CN106496052B - Your ketone compounds of a kind of Check and its preparation method and application - Google Patents
Your ketone compounds of a kind of Check and its preparation method and application Download PDFInfo
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- CN106496052B CN106496052B CN201610913130.3A CN201610913130A CN106496052B CN 106496052 B CN106496052 B CN 106496052B CN 201610913130 A CN201610913130 A CN 201610913130A CN 106496052 B CN106496052 B CN 106496052B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Abstract
The invention discloses a kind of Check that ketone compounds, shown in your ketone compounds structural formula such as formula (I) of the Check: where R1For halogen, C1~3Alkyl or C1~3Alkoxy；R2For hydroxyl or C1~3Alkoxy；R2For hydrogen, C1~3Alkyl or C1~3Alkoxy；R4For hydrogen or nitro；R5For hydrogen or nitro；R6For hydrogen, amino or hexa-atomic saturated heterocyclyl.Further, R1For halogen or C1~3Alkoxy.R2For hydrogen or C1~3Alkoxy.R4Or R5It is not simultaneously nitro, R6For hydrogen, amino or piperidyl.The compounds of this invention preparation is simple, and raw material is easy to get, and is provided simultaneously with good antioxidant activity and anti-tumor activity, the important in inhibiting in preparation prevention and treatment disease medicament relevant to free radical.Also has fabulous application prospect in preparation anti-liver cancer and anti-, lung cancer or uterine neck cancer drug simultaneously.
Description
Technical field
The invention belongs to technical field of compound preparation, more particularly, to a kind of Check that ketone compounds and its preparation
Methods and applications.
Background technique
Chalcone belongs to flavone compound, is widely present in fruit, vegetables, fragrance, tealeaves, soybean and each natural drug
In, there are the bioactivity such as preferable anti-oxidant, antitumor, anti-inflammatory, antiangiogenic, antibacterial and antimalarial.Its basic framework is
1,3- diaryl -2- propylene -1- ketone, comprising two by α, the bioactivity of the aromatic rings that beta unsaturated ketone separates, chalcone depends on
In this unique structure.
Nowadays, cancer has become the common disease and frequently-occurring disease for threatening human health, therefore develops safe and effective antitumor
Medicine is particularly important the survival and development of the mankind.Over the past decade, numerous scholars have carried out a large amount of knot around chalcone
Structure modifies work, to obtain efficient, less toxic chalcone compounds.Studies have shown that chalcone compounds pharmacological activity
Extensively, safety, and structure is simple, preparation is convenient, is a kind of good drug development primer.By the exploitation of more than ten years, mesh
Before have the listing of multiple chalcones medicines, such as sofalcone and metochalcone.The antitumor mechanism of such compound is broadly divided into
The following aspects: arresting cell cycle；Promote apoptosis of tumor cells；Inhibit Tumor Angiongesis；Into the expression of tumor suppressor gene；
The increase of protein tyrosine kinase (PTK) expression, to inhibit the transduction of cell signal；Secretion of the induction of lymphocyte to IL-2
Deng.Therefore, the relationship of the structure of further research chalcone compounds, pharmacological activity and toxicity, to exploitation chalcones
Antineoplastic is a particularly significant and valuable job, and the research of anti-cancer agent will also have broad prospects.
Oxidative stress is generated by active oxygen, can be to intracellular albumen, lipid, nucleus and other macromolecular complex
Matter causes the damage in physiological function.Oxidative stress can lead to aging and the other diseases of human body, such as Parkinson and A Erci
The neurodegenerative diseases such as the silent disease in sea, find using natural products as the antioxidant of lead compound, such as tea polyphenols, vitamin C
And flavone compound, disease important in inhibiting relevant to free radical to treatment.In recent years, research finds artificial synthesized
Chalcone also has good antioxidant activity, and in the research to the bioactivity of chalcone, chalcone is good anti-oxidant
Activity starts the concern for causing more and more people.
Therefore it provides more having anti-oxidant and anti-tumor capacity, and more preferable active Check that ketone chemical combination can be obtained
Object is the task of top priority.
Summary of the invention
It is an object of the invention to provide a kind of Check that ketone compounds according to deficiency in the prior art.
Another object of the present invention is to provide the preparation methods of your ketone compounds of above-mentioned Check.
