CN106946864A - Suppress the α of HIF 1 antitumor drug candidate and preparation method - Google Patents
Suppress the α of HIF 1 antitumor drug candidate and preparation method Download PDFInfo
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Abstract
The invention discloses the antitumor drug candidate of suppression HIF 1 α a kind of and preparation method, the glycolysis ability of tumour cell can be suppressed by proposing meter synthesis compound, glycolysis suppresses using hypoxia-inducible factor-1 alpha as target spot, design synthesis is using flavones native compound as parent nucleus, modify the serial chrysin derivative of benzimidizole derivatives synthesis, screened using the suppression level of anti tumor activity in vitro, target point protein, filter out the compound for acting on hypoxia-inducible factor-1 alpha.Pick out the drug candidate for suppressing glycolysis；Potential new drug candidate is provided for treatment tumour.
Description
Technical field
The invention belongs to the antitumor drug candidate and system of malignant tumour technical field, more particularly to a kind of suppression HIF-1 α
Preparation Method.
Background technology
Tumour is a kind of common and occurs frequently disease, and wherein malignant tumour has most serious to human health at present
Harm.Blood vessel is that tumour growth and survival provide enough oxygen and nutriment, and eliminates metabolic waste.Therefore, tumour
Blood-vessels target treatment turns into effective ideas of cancer therapy.The progress beginning of the seventies in last century of tumor vessel inhibitor,
Folkman proposes that growth and diffusion of the tumor neogenetic blood vessels to tumour play an important role first.Bergers etc. is further ground
Study carefully and also indicate that:Tumour cell needs the support of new vessels and functional vascular in propagation and transfer process；Moreover, in recent years
Numerous studies have proven to:The growth of tumour is both needed to provide sufficient oxygen and nutrient by blood vessel with existence, and excludes metabolic waste,
If the support without blood vessel and new vessels, the growth of tumour is not over 2mm, and therefore, tumor vascular targeting therapy is arisen at the historic moment,
As a kind of effective ideas of cancer therapy.With poor selectivity, toxicity is big and is also easy to produce the traditional anti-tumor medicine of drug resistance not
Together, tumor vascular targeting therapy has many advantages such as selectivity is strong, small toxicity, antitumor spectra are wide, can directly act on tumour blood
Endothelial cell, suppresses all kinds of tumour growths dependent on vascular system.In addition, normal physiological of the Advancement of targeting antiangiogenesis therapy to body
Function effect very little, and for Normal tissue vascular, tumor vasculature is imperfect, endothelial cell is in propagation shape
State, is more subject to the attack of blood-vessels target medicine.
In clinical application, the effect that vascular disrupting agents are used alone is bad, and tumour can still survive after blood vessel blocking,
It is probably warburg effects to think reason.Warburg effects are to observe most of cancer cells in the case of aerobic or anaerobic
The main glycolysis by high-speed produces energy, and produces energy mainly by entering in mitochondria in most of normal cells
Row aerobic respiration.The tumour cell of pernicious fast-growth generally has the 200 of the up to glycolysis speed of its normal source tissue
Times glycolysis speed, even if oxygen is sufficient also can this thing happens.
