CN109970738A - A kind of sparteine N- isoflavone compound and preparation method and application - Google Patents
A kind of sparteine N- isoflavone compound and preparation method and application Download PDFInfo
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Abstract
The present invention relates to a kind of sparteine N- isoflavone compound and its preparation method and application, the structural formulas of the compound are as follows:Wherein, R1Selected from one of hydroxyl, alkoxy, amido or halogen, R2Selected from one of hydrogen, alkyl or aryl, R3It is combined selected from one or more of hydroxyl, alkoxy, amido or halogen.Compared with prior art, the present invention is spliced to isoflavone compound as structural unit on 12 N of sparteine by combinatorial compound technology, to synthesize a series of sparteine-isoflavone derivatives, plays new active pharmacological action.
Description
Technical field
The present invention relates to technical field of medicine synthesis, and in particular to a kind of sparteine N- isoflavone compound and its system
Preparation Method and application.
Background technique
Sparteine (cytisine) is in 1865 by Husemann and Marme from Cytisus Laburnum Med
Separated for the first time in seed, be distributed in more laburnum, Thermopsis, Cytisus, in sophora plant.The alkaloid, which has, to be increased
Heart tonifying myotility, enhancing locomitivity, improves the pharmacological actions such as cognitive function, antidepression, analgesia, antitumor at excited breathing,
The especially stronger anticancer activity of such compound.Sparteine belongs to piperazine alkaloid, structural modification in quinoline promise and concentrates on 12
The derivatization of position N, mainly there is alkylation, acylation, Benzylation, benzoyl, glycosylation etc..
Isoflavone compound (isoflavonoid) is a kind of compound that a kind of basic parent nucleus is 3- phenyl chromone,
Be widely present in leguminous plant and herbage etc. in, be a kind of Secondary metabolites.In recent decades, as the modern times separate
Technology and the development of structural research method, people's isolated various osajin chemical combination from plant or animal or marine organisms
Object, many researchs find that this kind of compounds have a variety of bioactivity and good pharmacological action, such as antitumor, anti-high blood
It is a kind of valuable that sugared, antimycotic, antiviral, anti-inflammatory, antioxidant and cardiovascular disease etc., which are a kind of valuable drugs,
Multiple bioactive molecules are keyed together by specified chemical using splicing strategy in Field of Drug Discovery, are people by drug
It finds novel bioactive molecule and opens the brand-new visual field.
Summary of the invention
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide a kind of sparteine N- is different
Flavone compound and preparation method and application.
The purpose of the present invention can be achieved through the following technical solutions: a kind of sparteine N- isoflavone compound,
The structural formula of the compound is as follows:
Wherein, R1Selected from one of hydroxyl, alkoxy, amido or halogen, R2Selected from one of hydrogen, alkyl or aryl,
R3It is combined selected from one or more of hydroxyl, alkoxy, amido or halogen.
Using 4.5 software of DISCOVERY STUDIO carry out molecular simulation, therefrom we it is concluded that, change of the invention
Adduct molecule is substantially at the active cavity center of HER2 receptor protein, by ASP26, PRO360, ALA233, HIS229,
Multiple ammonia residues such as LEU275 surround, and form stronger hydrophobic effect.These residues constitute HER2 around substrate molecule
The active pocket of albumen.Wherein substrate molecule 5-OH, 7-OH and ASP26, ALA233 amino acid residue form dihydrogen bond, are main
The pharmacophoric group wanted, therefore 5-OR2 is necessary for that the functional group of hydrogen bond can be formed with ASP26 amino acid residue.
The compound further includes salt corresponding to structure above, and the salt passes through the corresponding substance of structure above
Be made with inorganic acid or organic acid reaction, wherein the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, amidosulfonic acid or
One of phosphoric acid, the organic acid be selected from citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid,
Methanesulfonic acid, naphthalene sulfonic acids, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, three
Fluoroacetic acid, stearic acid, flutter acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, to amido benzene sulphur
One of acid, Aspirin or isethionic acid.
A kind of preparation method of sparteine N- isoflavone compound as described above, comprising the following steps:
(1) existMiddle addition N, N- dimethylformamide dimethyl acetal, reaction obtainThen it reacts and generates under the action of iodine
(2) step (1) is preparedWith it is commercially availableMixing,
Reaction is prepared
(3) step (2) is preparedWith sparteine, formalin in DMAP
Catalysis under, react up to described
Preferably, in step (1),Molal weight and N, N- dimethylformamide dimethyl acetal the ratio between volume
For 1mmol:(5~7) mL, reaction temperature is 70~80 DEG C, and the reaction time is 4~8h；With list
The molar ratio of matter iodine is 1:(1.1~2.0), reaction temperature is 10~35 DEG C, and the reaction time is 12~48h.