A further object of the present invention is to provide above-mentioned Check that ketone compounds in preparing anti-oxidant and anticancer drug
Using.
The purpose of the present invention is achieved through the following technical solutions:
The present invention provides a kind of Check that ketone compounds, shown in your ketone compounds structural formula such as formula (I) of the Check:
Wherein, R1For halogen, C1~3Alkyl or C1~3Alkoxy；R2For hydroxyl or C1~3Alkoxy；R2For hydrogen, C1~3
Alkyl or C1~3Alkoxy；R4For hydrogen or nitro；R5For hydrogen or nitro；R6For hydrogen, amino or hexa-atomic saturated heterocyclyl.
Preferably, R1For halogen or C1~3Alkoxy.
It is highly preferred that R1For bromo, methoxy or ethoxy.
Preferably, R2For hydrogen or C1~3Alkoxy.
It is highly preferred that R2For hydrogen or methoxyl group.
Preferably, R6For hydrogen, amino or piperidyl.
More specifically, compound provided by the invention is as follows:
Present invention simultaneously provides the preparation methods of your ketone compounds of the Check, work as R6When for amino, by compound
Reaction, then reduction obtains the Check that ketone compounds, wherein R1For halogen
Base, C1~3Alkyl or C1~3Alkoxy；R2For hydroxyl or C1~3Alkoxy；R2For hydrogen, C1~3Alkyl or C1~3Alcoxyl
Base；R4For hydrogen or nitro；R5For hydrogen or nitro.
The present invention goes back while providing the Check preparation method of your ketone compounds, works as R4Or R5In it is any be nitro, and
R4Or R5When not simultaneously being nitro, by compound
With hexa-atomic saturated heterocyclic compound
Reaction obtains the Check that ketone compounds, wherein R1For halogen, C1~3Alkyl or C1~3Alkoxy；R2For hydroxyl or
C1~3Alkoxy；R3For hydrogen, C1~3Alkyl or C1~3Alkoxy；R6For hydrogen, amino or hexa-atomic saturated heterocyclyl.
The compound that the present invention is prepared has the preferable ability for removing DPPH free radical, has good anti-oxidant
Activity can be used for preparing in antioxidative drug.
It is applied to inhibit in tumour test in addition, compound is prepared in the present invention, with HepG2(human liver cancer is thin for cell
Born of the same parents), A549 cell (human lung carcinoma cell) and Hela (human cervical carcinoma) cell test respectively, discovery the compounds of this invention has
Preferable anti-tumor activity has fabulous application prospect in the preparation of antitumor drugs.
Compared with prior art, the present invention has the following advantages and beneficial effects:
The compounds of this invention preparation is simple, and raw material is easy to get, and is provided simultaneously with good antioxidant activity and antitumor work
Property, the important in inhibiting in preparation prevention and treatment disease medicament relevant to free radical.Simultaneously also in preparation anti-liver cancer and anti-, lung
Has fabulous application prospect in cancer or uterine neck cancer drug.
Specific embodiment
The present invention is described in further details below by embodiment, these embodiments are only used to illustrate the present invention,
It does not limit the scope of the invention.
Embodiment 1
P1:(E) -4- hydroxyl -3,5- dimethoxy-4 ' '-amino chalcone
In 50ml reaction flask, syringaldehyde 0.72g, p-nitroacetophenone 0.64g, piperidinyl-1 ml is added, 160 DEG C of reactions are stirred
Lower reflux 15min is mixed, peony thick liquid is obtained.After being cooled to room temperature, be added strong caustic, adjust pH to 12 with
On, under ice bath, concentrated hydrochloric acid is added and is acidified to pH 1-2, filters to obtain red solid, it is orange that dehydrated alcohol adds a small amount of acetone recrystallization to obtain
Red crystals, i.e. (E) -4- hydroxyl -3,5- dimethoxy-4 ' '-nitro chalcone.