The energy of tumour cell is essentially from glycolysis.Anoxic is a universals of entity tumor, for tumour
Progress plays key effect.Even Otto Warburg scholars have found that many tumour cells were also produced in the case of normal oxygen
Many lactic acid, is referred to as false anoxic.The fast breeding of tumour needs the supply of lasting oxygen and nutrition.When the speed of tissue growth
When the ability of these nutritional ingredients is supplied considerably beyond peripheral vessels, anoxic is just arisen at the historic moment.The angiogenesis of anoxic and tumour,
Invasion and attack transfer, chemicotherapy resistance and prognosis mala etc. are closely related.The pyruvic acid that glycolytic pathway is produced can be directly entered tricarboxylic
Sour circulation approach is converted into lactic acid by lactic dehydrogenase (lactate dehydrogenase, LDH).In glucose through sugar
During diphosphate pathway generation lactic acid, the key metabolic enzymes such as HK, PFK, PK and LDH are relevant with tumour, and by carcinogen
Transcription factor such as hypoxia-inducible factor lα (hypoxia inducible factor-1 α, HIF-1 α) etc. in signal transduction pathway
Regulation and control.(1) hypoxia inducible factor inhibitor hypoxic inducing factor-1 (hypoxia-inducible factor 1, HIF-1) is
The most key transcriptional regulatory factor in the regulation and control of anoxic effect..HIF-1 high table is selectively continued in solid tumor tissue
Reach, the generation development of downstream key controlling gene and tumour is closely related, such as promote angiogenesis, cell survival, suppress tumour
Apoptosis, metabolism remodeling and the regulation of pH stable states.Glycolysis is the important hand that tumour cell obtains energy during anoxic
Section.HIF-1 α induce the expression of glycolytic ferment genoid by being combined with the DNA binding sites on target gene, increase glycolysis,
Promote anaerobic metabolism, therefore be conducive to existence of the tumour cell under anoxic.Influence the medicine flavones of HIF-1 α synthesis and degraded
Class compound Chrysin is by increasing the increased ubiquitination of its representing prolyl hydroxylase and degraded HIF-1 α.In addition, between Chrysin
Interfere HIF-1 α and heat shock protein 90.Chrysin is also found to suppress HIF-1 α expression by Akt signal pathways.In vain
Yang Suke suppresses the expression of VEGF by suppressing HIF-1 α.Mirzoeva etc. has found, in human prostate
In cancerous cell line PC3-M, apiolin lowers HIF-1 α mRNA and protein expression level, and reduces the stabilization of its protein structure
Property, and then HIF-1 downstream target genes VEGF activation is prevented, VEGF mRNA and protein expression level is lowered, suppresses prostate
The formation of cancer new vessels.Liu etc. is not, it was also found that acacetin (acacetin) to HIF-1 α mRNA expression although have
Significantly affect, but suppress VEGF activation by lowering its protein expression level, so that prevent oophoroma new vessels from being formed,
And this inhibitory action to VEGF can be eliminated by being overexpressed HIF-1 α.
The content of the invention
Suppress the antitumor drug candidate its preparation methods of HIF-1 α it is an object of the invention to provide one kind, it is intended to solve
In clinical application, the effect that vascular disrupting agents are used alone is bad, the problem of tumor vessel can still survive after blocking.
The present invention is achieved in that a kind of suppression antitumor drug candidates of HIF-1 α, and the suppression HIF-1 α are antitumor
Drug candidate has below formula：
Another object of the present invention is to provide a kind of suppression HIF-1 α preparation methods of antitumor drug candidate, institute
The preparation method for stating the suppression antitumor drug candidates of HIF-1 α comprises the following steps：
Step one, Chrysin, Anhydrous potassium carbonate and acetone are sequentially added in 250mL round-bottomed flasks, heating stirring flows back,
1,2- Bromofumes or 1,3- dibromopropane or Isosorbide-5-Nitrae-dibromobutane are added dropwise again, 60 DEG C of heating condensing refluxes, solution becomes clear
Become cloudy again clearly；Reaction process, column chromatography purifying are detected, eluant, eluent is：Methanol：Dichloromethane=1:50；
Step 2, benzimidizole derivatives are added in 250mL there-necked flasks, it is dissolved in 100mL acetone, are added carbonic acid
After potassium, stirring 10min, the chrysin derivative of purifying obtained by step one is added, TBAB is heated to 60 DEG C of stirrings anti-
Should, it is extracted with ethyl acetate, organic layer is washed with saturated common salt, then with anhydrous sodium sulfate drying, solvent under reduced pressure is used after being evaporated
Silica gel post separation produces target compound, and eluant, eluent is：Methanol：Dichloromethane=1:50.
Further, in the step one：Chrysin 2.54g, 0.01 (having changed) are sequentially added in 250mL round-bottomed flasks
Mol, Anhydrous potassium carbonate 5.52g, 0.04mol and acetone 100ml；1,2- Bromofume or 1,3- dibromopropane or Isosorbide-5-Nitrae-dibromo fourth
Alkane 0.04mol.