Preferably, in step (2),Molar ratio be 1:
(1.0~2.0), reaction temperature are 10~35 DEG C, and the reaction time is 4~8h.
Reaction using alkali and palladium acetate as catalyst, it is described
Alkali is sodium carbonate or potassium carbonate.
Preferably, in step (3),With the molar ratio of sparteine and formalin
For 1:(0.3~0.6): (0.4~0.8), reaction temperature are 60~80 DEG C, and the reaction time is 4~9h.
A kind of application of sparteine N- isoflavone compound as described above, the compound are used to prepare treatment tumour
Drug, such as breast cancer.
Compared with prior art, the beneficial effects of the present invention are embodied in following several respects:
(1) preparation method is efficient, easily operated, and product purity is high；
(2) migration of cancer cell can be effectively suppressed, there is good treatment of cancer effect.
Detailed description of the invention
Fig. 1 is the hydrogen spectrum of compound made from embodiment 1；
Fig. 2 is the carbon spectrum of compound made from embodiment 1；
Fig. 3 is the mass spectrum of compound made from embodiment 1；
Fig. 4 is that the compound that Examples 1 to 3 is prepared migrates MDA-MB-231 breast cancer cell under various concentration
The suppression result test chart of ability；
Fig. 5 be the compound that is prepared of Examples 1 to 3 under various concentration to 4T1 breast cancer cell transfer ability
Suppression result test chart；
Fig. 6 is compound made from embodiment 1 and HER2 receptor protein action diagram.
Specific embodiment
It elaborates below to the embodiment of the present invention, the present embodiment carries out under the premise of the technical scheme of the present invention
Implement, the detailed implementation method and specific operation process are given, but protection scope of the present invention is not limited to following implementation
Example.
Embodiment 1
The synthesis of compound CNF1, structural formula are as follows:
Preparation step is as follows:
(1) synthesis of 7- methoxymethyl ether -5- hydroxyl -3- iodine chromone；(2) synthesis of siskin isoflavonoid；(3) goldspink
Isoflavones and sparteine are with Mannich reaction synthesis object.
The specific process is as follows:
(1) K of 2.1 times of equivalents is added for raw material with 2,4,6- trihydroxy-acetophenones2CO3Selectivity makes 4,6 hydroxyls
Then separate out is added the chloromethyl methyl ether of 2.12 times of equivalents, obtains 2- hydroxyl -4,6- dimethyl methyl ether acetophenone, then
Be added N, N- dimethylformamide dimethyl acetal 74 DEG C at a temperature of with 88% yield synthesize ammonia ketenes, finally with a step simply at
The synthesis of 5,7- dimethyl methyl ether -3- iodine chromone is completed in ring reaction under the action of iodine with 75% yield.3- iodine color
Former ketone 4, which is dissolved in dichloro, to be placed on blender the dimethyl cellosolve for being sloughed 5 with moderate-speed mixer 4h and obtains 3- iodine chromone 5；Knot
The variation of structure formula is as follows:
(2) compound 5 and 6 synthesizes isoflavones 7 under Suzuki coupling reaction, and 7 methyl first are sloughed at 3MHCl
Ether sloughs methoxyl group under Boron tribromide later and obtains siskin isoflavonoid 9, and structural formula variation is as follows:
(3) sparteine and siskin isoflavonoid, formalin synthesize sparteine-N- methylene-under the catalysis of DMAP
(5,7,4 '-trihydroxy) isoflavones CNF1, structural formula variation are as follows:
Into isopropanol (5ml) solution of compound 9 (0.5mmol) be added sparteine (0.625mmol) and
Formalin (0.25ml, 37%), DMAP (1.2mg) place it in heating reaction 3h- in oil bath under a nitrogen
overnight.TCL monitors fully reacting, and flash column chromatography obtains compound CNF1.
The CNF1 being prepared is subjected to nuclear-magnetism and mass spectral analysis, obtained hydrogen is composed, carbon spectrum, mass spectrum are respectively such as Fig. 1,2,3
It is shown.
1H NMR (400MHZ, DMSO) cytisine protons:7.26 (1H, dd, J=6.8；8.8, H-4), 6.15
(1H, dd, J=1.6；9.2, H-3), 6.01 (1H, dd, J=1.2；7.2, H-5), 3.65,3.80 (2H, 2d, J=14.8,
CH2- 10), 2.84-3.04 (3H, m, H-11,13,7), 2.38-2.50 (3H, m, H-11,13,9), 1.70-1.83 (2H, m,
CH2-8).Isoflavone protons:8.18 (1H, s, H-2), 7.37 (2H, d, J=8.8, H-2', 6'), 6.81 (2H,
D, J=8.8, H-3 ', 5 '), 6.14 (1H, s, H-6), 3.68 (2H, s, CH2-8)。13C NMR (100MHZ, DMSO) 180.8,
164.1,162.6,161.2,157.8,155.8,154.1,151.8,139.1,130.6,122.4,121.6,116, 115.5,
104.5,104.3,100.8,98.9,59.9,59.3,55.3,50.5,49.8,34.8,27.7,25.2。 HRMS(ESI):m/z
=471.16 (calcd.471.16for C27H23N2O6[M-H]-).M.P.=237-239 DEG C.
