CN102920709B - Application of 2,3-dihydro-3-hydroxmethyl-6-methyl-[1,4]-benzoxazine in preparation of anti-breast cancer drug - Google Patents
Application of 2,3-dihydro-3-hydroxmethyl-6-methyl-[1,4]-benzoxazine in preparation of anti-breast cancer drug Download PDFInfo
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Abstract
The invention discloses an application of 2,3-dihydro-3-hydroxmethyl-6-methyl-[1,4]-benzoxazine in preparation of an anti-breast cancer drug, wherein the concentration of 2,3-dihydro-3-hydroxmethyl-6-methyl-[1,4]-benzoxazine which can effectively promote apoptosis of the human breast cancer cell MCF-7 is 50 uM. Tests show that 0.5 uM of the compound can inhibit growth of 50% human breast cancer cells; 50 uM of the compound can significantly retard the human breast cancer cell cycle, and induce apoptosis; and the in-vivo test can effectively inhibit growth of solid tumors in a mice without obvious toxic and side effects. Therefore, 2,3-dihydro-3-hydroxmethyl-6-methyl-[1,4]-benzoxazine can be taken as an effective, safe and reliable drug for treating breast cancer, and has development application prospect.
Description
Technical field
The present invention relates to the application of a kind of benzo-oxazine derivative in preparing anti-breast cancer medicines, relate in particular to a kind of 2, the 3-dihydro-3-hydroxymethyl-6-methyl-application of [Isosorbide-5-Nitrae]-benzoxazinyl in preparing anti-breast cancer medicines.
Background technology
Breast carcinoma is the highest cancer of incidence rate in women's malignant tumor, and sickness rate is ascendant trend year by year.Patient with breast cancer's primary treatment means are operation and chemotherapeutics, as paclitaxel etc.But treatment also exists serious untoward reaction simultaneously, be badly in need of the new determined curative effect of exploitation and safe and reliable cancer therapy drug.
2,3-dihydro-[Isosorbide-5-Nitrae]-benzo-oxazine derivatives are the very important construction units of a class, and this construction unit is proved has many pharmaceutically actives.Known 2,3-dihydro-2-replaces-[1,4]-benzo-oxazine derivatives have the pharmacologically actives such as antibacterial, antithrombotic, bradycardia, anti-central nervous system (CNS) be disorderly, as related as the patent No. patent that is US6649610, WO2005051934, WO2005058847 2,3-dihydro-2-replacement-[Isosorbide-5-Nitrae]-benzo-oxazine derivative structures; 2,3-dihydro-2,3-bis-replaces-[1,4]-benzo-oxazine derivatives have the pharmacologically actives such as analgesia, calmness, relieving constipation, as related as the patent No. patent that is GB1285711, GB1182770, GB883324 2,3-dihydro-2,3-bis-replacement-[Isosorbide-5-Nitrae]-benzo-oxazine derivative structures; In addition, contain substituent 2 on other position (as nitrogen and phenyl ring), 3-dihydro-[1,4]-benzo oxazinyl compounds have flesh pine, analgesia, schizophrenia, Antiparkinsonian, antiinflammatory, analgesic, prevention coronary heart disease and the pharmacological actions such as arteriosclerosis, inhibition phosphodiesterase, as related as the patent No. patent that is US3879522, GB1173942, WO8907596, WO2004087694, WO0230914, JP2000327663 2,3-dihydro-[Isosorbide-5-Nitrae]-benzo-oxazine derivative structures.Yet people are to 2; 3-dihydro-3-replaces-[1; 4] structure of-benzo-oxazine derivatives, activity and study on the synthesis are still rare; the patent that is only US6872823, US2006014946 just like the patent No. relate to 2; 3-dihydro-3-methyl-[1; 4]-benzo-oxazine derivative, this compounds is mainly as the important intermediate of synthetic Comprecin and plant protection product.Make a general survey of the benzoxazine compound of having delivered, find to there is not yet and report for work at the detailed drug effect aspect treatment breast carcinoma and pharmacological research about 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl.