In 50ml reaction flask, (E) -4- hydroxyl -3,5- dimethoxy-4 ' '-nitro chalcone 0.5g is added, methanol is molten
Solution, 60 DEG C are heated to reflux, and are added the total 0.75g of iron powder (in three batches), and 6mol/L dilute hydrochloric acid 3 is added dropwise and drips, appropriate ammonium chloride is added, instead
It after answering completely, filters, filtrate is spin-dried for, and dehydrated alcohol recrystallization obtains yellow crystals, i.e. (E) -4- hydroxyl -3,5- dimethoxy -
4 '-amino chalcones.Yellow crystals, mp 177.9-178.4 DEG C.Spectral data:1H NMR(400MHz,DMSO)δ8.93(s,
), OH 7.93 (d, J=8.7Hz, 2H, Ar '-H), 7.73 (d, J=15.6Hz, 1H,
), 7.53 (d, J=15.6Hz, 1H,
), 7.14 (s, 2H, Ar-H), 6.62 (d, J=8.7Hz, 2H, Ar '-H), 6.11 (s, 2H, NH2),3.84(s,6H,
OCH3).MS:m/z [M+H]+300。
Embodiment 2
P2:(E) the bromo- 4 '-amino chalcone of -4- hydroxy-3-methoxy -5-
In 50ml reaction flask, 4- hydroxy-3-methoxy -5- bromobenzaldehyde 0.96g, p-nitroacetophenone 0.54g is added,
1ml piperidines, 160 DEG C of reactions stir the lower 15min that flows back, obtain peony thick liquid.After being cooled to room temperature, dense hydroxide is added
Sodium solution adjusts pH to 12 or more, under ice bath, concentrated hydrochloric acid is added and is acidified to pH 1-2, filters to obtain gray solid, dehydrated alcohol adds
A small amount of acetone recrystallization obtains yellow crystals, i.e. bromo- the 4 '-nitro chalcone of (E) -4- hydroxy-3-methoxy -5-.
In 50ml reaction flask, the bromo- 4 '-nitro chalcone 0.4g of (E) -4- hydroxy-3-methoxy -5- is added, methanol is molten
Solution, 60 DEG C are heated to reflux, and are added iron powder 0.6g (in three batches), and 6mol/L dilute hydrochloric acid 3 is added dropwise and drips, appropriate ammonium chloride is added, reacts
Completely.It filters, is spin-dried for, obtains dark oil solid.Ethyl acetate dissolution, is precipitated ammonium chloride, filters, and filtrate adds water to extract, acetic acid
Methacrylate layer is spin-dried for, and obtains yellow crystals.That is the bromo- 4 '-amino chalcone of (E) -4- hydroxy-3-methoxy -5-.Yellow crystals,
mp167.1-169.9℃.Spectral data:1H NMR (400MHz, DMSO) δ 10.11 (s, 0H), 8.01 (d, J=8.4Hz, 2H,
Ar '-H), 7.87 (d, J=15.6Hz 1H,
), 7.69 (s, 1H, Ar-H), 7.58 (d, J=15.6,1H,
),
7.54 (s, 1H, Ar-H), 6.69 (d, J=8.4,2H, Ar '-H), 6.21 (s, 2H, NH2), 3.99 (s, 3H, OCH3).MS:m/z
[M+H]+348[M+2+H]+350。
Embodiment 3
P8:(E) the bromo- 4 '-amino chalcone preparation of -4- hydroxyl -3- ethyoxyl -5-
In 50ml reaction flask, 4- hydroxyl -3- ethyoxyl -5- bromobenzaldehyde 0.8g, p-nitroacetophenone 0.6g is added,
1ml piperidines, 160 DEG C of reactions stir the lower 15min that flows back, obtain peony thick liquid.After being cooled to room temperature, dense hydroxide is added
Sodium solution adjusts pH to 12 or more, under ice bath, concentrated hydrochloric acid is added and is acidified to pH 1-2, filters to obtain gray solid, dehydrated alcohol adds
A small amount of acetone recrystallization obtains yellow crystals, i.e. bromo- the 4 '-nitro chalcone of (E) -4- hydroxyl -3- ethyoxyl -5-.
In 50ml reaction flask, the bromo- 4 '-nitro chalcone 0.4g of (E) -4- hydroxyl -3- ethyoxyl -5- is added, methanol is molten
Solution, 60 DEG C are heated to reflux, and are added iron powder 0.6g (in three batches), and 6mol/L dilute hydrochloric acid 3 is added dropwise and drips, appropriate ammonium chloride is added, reacts
Completely.It filters, is spin-dried for, obtains dark oil solid.Ethyl acetate dissolution, is precipitated ammonium chloride, filters, and filtrate adds water to extract, acetic acid
Methacrylate layer is spin-dried for, and obtains yellow crystals.That is the bromo- 4 '-amino chalcone of (E) -4- hydroxyl -3- ethyoxyl -5-.Yellow crystals.
