CN108276394A - Daidzein derivative, preparation method and application - Google Patents
Daidzein derivative, preparation method and application Download PDFInfo
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- CN108276394A CN108276394A CN201810063297.4A CN201810063297A CN108276394A CN 108276394 A CN108276394 A CN 108276394A CN 201810063297 A CN201810063297 A CN 201810063297A CN 108276394 A CN108276394 A CN 108276394A
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- daidzein
- nitrogen heterocycle
- compound represented
- daidzein derivative
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- 229930017320 daidzein derivative Natural products 0.000 title claims abstract description 34
- 150000001950 daidzein derivatives Chemical class 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 35
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 125000001424 substituent group Chemical group 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 76
- ZQSIJRDFPHDXIC-UHFFFAOYSA-N daidzein Chemical compound C1=CC(O)=CC=C1C1=COC2=CC(O)=CC=C2C1=O ZQSIJRDFPHDXIC-UHFFFAOYSA-N 0.000 claims description 32
- 235000007240 daidzein Nutrition 0.000 claims description 16
- 239000002246 antineoplastic agent Substances 0.000 claims description 8
- 229940041181 antineoplastic drug Drugs 0.000 claims description 8
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 25
- 210000004881 tumor cell Anatomy 0.000 abstract description 12
- 230000009036 growth inhibition Effects 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 9
- 230000012010 growth Effects 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
- 0 C*(C*[n]1c(CC(C)=C)ncc1)Oc(cc1OC=C2c3ccc(*)cc3)ccc1C2=O Chemical compound C*(C*[n]1c(CC(C)=C)ncc1)Oc(cc1OC=C2c3ccc(*)cc3)ccc1C2=O 0.000 description 7
- 230000000259 anti-tumor effect Effects 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 229960002949 fluorouracil Drugs 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical class BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 150000002460 imidazoles Chemical class 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000000178 1,2,4-triazoles Chemical class 0.000 description 1
- -1 2- ethyl imidazol Chemical compound 0.000 description 1
- 150000008614 2-methylimidazoles Chemical class 0.000 description 1
- ULKLGIFJWFIQFF-UHFFFAOYSA-N 5K8XI641G3 Chemical class CCC1=NC=C(C)N1 ULKLGIFJWFIQFF-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010067572 Oestrogenic effect Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 235000021374 legumes Nutrition 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of Daidzein derivatives, as shown in formula (I), wherein R is nitrogen heterocycle or substituted nitrogen heterocycle；Substituent group is selected from the alkyl of C1~C10 in the substituted nitrogen heterocycle；N is the integer more than or equal to 1.Compared with prior art, Daidzein derivative provided by the invention has good growth inhibition effect to kinds of tumor cells, especially when n is 3, has higher inhibition growth activity for A549 cells, Hela cells and HepG2 three classes tumour cells.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology more particularly to a kind of Daidzein derivative, preparation method and answer
With.
Background technology
Cancer is that a kind of larger disease is threatened human health in modern society.The means and medicine of existing treating cancer
Object people cannot meet the appearance of actual demand, especially drug resistant tumor cells, accelerate the demand to anti-cancer drugs.
Daidzein is widely present in legume, studies have shown that daidzein and estrogen have similar structure
And molecular weight, it has estrogenic effect, can adjust the cell cycle, while having antioxidation, and daidzein
Possess the functions such as activity, antibacterial, anti-inflammatory, antiallergy, the anti-diabetic complication for inhibiting enzyme, to the tumour of the mankind, aging, the heart
The treatment and prevention of angiosis and certain moving back property row lesion class diseases are significant, therefore, to daidzein and its derivative
The research of object causes interest and the attention extensively of domestic and international chemist, drug scholar.
Invention content
Spread out in view of this, the technical problem to be solved in the present invention is to provide a kind of daidzein with anti-tumor activity
Biology, preparation method and application.
The present invention provides a kind of Daidzein derivatives, as shown in formula (I)：
Wherein, R is nitrogen heterocycle or substituted nitrogen heterocycle；Substituent group is selected from the substituted nitrogen heterocycle
The alkyl of C1~C10；N is the integer more than or equal to 1.
Preferably, the number of nitrogen-atoms is 2~3 in the nitrogen heterocycle.