Therefrom we can analyze out: can confirm its structure from above-mentioned hydrogen spectrum, carbon spectrum and mass spectrum is sparteine-N-
Methylene-(5,7,4 '-trihydroxy) isoflavone compounds, i.e. compound CNF1.
The CNF1 being prepared is subjected to molecular simulation, result such as Fig. 6 using 4.5 software of DISCOVERY STUDIO
It is shown, it can be seen from the figure that CNF1 molecule is substantially at the active cavity center of HER2 receptor protein, by ASP26,
Multiple ammonia residues such as PRO360, ALA233, HIS229, LEU275 surround, and form stronger hydrophobic effect.These residues are the bottom of at
Object surrounding molecules constitute the active pocket of HER2 albumen.Wherein substrate molecule 5-OH, 7-OH and ASP26, ALA233 amino acid
Residue forms dihydrogen bond, is main pharmacophoric group, therefore 5-OR2 is necessary for that the official of hydrogen bond can be formed with ASP26 amino acid residue
It can group.
Embodiment 2
The synthesis of compound CNF2, structural formula are as follows:
Wherein R1=OH, R2=H, R3=R4=OCH3.Specific preparation process is as follows:
(1) isoflavones intermediate is prepared, synthetic route is as follows:
It takes 19 compound of compound and 3,4- dimethoxyphenylboronic to carry out Suzuki coupling reaction and obtains isoflavones chemical combination
Object 21, specific steps:
By polyethylene glycol 10000 (21g) and Pd (OAc)2(0.025g, 0.11mmol) is added to containing sodium carbonate
In methanol (25ml) solution of (0.548g, 5.17mmol), but nitrogen under be placed in 50 DEG C oil bath under stirring until system become
After black, at once by compound 19 (0.820g, 2.17mmol) and 3,4- dimethoxyphenylboronic (1.395g, 5.41mmol)
Mixture be added in system.3h is reacted, TCL shows fully reacting.Water is added, PEG10000 is precipitated at solid, filters,
The solid being precipitated is washed with ethyl acetate, ethyl acetate cleaning solution and water phase are merged, and is extracted with ethyl acetate, organic layer is used
Anhydrous sodium sulfate is dry, solvent is removed under reduced pressure, rapid column chromatography (PE:EA=8:1) obtains compound as white solid 21 (93%)
Compound 21 (0.2g, 0.43mmol) is added in methanol solution, 3MHCl is added and is heated back flow reaction
2h, TCL monitor fully reacting.Water is added, and is extracted with dichloro, is successively washed with water, strong brine, anhydrous sodium sulfate is dried.Subtract
Pressure rotation goes solvent to obtain residue, rapid column chromatography (PE:EA=4:1) obtain white solid isoflavone compounds 21 (0.11mg,
91%)
(2) it is different to synthesize sparteine-N- methylene-under the catalysis of DMAP for sparteine and isoflavones 21, formalin
Flavones CNF2.
Into isopropanol (5ml) solution of compound 21 (0.5mmol) be added sparteine (0.625mmol) and
Formalin (0.25ml, 37%), DMAP (1.2mg) place it in heating reaction 3h- in oil bath under a nitrogen
overnight.TCL monitors fully reacting, and flash column chromatography obtains compound CNF2.
Embodiment 3
The synthesis of compound CNF3, structural formula are as follows:
Wherein R1=OH, R2=H, R3=H, R4=OCH3, specific preparation process is as follows:
(1) isoflavones intermediate is prepared, synthetic route is as follows:
Specific steps are same as above embodiment two substantially, and key intermediate is replaced with to methoxyphenylboronic acid, and synthesis condition omits
Adjustment, as shown in technology path,
(2) it is different to synthesize sparteine-N- methylene-under the catalysis of DMAP for sparteine and isoflavones 20, formalin
Flavones CNF3.
Specific steps are with embodiment two, and isoflavones replaces with compound 20, remaining is constant.