Mp152.2-152.6 DEG C of spectral data:1H NMR (400MHz, DMSO) δ 7.97 (d, J=8Hz, Ar '-H), 7.78 (d, J=
15.2Hz,1H,), 7.51 (d, J=15.6Hz, 1H,
),7.63(s,1H,Ar-H),7.48(s,1H,Ar-H),
6.71 (d, J=7.6Hz, 2H, Ar '-H), 4.20 (q, J=6.4Hz, 2H, CH2), 1.39 (t, J=6.8Hz, 3H, CH3)。MS:
m/z[M+H]+362[M+2+H]+364。
Embodiment 4
P12:(E) -4- hydroxyl -3,5- dimethoxy -2 '-nitro chalcone preparation
In 50ml reaction flask, syringaldehyde 0.72g, ortho-nitroacetophenone 0.64g, piperidinyl-1 ml is added, methanol 5 drips, and 160
DEG C reaction, stirs the lower 15min that flows back, obtains peony thick liquid.After being cooled to room temperature, strong caustic and acetone is added
In right amount, 4mol/l dilute hydrochloric acid is added dropwise, until solution turned yellow color, is precipitated red solid, acetone recrystallization obtains red crystals, i.e.,
(E) -4- hydroxyl -3,5- dimethoxy -2 '-nitro chalcone.Red crystals.mp 166.8-171.7℃.Spectral data:1H
NMR (400MHz, DMSO) δ 8.18 (d, J=8Hz, 1H, Ar '-H), 7.90 (t, J=7.6Hz, 1H, Ar '-H), 7.80 (t, J=
7.6Hz, 1H, Ar '-H), 7.69 (d, J=8.4Hz, 1H, Ar '-H), 7.28 (d, J=16Hz, 1H,
), 7.11 (d, J=
16Hz,1H,
), 7.04 (s, 2H, Ar-H), 3.78 (s, 6H, OCH3)。MS:m/z[M-H]+328。
Embodiment 5
P13:(E the preparation of) -4- hydroxyl -3,5- dimethoxy-4 ' '-piperidyl -3 '-nitro chalcone
In 50ml reaction flask, syringaldehyde 0.5g is added, the fluoro- 3- nitro-acetophenone 0.5g of 4-, piperidinyl-1 ml, 160 DEG C anti-
It answers, stirs the lower 15min that flows back, have the generation of yellow green gas in reaction process, obtain peony thick liquid.After being cooled to room temperature,
It is added strong caustic and appropriate methanol, under ice bath, concentrated hydrochloric acid is added, solution turned yellow filters to obtain yellow in solution rufous
Solid, acetone recrystallization obtain yellow powder, i.e. (E) -4- hydroxyl -3,5- dimethoxy-4 ' '-piperidyl -3 '-nitro Cha Er
Ketone.Yellow powder.mp 130.9-132.0℃.Spectral data:1H NMR(400MHz,DMSO)δ9.11(s,OH)8.51(s,
Ar '-H), 8.28 (d, J=9.2Hz, 1H, Ar '-H), 7.80 (d, J=15.6Hz, 1H,
), 7.70 (d, J=15.2Hz,
1H,
), 7.34 (d, J=8.8Hz, 1H, Ar '-H), 7.22 (s, 2H, Ar-H), 3.86 (s, 6H, OCH3),3.17(s
4H, Pip-H), 1.62 (s, 6H, Pip-H).MS:m/z[M+H]+413。
Embodiment 6
P14:(E) -4- hydroxy-3-methoxy -4 '-piperidyl -3 '-nitro chalcone preparation
In 50ml reaction flask, 3-methoxy-4-hydroxybenzaldehyde 0.82g, the fluoro- 3- nitro-acetophenone 1.0g of 4- is added,
Piperidinyl-1 ml, 160 DEG C of reactions stir the lower 15min that flows back, have the generation of yellow green gas in reaction process, obtain peony viscous fluid
Body.After being cooled to room temperature, it is added strong caustic and acetone solution, under ice bath, concentrated hydrochloric acid is added in solution rufous, molten
Liquid turns yellow, and filters to obtain yellow solid, and acetone recrystallization obtains yellow powder, i.e. (E) -4- hydroxy-3-methoxy -4 '-piperidines
Base -3 '-nitro chalcone.Yellow powder.Mp199.4-200.8 DEG C of spectral data:1H NMR(400MHz,DMSO)δ8.51
(s, Ar '-H), 8.26 (d, J=8.8Hz 1H, Ar '-H), 7.77 (d, J=15.6Hz, 1H,
), 7.68 (d, J=
15.2Hz,1H,
), 7.51 (s, 1H, Ar-H), 7.32 (d, J=8Hz, 2H, Ar '-H), 6.85 (d, J=8Hz, 1H,