Preferably, the nitrogen heterocycle is five-membered ring or hexatomic ring.
Preferably, the nitrogen heterocycle is selected from imidazole radicals or 1,2,4- triazol radicals.
Preferably, the substituent group in the substituted nitrogen heterocycle is selected from the alkyl of C1~C5.
Preferably, the integer that the n is 2~4.
Preferably, as shown in formula (I-1)~formula (I~5)：
Wherein, n1~n5It is each independently selected from 2~4 integer.
Preferably, as shown in formula (I-a)~formula (I~e)：
The present invention also provides a kind of preparation methods of Daidzein derivative, including：
S1 daidzein is reacted under alkaline condition with halogenated alkane shown in formula (II)), is obtained shown in formula (III)
Compound；
S2 the formula (III) compound represented is reacted under alkaline condition with formula (IV) compound represented), is obtained
Formula (I) compound represented；
Wherein, X is halogen；R is nitrogen heterocycle or substituted nitrogen heterocycle；It is taken in the substituted nitrogen heterocycle
Dai Ji is selected from the alkyl of C1~C10；N is the integer more than or equal to 1.
The present invention also provides above-mentioned Daidzein derivative application in preparations of anti-tumor drugs.
The present invention provides a kind of Daidzein derivatives, as shown in formula (I), wherein R is nitrogen heterocycle or substituted
Nitrogen heterocycle；Substituent group is selected from the alkyl of C1~C10 in the substituted nitrogen heterocycle；N is the integer more than or equal to 1.
Compared with prior art, Daidzein derivative provided by the invention makees kinds of tumor cells with good growth inhibition
With especially when n is 3, for A549 cells, Hela cells and HepG2 three classes tumour cells with higher inhibition growth
Activity.
Description of the drawings
Fig. 1 is that Daidzein derivative and antitumor drug 5 FU 5 fluorouracil evaluate the growth inhibition ratio of HeLa cells
Figure；
Fig. 2 is that Daidzein derivative and antitumor drug 5 FU 5 fluorouracil evaluate the growth inhibition ratio of HepG2 cells
Figure；
Fig. 3 is that Daidzein derivative and antitumor drug 5 FU 5 fluorouracil evaluate the growth inhibition ratio of A549 cells
Figure.
Specific implementation mode
Below in conjunction with the embodiment of the present invention, technical scheme in the embodiment of the invention is clearly and completely described,
Obviously, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based in the present invention
Embodiment, every other embodiment obtained by those of ordinary skill in the art without making creative efforts, all
Belong to the scope of protection of the invention.
The present invention provides a kind of Daidzein derivatives, as shown in formula (I)：
Wherein, R is nitrogen heterocycle or substituted nitrogen heterocycle；The number of nitrogen-atoms is preferred in the nitrogen heterocycle
It is 2~3；The nitrogen heterocycle is preferably five-membered ring or hexatomic ring；In the present invention, the nitrogen heterocycle is preferably imidazoles
Base or 1,2,4- triazol radicals.
Substituent group is the alkyl of C1~C10 in the substituted nitrogen heterocycle, the preferably alkyl of C1~C5, more preferably
It is further preferably methyl and/or ethyl for the alkyl of C1~C3.
N is the integer more than or equal to 1, and preferably 1~5 integer, more preferably 2~4 integer is further preferably 3.
According to the present invention, the Daidzein derivative is more preferably as shown in formula (I-1)~formula (I-5)：
Wherein, n1~n5It is each independently 2~4 integer.
According to the present invention, the Daidzein derivative is most preferably as shown in formula (I-a)~formula (I~e)：
Daidzein derivative provided by the invention has good growth inhibition effect to kinds of tumor cells, especially
When n is 3, there is higher inhibition growth activity for A549 cells, Hela cells and HepG2 three classes tumour cells.
The present invention also provides a kind of preparation methods of above-mentioned Daidzein derivative, including：
S1 daidzein is reacted under alkaline condition with halogenated alkane shown in formula (II)), is obtained shown in formula (III)
Compound；
S2 the formula (III) compound represented is reacted under alkaline condition with formula (IV) compound represented), is obtained
Formula (I) compound represented；
Wherein, X is halogen, preferably Br or Cl；R is nitrogen heterocycle or substituted nitrogen heterocycle；It is described substituted
Substituent group is selected from the alkyl of C1~C10 in nitrogen heterocycle；N is the integer more than or equal to 1；The R and n is same as above,
This is repeated no more.