Further, in the step 2：Benzimidizole derivatives 0.015mol is sequentially added in 250mL round-bottomed flasks,
Anhydrous potassium carbonate 5.52g, 0.04mol, the chrysin derivative 0.01mol of step one gained purifying, TBAB
0.03g, 0.0001mol and acetone 100ml.
Antitumor drug candidates of suppression HIF-1 α that the present invention is provided and preparation method thereof, proposing meter synthesis compound can press down
The glycolysis ability of tumour cell processed, glycolysis suppresses using hypoxia-inducible factor-1 alpha as target spot, and design synthesis is naturally changed with flavones
Compound is parent nucleus, the serial chrysin derivative of modification benzimidizole derivatives synthesis, using anti tumor activity in vitro, target point protein
Suppression level screened, filter out act on suppress hypoxia-inducible factor-1 alpha compound.Pick out and act on suppression sugar
The drug candidate of glycolysis, potential new drug candidate is provided for treatment tumour.It is most heavy in terms of tumour cell glycolysis is reduced
Want for HIF-1 α, the species of HIF-1 alpha inhibitors is a lot, and flavonoids is found in the inhibitor for finding to suppress HIF-1 α synthesis
Compound and benzimidazoles compound, and the vascular disrupting agents found earliest are acetic acid flavones, so intending using flavones as parent nucleus knot
Structure, opposite side introduces benzimidazole or benzimidizole derivatives, and synthesis is desirable to suppress glycolysis by suppressing HIF-1 α.
Brief description of the drawings
Fig. 1 is the preparation method flow chart of the antitumor drug candidates of suppression HIF-1 α provided in an embodiment of the present invention.
Fig. 2 is experimental result schematic diagram provided in an embodiment of the present invention.
Embodiment
In order to make the purpose , technical scheme and advantage of the present invention be clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
The application principle of the present invention is explained in detail below in conjunction with the accompanying drawings.
The antitumor drug candidates of suppression HIF-1 α provided in an embodiment of the present invention have below formula：
As shown in figure 1, the preparation method of the antitumor drug candidates of suppression HIF-1 α provided in an embodiment of the present invention include with
Lower step：
S101：Sequentially add Chrysin (2.54g, 0.01mol) in 250mL round-bottomed flasks, Anhydrous potassium carbonate (5.52g,
0.04mol) and acetone (100ml), heating stirring backflow, then be added dropwise 1,2- Bromofumes or 1,3- dibromopropane or Isosorbide-5-Nitrae-
Dibromobutane (0.04mol), 60 DEG C of heating condensing refluxes, solution becomes clarification and become cloudy again.TCL (thin-layered chromatography) detection reactions
Process, column chromatography is purified, and eluant, eluent is：Methanol：Dichloromethane=1:50.
S102：Benzimidizole derivatives (0.015mol) are added in 250mL there-necked flasks, it is dissolved in 100mL acetone,
Add after potassium carbonate (5.52g, 0.04mol), stirring 10min, add the chrysin derivative of purifying obtained by step one
(0.01mol), TBAB (TBAB) (0.03g, 0.0001mol), is heated to 60 DEG C of stirring reactions, (TCL detection reactions
Process), it is extracted with ethyl acetate, organic layer is washed with saturated common salt, then with anhydrous sodium sulfate drying, after solvent under reduced pressure is evaporated
Target compound is produced with silica gel post separation, eluant, eluent is：Methanol：Dichloromethane=1:50.
The preparation method reaction equation of the antitumor drug candidates of suppression HIF-1 α provided in an embodiment of the present invention is as follows：
The application principle of the present invention is further described with reference to specific embodiment.
Embodiment 1：7- (2- bromine oxethyls) -5- hydroxyl -2- phenyl -4H- benzopyrone -4- ketone
Sequentially add Chrysin (2.54g, 0.01mol) in 250mL round-bottomed flasks, Anhydrous potassium carbonate (5.52g,
0.004mol) and acetone (100ml), heating stirring backflow, then 1,2- Bromofumes (0.04mol), 60 DEG C of heating is added dropwise
Condensing reflux, solution becomes clarification and become cloudy again.TCL (thin-layered chromatography) detects reaction process, column chromatography purifying, and eluant, eluent is：
Methanol：Dichloromethane=1:50.
