired product.When solvent is
CH2Cl2、CH3When CN or MeOH, available compound 2a and 2b.Finally find CH3OH is optimal.
In selection CH3After OH is as solvent, the influence of the usage amount of DDQ has also been investigated.As a result, it has been found that：When DDQ is less than 1.0
When equivalent, reaction can not be fully finished.However, products collection efficiency can not be further increased when DDQ is more than 1.2 equivalents.Cause
This, is enough to complete reaction using the DDQ of 1.2 equivalents.
The final reaction is in CH3In OH, DDQ (1.2 equivalent) is used as oxidant, completes at room temperature.
In addition, experimenter is also added to auxiliary agent (such as CF in the reaction system3CO2H (TFA), as a result, it has been found that experiment knot
Fruit is basically unchanged.
In addition, experimenter also carries out reaction under nitrogen protection, as a result, it has been found that experimental result is basically unchanged.
3 MTT cell toxicity test of embodiment
Following human tumor cell line is used in MTT cell toxicity test：Melanoma A375, gastric cancer AGS, colorectum
Cancer (HCT-8 and HCT-8/T), lung cancer A549, breast cancer (MDA-MB-231, SKBR3, MB453, MCF-7, MCF-7/ADR) into
Measurement is gone.
By all cell lines at 37 DEG C, 5%CO2Wet atmosphere in have 10% fetal calf serum, parasiticin
Culture is adherent monolayer in culture bottle in the DMEM culture medium of (50kU/L) and streptomysin (50mg/L).Use trypsase
Cell is collected, and with 5 × 104The final concentration of/mL is resuspended.100 microlitres of aliquots of each cell suspending liquid are equably divided
It is fitted in 96 orifice plates that (cell number in every hole is 5 × 103).With the specified hole of the compound processing of various concentration.After 72 hours,
10 μ L (5mg/mL) of MTT solution is added in each hole, and plate is further incubated for 4 hours, make living cells by yellow MTT also
Original is dissolved in DMSO100 μ L at navy blue first a ceremonial jade-ladle, used in libation crystal.It is surveyed by microplate (Biotek, VT, USA) in 490nm
Determine the absorbance in single hole.Concentration (the IC for inhibiting 50% growth required is calculated from cytotoxicity curve by Bliss method50
Value, unit：μM).Cis-platinum is used as positive control.Test result is referring to table 3.
Table 3
MCF-7/ADR：Persister, height expression P-gp；MCF-7：It repeats
In addition, experimenter also tests compound 2b, as a result, it has been found that, compound 2b has one to above-mentioned cell line
Fixed effect, but relatively 2a is weak.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (10)
1. a kind of limonin compound, shown in structure such as formula (I)：
In formula, R1、R2It is each independently isobutyryl.
2. the preparation method of compound as described in claim 1, which is characterized in that including step：From mangrove
It is extracted in the seed of Xylocarpus moluccensis and obtains the compound.
3. a kind of limonin dimer, structure such as formula (IIa) or (IIb) are shown：
In various, R1、R2It is each independently isobutyryl.
4. a kind of preparation method of limonin dimer as claimed in claim 3, which is characterized in that including step：Lazy
Property solvent in, in the presence of an oxidizer, by compound (I) carry out polymerization reaction, to form compound (IIa) and compound
(IIb)；
In various, R1、R2Definition as claimed in claim 3,
The atent solvent is selected from the group：CH2Cl2、CH3CN, MeOH, EtOH, CHCl3、CH3COOCH2CH3、H2O, and combinations thereof；
The oxidant is selected from the group：MnO2、Ag2O、FeCl3·6H2O, cerous nitrate (IV) ammonium and the chloro- 5,6- dicyan of 2,3- bis-
Base benzoquinones.
5. preparation method as claimed in claim 4, which is characterized in that the equivalent proportion of the oxidant and compound (I) is 1：1
~1：2.
6. preparation method as claimed in claim 4, which is characterized in that the temperature of the polymerization reaction is room temperature.
7. preparation method as claimed in claim 4, which is characterized in that the time of the polymerization reaction is 1-12 hours.
8. the purposes of limonin compound as described in claim 1 or limonin dimer as claimed in claim 3,
It is characterized in that, being used to prepare treating cancer or inhibiting the drug of cancer cell growth.
9. purposes as claimed in claim 8, which is characterized in that the cancer is selected from the group：Melanoma, gastric cancer, colon are straight
Intestinal cancer, lung cancer, breast cancer, and combinations thereof.
10. purposes as claimed in claim 8, which is characterized in that the cancer cell is selected from the group：A375,AGS,HCT-8,
HCT-8/T, A549, MDA-MB-231, SKBR3, MB453, MCF-7, MCF-7/ADR, and combinations thereof.
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| CN201610975533.0A CN107955060B (en) | 2016-11-07 | 2016-11-07 | Limonin compound and its dimer |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1513853A (en) * | 2003-08-07 | 2004-07-21 | 中国科学院南海海洋研究所 | Limonin compound-wood fruit chinaberry lactone and its use |
| JP2012184195A (en) * | 2011-03-04 | 2012-09-27 | Chiba Univ | Xylogranin a and xylogranin b |
| CN103864876A (en) * | 2012-12-18 | 2014-06-18 | 中国科学院上海药物研究所 | Xylogranatumin G and preparation method and application thereof |
-
2016
- 2016-11-07 CN CN201610975533.0A patent/CN107955060B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1513853A (en) * | 2003-08-07 | 2004-07-21 | 中国科学院南海海洋研究所 | Limonin compound-wood fruit chinaberry lactone and its use |
| JP2012184195A (en) * | 2011-03-04 | 2012-09-27 | Chiba Univ | Xylogranin a and xylogranin b |
| CN103864876A (en) * | 2012-12-18 | 2014-06-18 | 中国科学院上海药物研究所 | Xylogranatumin G and preparation method and application thereof |
Non-Patent Citations (5)
| Title |
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| Moluccensins A-G, phragmalins with a conjugated C-30 carbonyl group from a krishna mangrove, xylocarpus moluccensis;Min-Yi Li;《Journal of natural products》;20090910;第72卷(第9期);第1657-1662页 * |
| Protolimonoids and limonoids from the Chinese mangrove plant Xylocarpus granatum;Jianxin Cui;《Helvetica chimica acta》;20091231;第92卷(第1期);第139-150页 * |
| Thaixylomolins O–R: four new limonoids from the trang mangrove，Xylocarpus moluccensis;Yi-Guo Dai;《RSC Advances》;20160825;第6卷(第89期);第85978-85984页 * |
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| Xylomexicanins E-H, new limonoids from Xylocarpus granatum;Yi-Bing Wu;《Tetrahedron》;20140509;第70卷(第30期);第4557-4562页 * |
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