Daidzein is reacted under alkaline condition with halogenated alkane shown in formula (II)；The daidzein and formula (II)
Shown in the molar ratio of halogenated alkane be preferably 1：(5~15), more preferably 1：(8~12) are further preferably 1：10；The alkalinity
Condition is preferably added to alkali compounds raising；The alkali compounds is that alkali compounds well known to those skilled in the art is
Can, special limitation is had no, is preferably bicarbonate, more preferably sodium bicarbonate and/or saleratus in the present invention；The alkali
Property compound and daidzein molar ratio be preferably (1.5~2.5)：1, more preferably 2：1；The reaction is preferred in the present invention
It carries out in organic solvent；The organic solvent is organic solvent well known to those skilled in the art, has no special limit
System is preferably acetone in of the invention；The ratio of the acetone and daidzein is preferably (50~200) ml：1g, more preferably
(50~150) ml：1g is further preferably 100ml：1g；The temperature of the reaction is preferably 50 DEG C~80 DEG C, more preferably 60 DEG C~
70 DEG C, be further preferably 65 DEG C；The time of the reaction is preferably 40~60h, more preferably 45~50h, is further preferably 48h.
After reaction, preferably product is detached from reaction system, again under these conditions by unreacted substance
Continue to react, repeats 3~4 separation, the collection of products of each reaction is purified；The method of the separation is ability
Method known to field technique personnel has no special limitation, petroleum ether, mistake is preferably added in the reaction system in the present invention
After filter, product is obtained.
The reaction equation of this step is as follows：
The formula (III) compound represented is reacted under alkaline condition with formula (IV) compound represented；The formula
(III) molar ratio of compound represented and formula (IV) compound represented is preferably 1：(1.5~2.5), more preferably 1：
(1.8~2.2) are further preferably 1：2；The alkaline condition is preferably added to alkali compounds offer；The alkali compounds is this
Alkali compounds known to field technology personnel has no special limitation, is preferably carbonate in the present invention, more preferably
Sodium carbonate and/or potassium carbonate；The molar ratio of the alkali compounds and formula (III) compound represented be preferably (1.5~
2.5)：1, more preferably 2：1；The reaction preferably carries out in organic solvent；The organic solvent is that those skilled in the art are ripe
The organic solvent known has no special limitation, is preferably acetone in the present invention；The temperature of the reaction is preferably 50 DEG C~
80 DEG C, more preferably 60 DEG C~70 DEG C, be further preferably 65 DEG C；The time of the reaction is preferably 40~60h, more preferably 45~
50h is further preferably 48h.
After reaction, it preferably filters, after solution is removed solvent, obtains crude product；The crude product preferably carries out water
It washes, column chromatography after purification, is made (I) compound represented；Column chromatography purifying eluent used is preferably dichloromethane
The mixed solution of alkane and methanol；The volume ratio of the dichloromethane and methanol is preferably 50：1.
The present invention also provides a kind of the answering in the preparation of antitumor drugs of Daidzein derivative shown in above-mentioned formula (I)
With.
MTT organons may be used in the antitumor activity of target compound of the present invention, are swollen with various by target compound
The interaction of oncocyte studies it under the conditions of various concentration, inhibits the effect of tumour growth as one of evaluation means, uses
The inhibiting rate of tumour cell is showed.Contain succinate dehydrogenase in the mitochondria of living cells, it can make exogenous MTT also
Originally it was that bluish violet not soluble in water crystallizes first a ceremonial jade-ladle, used in libation, and is deposited in cell, and cell is without this function after death.MTT makees with cell
With rear, with the first a ceremonial jade-ladle, used in libation in dmso solution cell, its light absorption is measured at 490nm or 570nm wavelength using microplate reader
Value, can reflect the inhibition situation of growth of tumour cell indirectly.Within the scope of certain cell number, MTT crystallize first a ceremonial jade-ladle, used in libation formed amount with
Viable count is directly proportional.