Embodiment 2：7- (3- bromines propoxyl group) -5- hydroxyl -2- phenyl -4H- benzopyrone -4- ketone
Sequentially add Chrysin (2.54g, 0.01mol) in 250mL round-bottomed flasks, Anhydrous potassium carbonate (5.52g,
0.004mol) and acetone (100ml), heating stirring backflow, then 1,3- dibromopropanes (0.04mol), 60 DEG C of heating is added dropwise
Condensing reflux, solution becomes clarification and become cloudy again.TCL (thin-layered chromatography) detects reaction process, column chromatography purifying, and eluant, eluent is：
Methanol：Dichloromethane=1:50.
Embodiment 3：7- (4- bromines butoxy) -5- hydroxyl -2- phenyl -4H- benzopyrone -4- ketone
Sequentially add Chrysin (2.54g, 0.01mol) in 250mL round-bottomed flasks, Anhydrous potassium carbonate (5.52g,
0.004mol) and acetone (100ml), heating stirring backflow, then Isosorbide-5-Nitrae-dibromobutane (0.04mol), 60 DEG C of heating is added dropwise
Condensing reflux, solution becomes clarification and become cloudy again.TCL (thin-layered chromatography) detects reaction process, column chromatography purifying, and eluant, eluent is：
Methanol：Dichloromethane=1:50.
Embodiment 4：5- hydroxyls -7- (2- (chloro- 1H- benzos [d] imidazoles -1- bases of 2-) ethyoxyl) -2- phenyl -4H- chromenes -
4- ketone
2-Chlorobenzimidazole (0.0015mol) is added in 100mL there-necked flasks, it is dissolved in 30mL acetone, adds carbon
After sour potassium (0.552g, 0.004mol), stirring 10min, the faint yellow solid 7- (2- bromine oxethyls) that addition embodiment 1 is obtained-
5- hydroxyl -2- phenyl -4H- benzopyrone -4- ketone (0.36g, 0.001mol), TBAB (TBAB) (0.03g,
0.0001mol), 60 DEG C of stirring reactions are heated to, (TCL detects reaction process) is extracted with ethyl acetate, organic layer is eaten with saturation
Salt is washed, and then with anhydrous sodium sulfate drying, solvent under reduced pressure produces target compound, eluant, eluent after being evaporated with silica gel post separation
For：Methanol：Dichloromethane=1:50.Pale yellow powder, yield is 56%.1H NMR (400MHz, cdcl3) δ 12.71 (s, 1H),
7.84 (dd, J=8.1,1.6Hz, 2H), 7.69 (d, J=7.6Hz, 1H), 7.55-7.47 (m, 3H), 7.44 (d, J=7.3Hz,
1H), 7.37-7.26 (m, 2H), 6.64 (s, 1H), 6.39 (d, J=2.2Hz, 1H), 6.28 (d, J=2.3Hz, 1H), 4.64
(t, J=5.3Hz, 2H), 4.37 (t, J=5.4Hz, 2H).
Embodiment 5:5- hydroxyls -7- (2- (5- nitro -1H- benzos [d] imidazoles -1- bases) ethyoxyl) -2- phenyl -4H- colors
Alkene -4- ketone
6- nitrobenzimidazoles (0.0015mol) are added in 100mL there-necked flasks, it is dissolved in 30mL acetone, are added
After potassium carbonate (0.0552g, 0.004mol), stirring 10min, faint yellow solid 7- (the 2- bromine ethoxies that embodiment 1 is obtained are added
Base) -5- hydroxyl -2- phenyl -4H- benzopyrone -4- ketone (0.36g, 0.001mol), TBAB (TBAB)
(0.03g, 0.0001mol), is heated to 60 DEG C of stirring reactions, (TCL detects reaction process), is extracted with ethyl acetate, organic layer
Washed with saturated common salt, then with anhydrous sodium sulfate drying, solvent under reduced pressure produces target chemical combination after being evaporated with silica gel post separation
Thing, eluant, eluent is：Methanol：Dichloromethane=1:50.Pale yellow powder, yield is 52%.1H NMR (400MHz, cdcl3)δ
12.75 (d, J=3.9Hz, 1H), 8.74 (s, 1H), 8.52 (s, 1H), 8.33-8.18 (m, 2H), 7.86 (dd, J=13.7,
8.3Hz, 2H), 7.58 (d, J=9.0Hz, 1H), 7.52 (t, J=8.1Hz, 2H), 6.65 (s, 1H), 6.43 (dd, J=17.4,
2.2Hz, 1H), 6.30 (s, 1H), 4.74-4.64 (m, 2H), 4.41 (dd, J=10.4,5.3Hz, 2H).