Summary of the invention
For the deficiency of existing breast cancer treatment, it is a kind of 2 that the problem to be solved in the present invention is to provide, the 3-dihydro-3-hydroxymethyl-6-methyl-application of [Isosorbide-5-Nitrae]-benzoxazinyl in preparing anti-breast cancer medicines.
Of the present invention 2, the 3-dihydro-3-hydroxymethyl-6-methyl-application of [Isosorbide-5-Nitrae]-benzoxazinyl in preparing anti-breast cancer medicines.
Wherein: can effectively promote 2 of apoptosis in breast cancer cell line MCF-7,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl concentration are 50 μ M.
Of the present invention 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl chemical constitutions are as shown in general formula (I):
Above-mentioned 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl make with following method:
Under reflux temperature, to the EtOH/H of 2-nitro-4-methyl Phenoxymethyl oxirane (1.254g, 6mmol) and acetic acid (3mL, 53mmol)
2o(v/v=9: 1,300mL) add iron powder (1.008g, 18mmol) in solution.Reactant mixture continues 70 minutes (the TLC detection reaction is complete) that reflux.Cooling, to room temperature, with saturated Na
2cO
3solution is adjusted its pH=8, with the celite sucking filtration, concentrates the ethanol in filtrate, with ethyl acetate extraction (15mL * 3).The washing organic facies, anhydrous MgSO
4drying, conventional filtration, concentrated, obtain crude product.
Above-mentioned crude product is separated with silica gel column chromatography (petrol ether/ethyl acetate=1: 3), obtain 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl.
In order to understand better essence of the present invention, below by pharmacological evaluation and the result of 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl, its application in preparing anti-breast cancer medicines is described.
Cultivate human breast cancer cell MCF-7 with conventional method, and the collection growth conditions is good and the cell in logarithmic (log) phase is used for experimentation.Adopt the Celluar and Molecular Biology method to test as follows, observe the impact of 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl on human breast cancer cell.
(1) after adding 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl to human breast cancer cell MCF-7, observe it than the change of cellular control unit number and form
The take the logarithm MCF-7 human breast cancer cell of phase, adding concentration in culture medium is 2 of 50 μ M, 3-dihydro-3-hydroxymethyl-6-methyl-[1,4]-benzoxazinyl, process 12h, 48h, using DMSO as the solvent control group, examine under a microscope the variation of breast cancer cell morphology and number, found that 2, breast cancer cell after 3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]- benzoxazinyl processing 12h and 48h is than the minimizing of the cell number of solvent control group and obvious morphological change (see figure 1) has occurred.
(2) quantitative analysis 2, the drug effect of 3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl to human breast cancer cell
Human breast cancer cell MCF-7 is inoculated in 96 orifice plates, through 2 of variable concentrations (100,80,60,50,10,1,0.5,0.25,0.1,0.05,0.01 μ M), 3-dihydro-3-hydroxymethyl-6-methyl-[1,4] after-benzoxazinyl are processed 48h, detect respectively the number of living cells by the SRB method, calculate survival rate.Survival rate=when dosing 0h (experimental group absorbance-absorbance) ÷ when dosing 0h (matched group OD value-absorbance) (take not celliferous culture fluid as the absorbance measurement blank background), experimental result: 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl act on human breast cancer cell MCF-7 half growth inhibitory concentration GI
50be 0.5 μ M.
(3) compound 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl effect human breast cancer cell inducing cell apoptosis situations
The take the logarithm MCF-7 human breast cancer cell of phase, adding respectively concentration in culture medium is 2 of 80,60,50,30,10,1 μ M, 3-dihydro-3-hydroxymethyl-6-methyl-[1,4]-benzoxazinyl, after effect 6h, 12h, 24h, 48h, discovery can effectively promote 2 of apoptosis in breast cancer cell line MCF-7, and 3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl optium concentrations are 50 μ M.
Use flow cytometry, found that concentration is 2 of 50 μ M, 3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl have the apoptosis-induced effect (see figure 2) of time dependence to human breast cancer cell MCF-7.