In order to further illustrate the present invention, with reference to embodiments to Daidzein derivative provided by the invention, its system
Preparation Method and application are described in detail.
Reagent used in following embodiment is commercially available.
Embodiment 1
Step 1：The preparation of formula (III-a) compound represented
By 5.08g (20mmol) daidzein, 20ml 1,3- dibromopropanes, 3.36g NaHCO3500ml round bottoms are added to burn
Bottle is added 400ml acetone, 48h is stirred at reflux at 65 DEG C；Then stop reaction, decompression filters, and is separated by solid-liquid separation.Solid is collected, Gu
Include reactant daidzein and NaHCO in body3；It include target compounds of formula (III-a) compound represented in liquid
With the 1,3- dibromopropanes of dissolving in acetone.Liquid in rotation evaporation removes acetone, obtains 1, the 3- dibromopropanes of oily and thick
The mixture of product.1, the 3- dibromopropanes in petroleum ether extraction mixture are added, target compound does not dissolve in petroleum ether, has
White solid is precipitated, and is filtered by depressurizing, and is separated by solid-liquid separation, and collects solid crude product.By the method for vacuum distillation, by petroleum ether
It detaches, recycles with unreacted 1,3- dibromopropanes.
By unreacted 1,3- dibromopropanes, unreacted daidzein and NaHCO3Again reactor is put into, is added
400ml acetone, flow back 48h at 65 DEG C, repeats the above separating step；It repeats 3~4 times.Column chromatography is used after crude product is collected
Method purifying (eluent group becomes：CH2Cl2:CH3OH=50:1, TLC monitoring, solvent CH2Cl2:CH3OH=8:1), most
It is formula (III-a) compound represented, yield 47.5% to obtain 3.56g white solids eventually.
Obtained white solid is detected using nuclear magnetic resonance, is obtained1HNMR(400MHz,)δ9.52(s,1H),
8.34 (s, 1H), 7.99 (d, J=8.9Hz, 1H), 7.36 (d, J=8.6Hz, 2H), 7.15 (s, 1H), 7.06 (d, J=
8.9Hz, 1H), 6.77 (d, J=8.7Hz, 2H), 4.20 (t, J=6.0Hz, 2H), 3.65 (t, J=6.5Hz, 2H), 2.26 (t,
J=6.3Hz, 2H).
Obtained white solid is detected using mass spectrograph, obtains ESI-MS m/z [M+H]+=376.21.
Obtained white solid is detected using melting point apparatus, obtains m.p.178 DEG C~179 DEG C.
Step 2：The preparation of formula (I-a) compound represented
By formula (III-a) compound represented of 750mg (2mmol) above-mentioned preparation, 272mg (4mmol) imidazoles, 552mg
K2CO3250ml round-bottomed flasks are added in (4mmol), and 80ml acetone is then added, 48h is stirred at reflux at 65 DEG C.Then stop reaction,
Decompression filters, and is separated by solid-liquid separation, and solution rotary evaporation is removed solvent, solid is washed with distilled water the imidazoles in crude product, subtracts
Pressure filters, and collects solid crude product.Column chromatography is crossed after crude product is collected purifies (eluent CH2Cl2:CH3OH=50:1,
TLC is monitored, solvent CH2Cl2:CH3OH=8:1) light yellow solid 349mg, as formula (I-a) compound represented, are obtained,
Yield 48.2%.
The light yellow solid obtained in step 2 is detected using nuclear magnetic resonance, is obtained1HNMR(400MHz,)δ9.53
(s, 1H), 8.32 (s, 1H), 7.99 (d, J=8.8Hz, 1H), 7.61 (s, 1H), 7.36 (d, J=8.4Hz, 2H), 7.18 (s,
1H), 7.10 (s, 1H), 6.99 (d, J=8.7Hz, 1H), 6.86 (s, 1H), 6.77 (d, J=8.5Hz, 2H), 4.13 (t, J=
7.0Hz, 2H), 4.06-3.98 (m, 2H), 2.26-2.13 (m, 2H).
The light yellow solid obtained in step 2 is detected using mass spectrograph, obtains ESI-MS m/z [M+H]+=
363.13。
The light yellow solid obtained in step 2 is detected using melting point apparatus, obtains m.p.241 DEG C~242 DEG C.