Embodiment 6:5- hydroxyls -7- (2- (5- nitro -1H- benzos [d] imidazoles -1- bases) propoxyl group) -2- phenyl -4H- colors
Alkene -4- ketone
6- nitrobenzimidazoles (0.0015mol) are added in 100mL there-necked flasks, it is dissolved in 30mL acetone, are added
After potassium carbonate (0.552g, 0.004mol), stirring 10min, the faint yellow solid 7- (oxygen of 3- bromines third that embodiment 2 is obtained is added
Base) -5- hydroxyl -2- phenyl -4H- benzopyrone -4- ketone (0.37g, 0.001mol), TBAB (TBAB)
(0.03g, 0.0001mol), is heated to 60 DEG C of stirring reactions, (TCL detects reaction process), is extracted with ethyl acetate, organic layer
Washed with saturated common salt, then with anhydrous sodium sulfate drying, solvent under reduced pressure produces target chemical combination after being evaporated with silica gel post separation
Thing, eluant, eluent is：Methanol：Dichloromethane=1:50.Pale yellow powder, yield is 47%.1H NMR (400MHz, cdcl3)δ
12.75 (d, J=3.8Hz, 1H), 8.73 (d, J=2.1Hz, 1H), 8.41 (d, J=2.1Hz, 1H), 8.22 (dd, J=13.0,
5.8Hz, 1H), 8.10 (d, J=18.5Hz, 1H), 7.89-7.83 (m, 2H), 7.52 (dd, J=15.8,8.4Hz, 2H), 6.67
(d, J=1.6Hz, 1H), 6.47 (d, J=2.2Hz, 1H), 6.41 (d, J=2.2Hz, 1H), 6.36-6.32 (m, 1H), 4.57-
4.48 (m, 2H), 4.00 (dd, J=11.8,6.0Hz, 2H), 2.42 (dd, J=11.1,5.3Hz, 2H).
Embodiment 7:5- hydroxyls -7- (2- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) propoxyl group) -2- phenyl -4H- colors
Alkene -4- ketone
2- tolimidazoles (0.0015mol) are added in 100mL there-necked flasks, it is dissolved in 30mL acetone, are added
After potassium carbonate (0.552g, 0.004mol), stirring 10min, the faint yellow solid 7- (oxygen of 3- bromines third that embodiment 2 is obtained is added
Base) -5- hydroxyl -2- phenyl -4H- benzopyrone -4- ketone (0.37g, 0.001mol), TBAB (TBAB)
(0.03g, 0.0001mol), is heated to 60 DEG C of stirring reactions, (TCL detects reaction process), is extracted with ethyl acetate, organic layer
Washed with saturated common salt, then with anhydrous sodium sulfate drying, solvent under reduced pressure produces target chemical combination after being evaporated with silica gel post separation
Thing, eluant, eluent is：Methanol：Dichloromethane=1:50.Pale yellow powder, yield is 49%.1H NMR (400MHz, cdcl3)δ
12.73 (s, 1H), 7.94-7.81 (m, 2H), 7.68 (d, J=6.7Hz, 1H), 7.57-7.45 (m, 3H), 7.32-7.27 (m,
1H), 7.22-7.18 (m, 2H), 6.67 (s, 1H), 6.43 (d, J=2.2Hz, 1H), 6.36 (d, J=2.2Hz, 1H), 4.37
(t, J=6.6Hz, 2H), 3.96 (t, J=5.5Hz, 2H), 2.58 (s, 3H), 2.38-2.28 (m, 2H).