(4) at Mice Body inner evaluation compound 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl safeties
The BALB/C mice of 20g left and right is divided into to eight groups, 3 every group.Carry out respectively the compound 2 of disposable tail vein injection 40,20,10mg/kg, 3-dihydro-3-hydroxymethyl-6-methyl-[1,4]-benzoxazinyl and solvent, in 12h three gavages give 360,180, the compound 2 of 90mg/kg, 3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl and solvent.Observe and put to death afterwards in 14 days, dissect and get organ, routine blood test and blood biochemistry detection are carried out in blood sampling.Found that: in experimentation, without dead mouse and dystropy situation, body weight does not significantly descend, organ coefficient is normal, the routine blood test blood biochemistry index all in the reasonable scope.With the These parameters evaluation, determine that 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl is to BALB/C mice safety (body weight change is shown in Fig. 3 and Fig. 4).
(5) 2,3-dihydro-3-hydroxymethyls-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl is estimated the antitumor drug effect of tumor bearing nude mice
Set up human breast cancer cell MCF-7 solid tumor animal model with the BALB/C nude mice.Treat that solid tumor grows to 150-200mm
3the time, minute two groups of difference tail vein injection compounds 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl 40mg/kg and solvent.Every other day be administered once, altogether be administered five times.Detect tumor size every day, nude mice body weight, mortality rate.Solid tumor reaches 2000mm
3the time, put to death nude mice.Check result shows, application compound 2, and 3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl groups are compared with the solvent control group, and the medication group has significantly suppressed the growth of tumor, suppression ratio is that 50%(is shown in Fig. 5).
By above-mentioned experiment and result thereof, find that 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl are significant on the impact of human breast cancer cell.It is compound 2,3-dihydro-3-hydroxymethyl-6-methyl-[1,4]-benzoxazinyl can cause the growth inhibitory effect of human breast cancer cell 50% at 0.5 μ M, 50 μ M can obviously cause human breast cancer cell Cycle Arrest apoptosis-induced, in in vivo test 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl can effectively suppress the growth of mouse entity tumor and without obvious toxic-side effects.Indication 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl are expected to become the effective and safe and reliable medicine of anti-breast cancer, have development prospect.
The accompanying drawing explanation
Fig. 1: after 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae] ,-benzoxazinyl effect breast cancer cells, examine under a microscope cellular morphology and change and the number change situation.
Wherein, the little figure in upper left is 50 μ M2,3-dihydro-3-hydroxymethyl-6-methyl-[1,4]-benzoxazinyl effect 12h, the little figure in upper right is 50 μ M 2,3-dihydro-3-hydroxymethyl-6-methyl-[1,4]-benzoxazinyl effect 48h, the little figure in lower-left is DMSO effect 12h, the little figure in bottom right is DMSO effect 48h.
Fig. 2: the two methods of dying of Annexin V-FITC/PI detect 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl and induce human breast cancer cell MCF-7 apoptosis phenomenon.
Wherein, used 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl concentration are 50 μ M, and abscissa is action time 6h, 12h, 24h, 48h, and vertical coordinate is the ratio of apoptotic cell in tested cell mass.
Fig. 3: BALB/C mice tail vein injection compound 2, the body weight change situation of 14 days after 3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl.
Wherein, abscissa be time after administration (my god), vertical coordinate is Mouse Weight (gram).
Fig. 4: BALB/C mice gastric infusion compound 2, the body weight change situation of 14 days after 3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl.
Wherein, abscissa be time after administration (my god), vertical coordinate is Mouse Weight (gram).
Fig. 5: estimate the drug effect that 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae] ,-benzoxazinyl suppress tumor growth in human breast cancer cell MCF-7 solid tumor animal model.
Wherein, abscissa for administration for the first time after the time (my god), vertical coordinate is gross tumor volume (cubic millimeter).