Step 3：Formula (I-a) compound represented antitumor activity
By formula (I-a) compound represented of above-mentioned synthesis, it is evaluated using MTT organons, different tumour cells is inhibited to give birth to
Long inhibiting rate and IC50Value.
The cell culture used is tested in 37 DEG C, 5%CO2Sterile culture case in the environment of carry out, culture medium use
DMEM culture mediums containing 10%FBS.
Target compound concentration is arranged：Formula (I-a) compound represented is made into 10mmol/L with Bioexperiment with DMSO
Mother liquor, then it is 10 μm of ol/L, 20 μm of ol/L, 30 μm of ol/L, 40 μm of ol/L, 50 μm of ol/L, 60 μ to be diluted to concentration gradient with DMEM
The experiment sample of mol/L, 70 μm of ol/L, 80 μm of ol/L.Culture medium is 0 as blank control, i.e. drug concentration.
Mtt assay experiment flow：By taking A549 cell lines as an example, cell is recovered from liquefied ammonia, and cell is in after 3 passages
Normal adherent growth state.100 μ LPBS are added in the hole of the outermost circle of 96 orifice plates, by cell with the concentration in 20000/hole
For kind in the remaining hole of 96 orifice plates, a most right row do not plant cell as blank group.Wait for that cell is in adhered state for 24 hours after kind plate,
The drug of various concentration gradient is added, each concentration is set as 6 multiple holes of a row.After effect for 24 hours, drug is sucked out, is added
With the MTT solution through filter membrane degerming of the diluted 5mg/mL of PBS, per 20 μ L of hole, while 100 μ L DMEM being added per hole.Effect
After 4h, MTT is sucked out, DMSO is added, slight wobble 5min makes purple crystal be dissolved in DMSO.Using microplate reader in 490nm
The absorbance per hole is measured under wavelength, calculates chemical combination shown in growth inhibition ratio and formula (I-a) of the drug to tumour cell
IC of the object to different tumour cells50Value.Inhibiting rate is calculated using following formula：The growth inhibition ratio of cell=(1- medicine groups
A490/ control group A490).It obtains the results are shown in Table 1 and Fig. 1~Fig. 3, Fig. 1 is that Daidzein derivative and antitumor drug 5- fluorine are urinated
Pyrimidine evaluates figure to the growth inhibition ratio of HeLa cells, is indicated with inhibition rate of tumor cell；Fig. 2 is Daidzein derivative and resists
Tumour medicine 5 FU 5 fluorouracil evaluates figure to the growth inhibition ratio of HepG2 cells；Fig. 3 is Daidzein derivative and antineoplastic
Object 5 FU 5 fluorouracil evaluates figure to the growth inhibition ratio of A549 cells；From a left side in same drug concentration column diagram in Fig. 1~Fig. 3
It is followed successively by formula (I-a) compound represented, formula (I-b) compound represented, formula (I-c) compound represented, formula (I-d) to the right side
Compound represented, formula (I-e) compound represented and 5 FU 5 fluorouracil.
Embodiment 2
Step 1：The preparation of formula (III-a) compound represented
Specific steps are the same as step 1 in embodiment 1
Step 2：The preparation of compound shown in formula (I-b)
By 750mg (2mmol) formula (III-a) compound represented, 328mg 2-methylimidazoles, 552mg K2CO3It is added
80ml acetone is added in 250ml round-bottomed flasks, remaining step is the same as step 2 in embodiment 1.
Formula (I-b) compound represented obtained in embodiment 2 is detected using nuclear magnetic resonance, is obtained1H NMR
δ=9.54 (400MHz, DMSO) (s, 1H), 8.36 (s, 1H), 8.00 (d, J=7.5,1H), 7.36 (d, J=7.5,2H),
7.15 (d, J=1.4,1H), 6.82 (d, J=7.5,2H), 6.70 (d, J=7.4,2H), 6.57 (d, J=7.5,1H), 4.12
(t, J=5.1,2H), 4.08 (t, J=4.6,2H), 2.37 (s, 3H), 2.16 (p, J=4.9,2H).