Embodiment 8：5- hydroxyls -7- (2- (1H- benzos [d] imidazoles -1- bases) butoxy) -2- phenyl -4H- chromene -4- ketone
Benzimidazole (0.0015mol) is added in 100mL there-necked flasks, it is dissolved in 30mL acetone, adds potassium carbonate
After (0.552g, 0.004mol), stirring 10min, faint yellow solid 7- (4- bromines butoxy) -5- hydroxyls that embodiment 3 is obtained are added
Base -2- phenyl -4H- benzopyrone -4- ketone (0.39g, 0.001mol), TBAB (TBAB) (0.03g,
0.0001mol), 60 DEG C of stirring reactions are heated to, (TCL detects reaction process) is extracted with ethyl acetate, organic layer is eaten with saturation
Salt is washed, and then with anhydrous sodium sulfate drying, solvent under reduced pressure produces target compound, eluant, eluent after being evaporated with silica gel post separation
For：Methanol：Dichloromethane=1:50.Pale yellow powder, yield is 51%.1H NMR (400MHz, cdcl3) δ 12.71 (s, 1H),
7.92 (s, 1H), 7.89-7.83 (m, 2H), 7.81 (d, J=7.2Hz, 1H), 7.55-7.47 (m, 3H), 7.41 (d, J=
7.1Hz, 1H), 7.34-7.25 (m, 3H), 6.65 (s, 1H), 6.44 (d, J=2.2Hz, 1H), 6.33 (d, J=2.2Hz, 1H),
4.28 (t, J=7.0Hz, 2H), 4.03 (t, J=6.0Hz, 2H), 2.11 (dt, J=14.7,7.4Hz, 2H), 1.85 (dd, J=
15.2,5.8Hz, 2H).
Embodiment 9：5- hydroxyls -7- (2- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) butoxy) -2- phenyl -4H- colors
Alkene -4- ketone
2- tolimidazoles (0.0015mol) are added in 100mL there-necked flasks, it is dissolved in 30mL acetone, are added
After potassium carbonate (0.552g, 0.004mol), stirring 10min, faint yellow solid 7- (the 4- bromine fourth oxygen that embodiment 3 is obtained is added
Base) -5- hydroxyl -2- phenyl -4H- benzopyrone -4- ketone (0.39g, 0.001mol), TBAB (TBAB)
(0.03g, 0.0001mol), is heated to 60 DEG C of stirring reactions, (TCL detects reaction process), is extracted with ethyl acetate, organic layer
Washed with saturated common salt, then with anhydrous sodium sulfate drying, solvent under reduced pressure produces target chemical combination after being evaporated with silica gel post separation
Thing, eluant, eluent is：Methanol：Dichloromethane=1:50.Pale yellow powder, yield is 48%.1H NMR (400MHz, cdcl3)δ
12.72 (s, 1H), 7.89-7.84 (m, 2H), 7.72-7.65 (m, 1H), 7.52 (t, J=7.2Hz, 3H), 7.33-7.27 (m,
1H), 7.24-7.18 (m, 2H), 6.65 (s, 1H), 6.44 (d, J=2.2Hz, 1H), 6.33 (d, J=2.1Hz, 1H), 4.21
(t, J=7.1Hz, 2H), 4.03 (t, J=6.0Hz, 2H), 2.63 (s, 3H), 2.02 (dd, J=15.0,7.7Hz, 2H), 1.88
(dd, J=14.8,5.7Hz, 2H).
Embodiment 10：The anti tumor activity in vitro experiment of the compounds of this invention
Compound to the present invention carries out anti-tumour cell proliferative activity experiment, and test method is using conventional mtt assay.
Cell line selects gastric carcinoma cells MGC-803, human liver cancer cell HepG2 and human breast cancer cell line Bcap-37.Nutrient solution
It is dual anti-for DMEM+15%NBS+.