Pharmacological activity detection:
Tri- compound antitumor transfer activity experimental results of the above CNF1-CNF3:
Influence of three kinds of samples to transfer ability is studied using two kinds of tumour cells and cell scratch experiment model
The breast cancer MDA-MB-231 cell and uniform kind of breast cancer 4T1 cell for taking logarithmic growth state respectively exist
In Costar6 orifice plate, every hole final volume is 50% total volume, and cell density is controlled about 1.5 × 105A/ml.Every hole sets 3
Multiple holes, experiment are repeated 5 times.Supernatant is abandoned after cell will be paved with, it is standardized in the longitudinal direction of every hole bottom center with aseptic inoculation ring
Item simulates the straight line (impingement) of wound, measures wound sector width under microscope.It is cleaned 3 times with new culture medium, washes away floating
Cell stirs into the serum free medium of not drug containing in blank group.Sample is dissolved in serum free medium respectively, is added in experimental group
The solution of three kinds of compound samples, until final concentration of 10 μM, 30 μM and 90 μM.It crosses after sample-adding with negative control group
It takes pictures under microscope when will disappear and measures the width of impingement, computation migration distance, migration under each group impingement and microscope
Ratio (tumor cell migration distance/impingement original width).Three kinds of equal samples of compound can inhibit MDA-MB-231 cell
Migration, impingement tumor cell migration Distance Shortened, compared to the blank group, each administration group migration ratio be decreased obviously (* P <
0.05, * P < 0.01 *), and with the increase of compound dosage, migration ratio decline is bigger, illustrates that the inhibiting effect has dosage
Dependence (as shown in Figure 4).Three kinds of compound samples are to the transfer ability inhibitory effect of breast cancer 4T1 cell as shown in figure 5, moving
Ratio is moved to be decreased obviously.As can be seen that 3 kinds of compound antitumor cell migration effects connect with positive drug from Fig. 4 and Fig. 5
Closely, there is preferable external anti-breast cancer Nasopharyngeal neoplasms activity.
Claims (8)
1. a kind of sparteine N- isoflavone compound, which is characterized in that the structural formula of the compound is as follows:
Wherein, R1Selected from one of hydroxyl, alkoxy, amido or halogen, R2Selected from one of hydrogen, alkyl or aryl, R3Choosing
It is combined from one or more of hydroxyl, alkoxy, amido or halogen.
2. a kind of sparteine N- isoflavone compound according to claim 1, which is characterized in that the compound
It further include salt corresponding to structure above, the salt passes through the corresponding substance of structure above and inorganic acid or organic acid reaction
It is made, wherein the inorganic acid includes one of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, amidosulfonic acid or phosphoric acid, described organic
Acid selected from citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, naphthalene sulfonic acids, ethanesulfonic acid,
Naphthalenedisulfonic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, flutters acid, hydroxyl at maleic acid
Base maleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, para-anilinesulfonic acid, Aspirin or
One of isethionic acid.
3. a kind of preparation method of sparteine N- isoflavone compound as claimed in claim 1 or 2, which is characterized in that packet
Include following steps:
(1) existMiddle addition N, N- dimethylformamide dimethyl acetal, reaction obtainSo
It reacts and generates under the action of iodine afterwards
(2) step (1) is preparedWith it is commercially availableMixing, reaction
It is prepared
(3) step (2) is preparedIt is urged with sparteine, formalin DMAP's
Under change, react up to described
4. a kind of preparation method of sparteine N- isoflavone compound according to claim 3, which is characterized in that step
Suddenly in (1),Molal weight and the ratio between the volume of N, N- dimethylformamide dimethyl acetal be 1mmol:(5~7) mL,
Reaction temperature is 70~80 DEG C, and the reaction time is 4~8h；Molar ratio with iodine is 1:
(1.1~2.0), reaction temperature are 10~35 DEG C, and the reaction time is 12~48h.
5. a kind of preparation method of sparteine N- isoflavone compound according to claim 3, which is characterized in that step
Suddenly in (2),Molar ratio be 1:(1.0~2.0), reaction temperature
It is 10~35 DEG C, the reaction time is 4~8h.
6. a kind of preparation method of sparteine N- isoflavone compound according to claim 5, which is characterized in thatReaction using alkali and palladium acetate as catalyst, the alkali be carbonic acid
Sodium or potassium carbonate.
7. a kind of preparation method of sparteine N- isoflavone compound according to claim 3, which is characterized in that step
Suddenly in (3),It is 1:(0.3~0.6 with the molar ratio of sparteine and formalin): (0.4
~0.8), reaction temperature is 60~80 DEG C, and the reaction time is 4~9h.
8. a kind of application of sparteine N- isoflavone compound as claimed in claim 1 or 2, which is characterized in that the chemical combination
Object is used to prepare the drug for the treatment of tumour.
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| CN114315831A (en) * | 2021-12-22 | 2022-04-12 | 上海工程技术大学 | Novel symmetric cytisine type alkaloid compound and preparation and application thereof |
| WO2023241290A1 (en) * | 2022-06-13 | 2023-12-21 | 上海工程技术大学 | Pharmaceutical compound based on quinolizidine derivative, and preparation method therefor and use thereof |
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