Formula (I-b) compound represented obtained in embodiment 2 is detected using mass spectrograph, obtains ESI-MS m/z
[M+H]+=377.41.
Formula (I-b) compound represented obtained in embodiment 2 is detected using melting point apparatus, obtains m.p.268 DEG C
~270 DEG C.
Step 3：Formula (I-b) compound represented antitumor activity
From formula (I-b) compound represented synthesized by step 2 in embodiment 2, using MTT experiment method, according to reality
The operation for applying step 3 in example 1 obtains the results are shown in Table 1 and Fig. 1~Fig. 3.
Embodiment 3
Step 1：The preparation of formula (III-a) compound represented
Specific steps are the same as step 1 in embodiment 1.
Step 2：The preparation of formula (I-c) compound represented
By 750mg (2mmol) formula (III-a) compound represented, 384mg 2- ethyl imidazol(e)s, 552mg K2CO3It is added
80ml acetone is added in 250ml round-bottomed flasks, remaining step is the same as step 2 in embodiment 1.
Formula (I-c) compound represented obtained in embodiment 3 is detected using nuclear magnetic resonance, is obtained1H NMR
δ=9.53 (400MHz, DMSO) (s, 1H), 8.32 (s, 1H), 7.93 (d, J=7.5Hz, 1H), 7.36 (d, J=7.5Hz,
2H), 7.01 (d, J=1.4Hz, 1H), 6.87 (d, J=7.5Hz, 1H), 6.83 (d, J=7.5Hz, 1H), 6.73 (dd, J=
7.5,1.5Hz, 1H), 6.70 (d, J=7.6Hz, 2H), 4.20 (t, J=7.8Hz, 1H), 4.06 (t, J=7.7Hz, 2H),
3.93 (t, J=7.8Hz, 1H), 2.79 (q, J=6.7Hz, 2H), 2.17 (p, J=7.8Hz, 2H), 1.35 (t, J=6.7Hz,
3H).
Formula (I-c) compound represented obtained in embodiment 3 is detected using mass spectrograph, obtains ESI-MS m/z
[M+H]+=391.44.
Formula (I-c) compound represented obtained in embodiment 3 is detected using melting point apparatus, obtains m.p.206 DEG C
~208 DEG C.
Step 3：Formula (I-c) compound represented antitumor activity
Formula (I-c) compound represented synthesized by the step 2 in embodiment 3 is used into MTT experiment method, according to reality
The operation for applying step 3 in example 1 obtains the results are shown in Table 1 and Fig. 1~Fig. 3.
Embodiment 4
Step 1：The preparation of formula (III-a) compound represented
Specific steps are the same as step 1 in embodiment 1
Step 2：The preparation of formula (I-d) compound represented
By 750mg (2mmol) formula (III-a) compound represented, 440mg 2-ethyl-4-methylimidazoles, 552mg
K2CO3250ml round-bottomed flasks are added, 80ml acetone are added, remaining step is the same as step 2 in embodiment 1.
Formula (I-d) compound represented obtained in embodiment 4 is detected using nuclear magnetic resonance, is obtained1H NMR
δ=9.50 (400MHz, DMSO) (s, 1H), 8.35 (s, 1H), 8.00 (d, J=7.5Hz, 1H), 7.37 (d, J=7.6Hz,
2H), 7.21 (d, J=1.4Hz, 1H), 6.84 (dd, J=7.5,1.4Hz, 1H), 6.81 (s, 1H), 6.70 (d, J=7.6Hz,
2H), 4.06 (t, J=4.2Hz, 2H), 3.85 (t, J=7.6Hz, 1H), 3.66 (t, J=7.6Hz, 1H), 2.79 (q, J=
6.7Hz, 2H), 2.19 (s, 3H), 2.17-2.09 (m, 2H), 1.34 (t, J=6.7Hz, 3H).
Formula (I-d) compound represented obtained in embodiment 4 is detected using mass spectrograph, obtains ESI-MS m/z
[M+H]+=405.48.
Formula (I-d) compound represented obtained in embodiment 4 is detected using melting point apparatus, obtains m.p.80 DEG C.