Ar’-H),3.87(s,3H,OCH3) 3.16 (s, 4H, Pip-H), 1.61 (s, 6H, Pip-H).MS:m/z [M+H]+383。
Embodiment 7
P15:(E) -4- hydroxyl -3- ethyoxyl -4 '-piperidyl -3 '-nitro chalcone preparation
In 50ml reaction flask, the fluoro- 3- nitro-acetophenone 1.0g of 4- hydroxyl -3- ethoxy-benzaldehyde 0.9g, 4-, piperazine is added
Pyridine 1ml, 160 DEG C of reactions stir the lower 15min that flows back, have the generation of yellow green gas in reaction process, obtain peony thick liquid.
After being cooled to room temperature, it is added strong caustic and acetone solution, under ice bath, concentrated hydrochloric acid is added, solution becomes in solution rufous
Huang, filters to obtain yellow solid, and acetone recrystallization obtains yellow powder, i.e. (E) -4- hydroxyl -3- ethyoxyl -4 '-piperidyl -3 ' -
The preparation of nitro chalcone.Yellow powder.Mp199.6-204.6. spectral data:1H NMR(400MHz,DMSO)δ9.67(s,
OH), 8.51 (s, Ar '-H), 8.26 (d J=8.4Hz, 1H, Ar '-H), 7.76 (d, J=15.2Hz, 1H,
), 7.66 (d
J=15.6Hz, 1H,
), 7.50 (s, 1H, Ar-H), 7.32 (d, J=8.4Hz, 2H, Ar-H), 6.84 (d, J=8Hz,
1H, Ar '-H), 4.25 (q, J=6.8Hz, 3H, CH3) 1.37 (t, J=7.2Hz, 2H, CH2), 3.16 (s, 4H, Pip-H), 1.61
(s,6H,Pip-H).MS:m/z [M+H]+397。
Embodiment 8
P16:(E) -3,4,5- trimethoxy -4 '-piperidyl -3 '-nitro chalcone preparation
In 50ml reaction flask, 3,4,5-Trimethoxybenzaldehyde 1.12g, the fluoro- 3- nitro-acetophenone 1.0g of 4-, piperazine is added
Pyridine 1ml, 160 DEG C of reactions stir the lower 15min that flows back, have the generation of yellow green gas in reaction process, obtain peony thick liquid.
After being cooled to room temperature, concentrated hydrochloric acid dissolution is added, sodium hydroxide is then added, solution turned yellow has yellow mercury oxide precipitation, filters yellow
Color solid, petroleum ether ethyl acetate (4:1) system cross thin-layer chromatography column, obtain yellow crystals, i.e., (E) -3,4,5- trimethoxies -
4 '-piperidyls -3 '-nitro chalcone are yellow crystals.Mp139.3-139.8 DEG C of spectral data:1H NMR(400MHz,
DMSO) δ 8.51 (s, Ar '-H) 8.28 (d, J=9.2Hz, 1H, Ar '-H) 7.88 (d, J=15.2Hz 1H,
),7.70(d
J=15.2Hz, 1H,
), 7.35 (d, J=8.8Hz 1H, Ar '-H), 7.24 (s 2H, Ar-H), 3.87 (s, 6H, OCH3),
3.72 (s, 3H, OCH3), 3.17 (s, 4H, Pip-H), 1.62 (s, 6H, Pip-H).MS:m/z [M+H]+427。
Embodiment 9:
The chalcone derivative and ascorbic acid (VC) of synthesis remove the ability measurement of DPPH free radical
Configuration drug concentration 2mmol/l, gradient dilution to final concentration of 1,0.5,0.25,0.125,0.0625,
0.03125mmol/L is separately added into isometric DPPH solution and ethanol solution, the feature purple of the DPPH solution of drug is added
It shoals, there is absorption maximum at 517nm.P1, P2, P8, P12, P13, VC, which can be measured, according to the variation of absorbance removes DPPH certainly
It is respectively 26.69 μm of ol/L, 51.09 μm of ol/L, 45.05 μm of ol/L, 32.43 μm of ol/L, 16.67 μm of ol/ by the IC50 value of base
L, 10.23 μm of ol/L (IC50 that P14, P15, P16 remove DPPH free radical is greater than 100 μm of ol/L).The result shows that synthesized
Chalcone derivative has good antioxidant activity.