The specific embodiment
Embodiment 1
The preparation of 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl
Under reflux temperature, to the EtOH/H of 2-nitro-4-methyl Phenoxymethyl oxirane (1.254g, 6mmol) and acetic acid (3mL, 53mmol)
2o(v/v=9: 1,300mL) add iron powder (1.008g, 18mmol) in solution.Reactant mixture continues 70 minutes (the TLC detection reaction is complete) that reflux.Cooling, to room temperature, with saturated Na
2cO
3solution is adjusted its pH=8, with the celite sucking filtration, concentrates the ethanol in filtrate, with ethyl acetate extraction (15mL * 3).The washing organic facies, anhydrous MgSO
4drying, conventional filtration, concentrated, obtain crude product.
Above-mentioned crude product is separated with silica gel column chromatography (petrol ether/ethyl acetate=1: 3), obtain 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl (0.839g, 78%).
Structural formula is as follows:
Molecular formula: C
10h
13nO
2
Molecular weight: 179.22
Character: white solid
Fusing point: 122-123 ℃
Nuclear magnetic resonance data is as follows:
1H?NMR(CDCl
3,400MHz)δ:2.24(s,3H),3.14(dd,J=1.9,12.8Hz,1H),3.28(br?s,2H),3.37(dd,J=3.9,12.8Hz,1H),3.80(dd,J=1.5,12.3Hz,1H),3.89-3.95(m,1H),4.25(dd,J=2.7,12.3Hz,1H),6.60(s,1H),6.64(d,J=8.0Hz,1H),6.90(d,J=8.0Hz,1H)。
Mass spectrometric data is as follows:
EIMS(m/z,%):179(M
+,48),135(54),134(100),107(13),77(13)。
The elementary analysis data are as follows:
Anal.Calcd?for?C
10H
13NO
2:C,67.02;H,7.31;N,7.82;Found:C,66.80;H,7.36;N,7.49。
Ir data is as follows:
IR(KBr)v:3361,3272,2952,2920,1520,1305,1289,1066cm
-1。
Measure 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl to the breast cancer cell half-inhibition concentration of growing
Contain 5%CO at 37 ℃
2environment under, with DMEM/10% hyclone culture medium culturing human breast cancer cell MCF-7.The phase human breast cancer cell MCF-7 that takes the logarithm is inoculated in 96 orifice plates, cultivate 24h, add respectively 2 of variable concentrations (100,80,60,50,10,1,0.5,0.25,0.1,0.05,0.01 μ M), 3-dihydro-3-hydroxymethyl-6-methyl-[1,4]-benzoxazinyl, after cultivation, detect respectively the number of living cells by the SRB method, calculate survival rate.
Concrete, dosing adds 50 μ L trichloroacetic acid solution (30%) after cultivating 48h, fixes one hour for 4 ℃.Get rid of solution, high purity water rinses 4 times, adds 100 μ L sulphonyl rhodamine B dyeing 30 minutes after drying, and after drying, with 1% acetum, rinses 4 times.After drying, add Tris solution 100 μ L fully to dissolve, on microplate reader, under the 540nm wavelength, measure absorbance.
Calculate survival rate according to absorbance, survival rate=when dosing 0h (experimental group absorbance-absorbance) ÷ when dosing 0h (matched group OD value-absorbance) (take not celliferous culture fluid as the absorbance measurement blank background).
Experimental result: 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl act on human breast cancer cell MCF-7 half growth inhibitory concentration GI
50be 0.5 μ M.
Embodiment 3
The two methods of dying of Annexin V-FITC/PI detect 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl effect human breast cancer cell inducing cell apoptosis situations
With conventional method, the take the logarithm MCF-7 human breast cancer cell of phase, adding respectively concentration in culture medium is 2 of 80,60,50,30,10,1 μ M, 3-dihydro-3-hydroxymethyl-6-methyl-[1,4]-benzoxazinyl, after effect 6h, 12h, 24h, 48h, observe and find effectively to promote 2 of apoptosis in breast cancer cell line MCF-7,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl optium concentrations are 50 μ M.