The compound method of drug solution：With DMSO (Merck) dissolve after, add PBS (-) be made into 1mmol/mL solution or
Uniform suspension, then with DMSO PBS (-) dilution, ultimate density is respectively 384 μm of ol/L, 192 μm of ol/L, 96 μm of ol/
L、48μmol/L、24μmol/L、12μmol/L、6μmol/L、3μmol/L。
The antineoplastic 5 FU 5 fluorouracil and Chrysin of listing are made into reference substance solution with same condition.
Test procedure
It is 3 × 10 that 96 orifice plates, which add concentration per hole,4Individual/mL μ the L of cell suspension 100, i.e., 3000 cells/wells put 37
DEG C, 5%CO2In incubator.After 24 hours, sample liquid and reference substance liquid are separately added into, 10 μ L/ holes, 37 DEG C act on 72 hours.Often
Hole adds the 5mg/mL μ L of MTT (3- (4,5- dimethylthiazole -2- bases) -2,5- diphenyltetrazoliumbromide father-in-law bromide) solution 20, makees
With lysate DMSO is added after 4 hours, 100 μ L/ holes are put in incubator, and the secondary daily full-automatic ELIASAs of MK-2 survey 570nm OD
Value.Calculation of half inhibitory concentration IC50.
Result of the test refers to table 1, wherein, sample refers to the Chrysin benzimidizole derivatives 1-21 newly synthesized, embodiment
1-9 is the specific synthetic method and result of a portion compound.
Half-inhibition concentration IC50 (the units of the compound on tumor cell of table 1：μmol/L)
Anti-proliferativeactivityofcompoundsagainstthecancercelllines
SD=standarddeviation,
N.D=notdetected
Above test result indicate that, compound of the invention has good antitumor activity, and Chrysin benzimidazole spreads out
It is biological to gastric carcinoma cells MGC-803, human liver cancer cell HepG2, human breast cancer cell line Bcap-37 has show a certain degree of
Inhibitory activity, wherein compound 16 are imitated to gastric carcinoma cells MGC-803, human liver cancer cell HepG2, human breast cancer cell line Bcap-37
Fruit will be cooked further anti-tumor activity test in vivo than more significant with No. 16 compounds.Because new synthesis compound is to people
The effect of stomach cancer cell MGC -803 is good compared with other, therefore is built just from mouse stomach cancer cell MFC in anti-tumor activity test in vivo
Normal mouse tumor model.Embodiment 11：The internal anti-tumor activity test of No. 16 compounds of the invention
Experimental animal prepares：38 week old of healthy male mice 3~4 of experimental animal are randomly divided into 5 groups：Administration group (senior middle school
Low each 7 of Three doses), positive controls (5-Fluorouracil) 7, negative control group 10, raise with autoclaving water and feeding
Material, receptacle relative humidity 55% ± 10%, temperature (22 ± 2) DEG C, illumination 12h, light and shade alternating.
DMEM culture mediums, hyclone etc. needed for cell cultivation process are purchased from Gibco companies of the U.S..Microsurgery is real
Test after operating theater instruments is purchased from Shanghai City medicine equipment parent company, autoclaving and use.
After the mouse stomach cancer cell MFC cell recoveries frozen, in the DMEM culture mediums containing 10% hyclone,
37 DEG C, 5%CO2Cultivate, pass in incubator, culture to exponential phase, after pancreatin digestion with physiological saline it is resuspended into 1 ×
107/ mL cell suspensions, are being subcutaneously injected cell suspension, are forming a skin mound in the middle part of veutro on the left of mouse, include 0.2mL cells and hang
Liquid (2 × 106It is individual), 38 are inoculated with altogether, and about 125mm is reached in gross tumor volume3Start experiment when (being defined as the 0th day).
Observation and materials：The free drinking water of all mouse models, every two days observation mouse weights, the state of mind, ingest,
Activity and nourishment.Every two days observation mouse are subcutaneous into knurl situation, measurement subcutaneous tumors major diameter (a) and wide footpath (b), meter after modeling
Calculate volume (V=a × b2), using gross tumor volume and growth time as coordinate, draw growth curve.The knurl time is recorded as simultaneously,
Tumor shape, tumor surface skin conditions.After 2 weeks, all mouse and excised tumor are put to death, tumor size is observed.