Embodiment 10
Antitumor cytolytic activity (MTT experiment)
3 kinds of tumour cells used in antitumor cytolytic activity of the present invention: HepG2Cell (human liver cancer cell), A549 cell (people
Lung carcinoma cell) and Hela (human cervical carcinoma) cell.
The preparation of solution:
Culture medium: 10% newborn bovine serum and 1% Pen .- Strep solution is added in 1640 culture medium of HyClone.
PBS:10X PBS is diluted to 1X PBS with sterilizing ultrapure water.
The preparation of MTT solution: weighing MTT dry powder 1.0g, be dissolved in 200mL physiological saline, is removed with 0.22 μM of membrane filtration
After bacterium, -20 DEG C of refrigerator preservations are placed.
Human liver cancer cell HepG2MTT experiment:
By compound P1, P2, P8, P12, P13, P14, P15, cis-platinum (cis-platinum is as positive control drug) is matched with DMSO respectively
It is 10mmol/L that concentration, which is made, and as mother liquor, room temperature, which is protected from light, to be sealed.Appropriate mother liquor cell culture fluid is taken to dilute 100 times,
100 μm of ol/L of final concentration are obtained, compound and cis-platinum mother liquor are taken, being diluted to concentration gradient respectively is 1 μm of ol/L, 25 μm of ol/L, 50 μ
Mol/L, 75 μm of ol/L, 100 μm of ol/L, 5 concentration.Each concentration prepares the cell training for containing only the DMSO of corresponding percentage respectively
Nutrient solution is as negative control group.
The HepG of logarithmic growth phase2Cell is configured to single cell suspension 5 × 104Cells/mL, every hole in 96 orifice plates
100 μ L, overnight incubation in carbon dioxide cell incubator is added.Set up medicine group, control group.Old culture is sopped up with negative pressure pump
Liquid, and it is 100 μ L drug containing culture solutions that the prepared every pore volume of drug in advance, which is added,.48h is cultivated in carbon dioxide incubator.
After 48h, MTT, 37 DEG C of incubation 4h of incubator that concentration is 5mg/mL are added, 150 μ L DMSO are added by cell dissolution, enzyme mark
Instrument surveys the OD value under 595nm, is calculated according to cell proliferation inhibition rate formula: inhibiting rate=(ODDrug- ODIt is negative)/(ODIt is negative?
ODBlank) × 100%.IC50 value is calculated by software Graph Pad Prism 5, and experimental result is shown in Table 1.
Table 1, each compound are to HepG2Cell IC50 (μm ol/L)
| Compound | IC50(48h) |
| P1 | 33.05 |
| P2 | 22.9 |
| P8 | 7.80 |
| P12 | 10.7 |
| P13 | 9.42 |
| P14 | 33.05 |
| P15 | 43.34 |
| Cis-platinum | 5.91 |
In the sample that this experiment is tested, compound is to human liver cancer cell HepG2Growth has inhibiting effect.Especially compound
P8, P12, P13 have significant anti-tumor activity.
Hela cell MTT experiment:
By compound P1, P2, P8, P12, P13, P14, P15, cis-platinum (cis-platinum is as positive control drug) is matched with DMSO respectively
It is 10mmol/L that concentration, which is made, and as mother liquor, room temperature, which is protected from light, to be sealed.Appropriate mother liquor cell culture fluid is taken to dilute 100 times,
100 μm of ol/L of final concentration are obtained, compound and cis-platinum mother liquor are taken, being diluted to concentration gradient respectively is 1 μm of ol/L, 25 μm of ol/L, 50 μ
Mol/L, 75 μm of ol/L, 100 μm of ol/L, 5 concentration.Each concentration prepares the cell training for containing only the DMSO of corresponding percentage respectively
Nutrient solution is as negative control group.