The take the logarithm MDA-MB-231 cell of trophophase, be inoculated in the 6cm culture dish by 200,000 cell number 3ml culture volumes, inoculates altogether 16 culture dishs.After 24 hours, 16 culture dishs are divided into four groups.In four culture dishs of every group, two culture dishs add DMSO, and two culture dishs add 2 of 50 μ M, 3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl.Four groups are hatched respectively 6h, 12h, 24h, 48h.Then at peptic cell on ice, the collecting cell suspension, centrifugal rear with PBS washing 2 times.Add Annexin V buffer 400 μ L to cell mass, add 4 μ L AnnexinV-FITC/4 μ LPI after suspendible is even, lucifuge room temperature dyeing 10 minutes.Organize negative contrast flow cytometry with DMSO, found that 2 of 50 μ M, 3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl have the apoptosis-inducing effect (see figure 2) of time dependence to human breast cancer cell MCF-7.
Embodiment 4
At BALB/C mice interior evaluating 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl safeties
The BALB/C mice of 20g left and right is divided into to eight dosage groups, 3 every group.Carry out respectively the compound 2 of disposable tail vein injection 40,20,10mg/kg, 3-dihydro-3-hydroxymethyl-6-methyl-[1,4]-benzoxazinyl and solvent (water), in 12 hours three gavages give 360,180,90mg/kg 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl and solvent (water).Detect Mouse Weight, mortality rate, dystropy situation in 14 days after administration.Within the 14th day after administration, put to death, dissect the heart, liver, spleen, lung, kidney are carried out to precise weighing.Routine blood test and blood biochemistry detection are carried out in blood sampling, and wherein routine blood test detects and comprises mean constant of red blood cell, leukocyte number, number of platelets and hemoglobin concentration, and the blood biochemistry detection comprises glutamate pyruvate transaminase, glutamic oxaloacetic transaminase, GOT, alkali phosphatase, blood urea nitrogen and creatinine.
Found that: in experimentation, without dead mouse and dystropy situation, body weight does not significantly descend, and organ coefficient is normal, the routine blood test blood biochemistry index is all within normal range.Comprehensive These parameters, estimate and think that 2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl are to BALB/C mice safety (body weight change is shown in Fig. 3 and Fig. 4).
2,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl is estimated the antitumor drug effect of tumor bearing nude mice
The take the logarithm human breast cancer cell MCF-7 of phase, adjusting concentration is 5,000,000/100 μ L, gently is suspended from the DMEM culture medium, subcutaneous injection, in the right back back of BALB/C nude mice in 4 week age, is set up human breast cancer cell MCF-7 solid tumor animal model.
Monitoring implanted solid tumor growth situation, by vernier calliper dipstick metering solid tumor length, width, with (length x width
2÷ 2) estimation solid tumor volume.Treat that solid tumor grows to 500mm
3the time, be passaged to another right back back of BALB/C nude mice in 4 week age, go down to posterity altogether in 20 nude mices.
Treat that solid tumor of new generation grows to 150-200mm
3the time, be chosen as 16 desirable nude mices of tumor and divide two groups of tail vein injections 2 respectively, 3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl 40mg/kg and solvent (water).Every other day be administered once, altogether be administered five times.Detect tumor size every day, nude mice body weight, mortality rate.Solid tumor reaches 2000mm
3the time, put to death nude mice.Check result shows, application compound 2, and 3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl groups are compared with the solvent control group, and the medication group has significantly suppressed the growth of tumor, suppression ratio is that 50%(is shown in Fig. 5).
Claims (2)
1.2, the 3-dihydro-3-hydroxymethyl-6-methyl-application of [Isosorbide-5-Nitrae]-benzoxazinyl in preparing anti-breast cancer medicines.
2. application as described in claim 1, it is characterized in that: can effectively promote 2 of apoptosis in breast cancer cell line MCF-7,3-dihydro-3-hydroxymethyl-6-methyl-[Isosorbide-5-Nitrae]-benzoxazinyl concentration are 50 μ M.
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