Experimental result is shown in Fig. 2, and growth of the compound of experimental result 16 to mouse tumor has good inhibiting effect, and in dense
Dependence is spent, research and discussion further can be carried out to the mechanism of action of compound.
Fig. 2 is the growth curve of drafting using gross tumor volume and growth time as coordinate.
Presently preferred embodiments of the present invention is the foregoing is only, is not intended to limit the invention, all essences in the present invention
Any modification, equivalent and improvement made within refreshing and principle etc., should be included within the scope of the present invention.
Claims (4)
1. one kind suppresses the antitumor drug candidates of HIF-1 α, it is characterised in that the antitumor drug candidates of the suppression HIF-1 α are：
R1=CH3, R2=R3=H
R1=OCH3, R2=R3=H
R1=Cl, R2=R3=H
R1=C6H5, R2=R3=H
R1=CF3, R2=R3=H
R2=CH3, R1=R3=H
R2=OCH3, R1=R3=H
R3=NO2, R1=R2=H
R2=R3=CH3, R1=H.
2. a kind of preparation method of the antitumor drug candidates of suppression HIF-1 α as claimed in claim 1, it is characterised in that the suppression
The preparation method of the antitumor drug candidates of HIF-1 α processed comprises the following steps：
Step one, Chrysin, Anhydrous potassium carbonate and acetone are sequentially added in 250mL round-bottomed flasks, heating stirring flows back, then by
1,2- Bromofumes or 1,3- dibromopropane or Isosorbide-5-Nitrae-dibromobutane are added dropwise to, 60 DEG C of heating condensing refluxes, solution becomes clarification again
Become cloudy；Reaction process, column chromatography purifying are detected, eluant, eluent is：Methanol: dichloromethane=1: 50；
Step 2, benzimidizole derivatives are added in 250mL there-necked flasks, it is dissolved in 100mL acetone, are added potassium carbonate,
Stir after 10min, add the chrysin derivative of purifying obtained by step one, TBAB is heated to 60 DEG C of stirring reactions,
It is extracted with ethyl acetate, organic layer is washed with saturated common salt, then with anhydrous sodium sulfate drying, solvent under reduced pressure uses silica gel after being evaporated
Post separation is to obtain target compound, and eluant, eluent is：Methanol: dichloromethane=1: 50.
3. the preparation method of the antitumor drug candidates of the suppression HIF-1 α as claimed in claim 2, it is characterised in that described
In step one：Chrysin 2.54g, 0.01mol, Anhydrous potassium carbonate 5.52g, 0.04mol are sequentially added in 250mL round-bottomed flasks
And acetone 100ml；1,2- Bromofume or 1,3- dibromopropane or Isosorbide-5-Nitrae-dibromobutane 0.04mol.
4. the preparation method of the antitumor drug candidates of the suppression HIF-1 α as claimed in claim 2, it is characterised in that described
In step 2：Benzimidizole derivatives 0.015mol, Anhydrous potassium carbonate 5.52g are sequentially added in 250mL round-bottomed flasks,
0.04mol, the chrysin derivative 0.01mol of purifying, TBAB 0.03g, 0.0001mol and acetone obtained by step one
100ml。
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| CN114057736A (en) * | 2021-11-15 | 2022-02-18 | 北京师范大学 | Synthesis method of chrysin bridged indole derivatives and application of chrysin bridged indole derivatives in anti-tumor direction |
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| CN103108633A (en) * | 2010-06-09 | 2013-05-15 | 爱默蕾大学 | Trkb agonists and methods of use |
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| CN103108633A (en) * | 2010-06-09 | 2013-05-15 | 爱默蕾大学 | Trkb agonists and methods of use |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114057736A (en) * | 2021-11-15 | 2022-02-18 | 北京师范大学 | Synthesis method of chrysin bridged indole derivatives and application of chrysin bridged indole derivatives in anti-tumor direction |
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Application publication date: 20170714 |