The Hela cell of logarithmic growth phase, is configured to single cell suspension 5 × 104Cells/mL, every hole in 96 orifice plates
100 μ L, overnight incubation in carbon dioxide cell incubator is added.Set up medicine group, control group.Old culture is sopped up with negative pressure pump
Liquid, and it is 100 μ L drug containing culture solutions that the prepared every pore volume of drug in advance, which is added,.48h is cultivated in carbon dioxide incubator.
After 48h, MTT, 37 DEG C of incubation 4h of incubator that concentration is 5mg/mL are added, 150 μ L DMSO are added by cell dissolution, enzyme mark
Instrument surveys the OD value under 595nm, is calculated according to cell proliferation inhibition rate formula: inhibiting rate=(ODDrug- ODIt is negative)/(ODIt is negative?
ODBlank) × 100%.IC50 value is calculated by software Graph Pad Prism 5, and experimental result is shown in Table 2.
Table 2, each compound are to Hela cell IC50 (μm ol/L)
| Compound | IC50(48h) |
| P1 | 19.16 |
| P2 | 14.52 |
| P8 | 8.75 |
| P12 | 12.34 |
| P13 | 10.53 |
| P14 | 9.18 |
| P15 | 15.65 |
| Cis-platinum | 4.07 |
In the sample that this experiment is tested, each compound has inhibiting effect to the growth of Hela cell, has significant anti-swollen
Tumor activity.
Lung cell A549 MTT experiment:
By compound P8, P13, P14, P15, P16, cis-platinum (cis-platinum is as positive control drug) is configured to DMSO dense respectively
Degree is 10mmol/L, and as mother liquor, room temperature, which is protected from light, to be sealed.It takes appropriate mother liquor cell culture fluid to dilute 100 times, obtains dense eventually
Spend 100 μm of ol/L, take compound and cis-platinum mother liquor, be diluted to respectively concentration gradient be 1 μm of ol/L, 25 μm of ol/L, 50 μm of ol/L,
75 μm of ol/L, 100 μm of ol/L, 5 concentration.Each concentration prepares the cell culture fluid work for containing only the DMSO of corresponding percentage respectively
For negative control group.
The A549 cell of logarithmic growth phase, is configured to single cell suspension 5 × 104Cells/mL, every hole in 96 orifice plates
100 μ L, overnight incubation in carbon dioxide cell incubator is added.Set up medicine group, control group.Old culture is sopped up with negative pressure pump
Liquid, and it is 100 μ L drug containing culture solutions that the prepared every pore volume of drug in advance, which is added,.48h is cultivated in carbon dioxide incubator.
After 48h, MTT, 37 DEG C of incubation 4h of incubator that concentration is 5mg/mL are added, 150 μ L DMSO are added by cell dissolution, enzyme mark
Instrument surveys the OD value under 595nm, is calculated according to cell proliferation inhibition rate formula: inhibiting rate=(ODDrug- ODIt is negative)/(ODIt is negative?
ODBlank) × 100%.IC50 value is calculated by software Graph Pad Prism 5, and experimental result is shown in Table 3.
Table 3, each compound are to A549 cell IC50 (μm ol/L)
| Compound | IC50(48h) |
| P8 | 52.03 |
| P13 | 6.91 |
| P14 | 29.36 |
| P15 | 34.94 |
| P16 | 7.18 |
| Cis-platinum | 25.18 |
In the sample that this experiment is tested, each compound has inhibiting effect to human lung cancer cell A549's growth.Especially chemical combination
Object P13, P16 have significant anti-tumor activity.
Claims (1)
1. application of the Check that ketone compounds in preparation anti-liver cancer and anti-and uterine neck cancer drug, which is characterized in that the Check that ketone
Shown in structural formula of compound such as formula (I):
Wherein, R1For methoxyl group, R2Hydroxyl, R3For methoxyl group, R4For hydrogen, R5For nitro, R6For-N- piperidyl.
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