Step 3：Formula (I-d) compound represented antitumor activity
Formula (I-d) compound represented synthesized by the step 2 in embodiment 4 is used into MTT experiment method, according to reality
The operation for applying step 3 in example 1 obtains the results are shown in Table 1 and Fig. 1~Fig. 3.
Embodiment 5
Step 1：The preparation of formula (III-a) compound represented
Specific steps are the same as step 1 in embodiment 1.
Step 2：The preparation of formula (I-e) compound represented
By 750mg (2mmol) formula (III-a) compound represented, 276mg 1,2,4- triazoles, 552mg K2CO3It is added
80ml acetone is added in 250ml round-bottomed flasks, remaining step is the same as step 2 in embodiment 1.
Formula (I-e) compound represented obtained in embodiment 5 is detected using nuclear magnetic resonance, is obtained1H NMR
δ=9.50 (400MHz, DMSO) (s, 1H), 8.33 (d, J=19.4,2H), 8.06 (s, 1H), 7.95 (d, J=7.5,1H),
7.37 (d, J=7.4,2H), 7.03 (d, J=1.4,1H), 6.74 (dd, J=7.5,1.5,1H), 6.70 (d, J=7.4,2H),
4.44 (dt, J=10.5,5.1,2H), 4.09 (t, J=5.4,2H), 2.17 (p, J=5.2,2H).
Formula (I-e) compound represented obtained in embodiment 5 is detected using mass spectrograph, obtains ESI-MS m/z
[M+H]+=364.22.
Formula (I-e) compound represented obtained in embodiment 5 is detected using melting point apparatus, obtains m.p.240 DEG C
~242 DEG C.
Step 3：Formula (I-e) compound represented antitumor activity
Formula (I-e) compound represented synthesized by the step 2 in embodiment 5 is used into MTT experiment method, according to reality
The operation for applying step 3 in example 1 obtains the results are shown in Table 1 and Fig. 1~Fig. 3.
Table 1MMT methods measure the Daidzein derivative prepared in Examples 1 to 5 with 5 FU 5 fluorouracil to not
With the IC of tumour cell50Value
Claims (10)
1. a kind of Daidzein derivative, which is characterized in that as shown in formula (I)：
Wherein, R is nitrogen heterocycle or substituted nitrogen heterocycle；In the substituted nitrogen heterocycle substituent group be selected from C1~
The alkyl of C10；N is the integer more than or equal to 1.
2. Daidzein derivative according to claim 1, which is characterized in that of nitrogen-atoms in the nitrogen heterocycle
Number is 2~3.
3. Daidzein derivative according to claim 1, which is characterized in that the nitrogen heterocycle is five-membered ring or six
Membered ring.
4. Daidzein derivative according to claim 1, which is characterized in that the nitrogen heterocycle be selected from imidazole radicals or
1,2,4- triazol radicals.
5. Daidzein derivative according to claim 1, which is characterized in that taking in the substituted nitrogen heterocycle
Dai Ji is selected from the alkyl of C1~C5.
6. Daidzein derivative according to claim 1, which is characterized in that the integer that the n is 2~4.
7. Daidzein derivative according to claim 1, which is characterized in that as shown in formula (I-1)~formula (I~5)：
Wherein, n1~n5It is each independently selected from 2~4 integer.
8. Daidzein derivative according to claim 1, which is characterized in that as shown in formula (I-a)~formula (I~e)：
9. a kind of preparation method of Daidzein derivative, which is characterized in that including：
S1 daidzein is reacted under alkaline condition with halogenated alkane shown in formula (II)), obtains chemical combination shown in formula (III)
Object；
S2 the formula (III) compound represented is reacted under alkaline condition with formula (IV) compound represented), obtains formula
(I) compound represented；
R-H formulas (IV)；
Wherein, X is halogen；R is nitrogen heterocycle or substituted nitrogen heterocycle；Substituent group in the substituted nitrogen heterocycle
Alkyl selected from C1~C10；N is the integer more than or equal to 1.
10. the daidzein prepared by Daidzein derivative or claim 9 described in claim 1~8 any one spreads out
Biological application in preparation of anti-tumor drugs.
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| CN108997426A (en) * | 2018-07-19 | 2018-12-14 | 大连理工大学 | Target flavones alkoxy amino phosphate derivative, preparation and the application of Hsp60 |
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