CN103319431A - 2-mercaptoacetophenone-containing 1, 3, 4-oxadiazole derivative, its preparation method and antitumor activity - Google Patents
2-mercaptoacetophenone-containing 1, 3, 4-oxadiazole derivative, its preparation method and antitumor activity Download PDFInfo
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- 150000005072 1,3,4-oxadiazoles Chemical class 0.000 title abstract description 6
- DIYFBIOUBFTQJU-UHFFFAOYSA-N 1-phenyl-2-sulfanylethanone Chemical compound SCC(=O)C1=CC=CC=C1 DIYFBIOUBFTQJU-UHFFFAOYSA-N 0.000 title abstract 5
- 230000000259 anti-tumor effect Effects 0.000 title description 5
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical class N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 claims description 19
- 238000004821 distillation Methods 0.000 claims description 16
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 16
- -1 2-sulfydryl methyl phenyl Chemical group 0.000 claims description 12
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 12
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Abstract
The invention relates to a 2-mercaptoacetophenone-containing 1, 3, 4-oxadiazole derivative, which is characterized by having a general formula as the following. In the formula, R1 represents the following, and R2 represents -H -Br. The 2-mercaptoacetophenone-containing 1, 3, 4-oxadiazole derivative provided in the invention has an inhibiting effect on MCF-7 and A431, and has a strong inhibitory effect on A431. Therefore, the 2-mercaptoacetophenone-containing 1, 3, 4-oxadiazole derivative disclosed in the invention can be a potential antitumor drug. The invention also discloses a preparation method of the 2-mercaptoacetophenone-containing 1, 3, 4-oxadiazole derivative.
Description
Technical field
The present invention relates to contain 1,3 of 2-sulfydryl methyl phenyl ketone, 4-oxadiazole derivative and preparation method thereof and purposes as antitumor drug.
Background technology
Ozone (O
3) be oxygen (O
2) a kind of isomer, the content in atmosphere only accounts for 1/100000000th, its concentration is different because of sea level elevation.Ozonosphere is the relatively high part of ozone concn in the atmospheric stratosphere; it mainly is centered around the overhead place of 20-25 kilometer height of outside of the earth; can absorb the following ultraviolet ray of wavelength 306.3nm in the sunlight; be that ((wavelength≤290nm), the mankind on preserving our planet and animals and plants exempt from the injury of short wave ultraviolet to part UV-B with whole UV-C for wavelength 290～300nm).
Since the Industrial Revolution, human a large amount of coal combustion and oil, to the countless waste gas of earth atmosphere discharging, chlorine fluorine gas (such as freonll-11) wherein can destroy the high-altitude ozonosphere, so that global ozonosphere attenuation, some areas even ozone hole occurred are after ozonosphere is destroyed, it absorbs ultraviolet ability and greatly reduces, so that the human chance of accepting excessive ultraviolet radiation increases greatly.Excessive ultraviolet radiation has increased the sickness rate of skin carcinoma greatly.Most of cases are relevant with excessive ultraviolet radiation.Studies show that, the every loss 1% of the ozone of ozonosphere, the sickness rate of skin carcinoma will increase by 2%, and only in the U.S., the annual skin carcinoma case that just has above 3,000,000 directly and is indirectly lost above 200,000,000 dollars.Yet for the methods for the treatment of of skin carcinoma, such as operative treatment, radiotherapy and chemotherapy have great limitation.Therefore, seek efficient anti-skin carcinoma medicine and new treatment target spot and become an important and urgent task.
Focal adhesion kinase (focal adhesion kinase, FAK) be a kind of non-acceptor TYR protein kinase, be the central element in the mediated by integrin signal transduction pathway, can affect cell proliferation and survival by regulating a series of downstream signal after its activation.In skin cells, FAK regulates the migration of cytoskeleton.Studies show that in a large number, the high expression level of FAK and the transfer of tumour, invasion and attack are relevant.Therefore, the compound of inhibition FAK can be used as potential anti-skin carcinoma medicine.
1,3,4-oxadiazole is widely used in the pharmaceutical chemistry field, early stage studies show that, contains 1,3, the compound of 4-oxadiazole has multiple biological activity, and is such as anti-inflammatory, antibiotic, hypoglycemic etc., in addition, according to the people such as Usman Ghani, 1,3,4-oxadiazole derivative can be used as the kinase whose inhibitor of TYR.
Thioesters (Thioester) is the chemical substance that a sulphur atom and a part acyl group covalent attachment form, and general formula is R-S-CO-R '.Thioester bond is the high energy chemisty key, is similar to the inner high-energy phosphate bond of Triphosaden (ATP) that energy is provided in all organisms, and all ester bonds form the participation that all needs (comprising lipid) thioesters.These materials have participated in the synthetic of many kinds of substance in the cell, comprise peptide, lipid acid, sterol, terpenes, porphyrin and other.In addition, thioesters plays an important role in target ubiquitin degrade proteins.
On the basis of the above, we have designed and have a series ofly contained 1, the compound of 3,4-oxadiazole (anti-tumor activity is provided) and thioesters analogue (increasing compound to the targeting of receptor protein) estimates that this compounds can have good anti-tumor activity.
Summary of the invention
The object of the present invention is to provide a class to contain 1,3 of 2-sulfydryl methyl phenyl ketone, 4-oxadiazole derivative and their preparation method and purposes.
Technical scheme of the present invention is as follows:
One class contains 1,3 of 2-sulfydryl methyl phenyl ketone, and the 4-oxadiazole derivative is characterized in that it has following general formula:
R in the formula
1For:
R in the formula
2For:
——H
——Br
A kind ofly prepare above-mentioned 1,3 of the 2-sulfydryl methyl phenyl ketone that contains, the method for 4-oxadiazole derivative is characterized in that it is comprised of the following step:
Step 1: get the 1mmol carboxylic acid and add the 50mL dehydrated alcohol, and add the vitriol oil of 5mL, backflow is spent the night.Underpressure distillation approximately remains 1/5th, adds 20mL water, uses ethyl acetate extraction, and successively with saturated NaHCO3 and saturated NaCl washing, uses at last anhydrous MgSO4 dry, and underpressure distillation can obtain target compound.
Step 2: the ester that produces in the step 1 is dissolved in the dehydrated alcohol of 50mL, and adds the hydrazine hydrate of 15ml, backflow is spent the night.With reacted solvent underpressure distillation, until there is not liquid to flow out, add entry, obtain hydrazides.
Step 3: get in the round-bottomed flask that the hydrazides that obtains in the 1mmol step 2 joins 50mL, be dissolved in the 30mL dehydrated alcohol, add equimolar dithiocarbonic anhydride, (potassium hydroxide) refluxed 24 hours under alkaline condition, recrystallization obtains a series of 2-sulfo-s-1 after the reacting coarse product drying, 3,4 oxadiazole derivatives.
Step 4: get 1mmol step 3 gained 2-sulfo--1,3,4 oxadiazole derivatives and etc. molar mass 2-bromoacetophenone/2,4 '-dibromo-benzene ethyl ketone adds the round-bottomed flask of 25mL, and be dissolved in 5mL 80% ethanol, stirring at room 4-6h, unnecessary solvent is removed in underpressure distillation, then will react crude extract and pour in the frozen water, leave standstill 1-2h, filter, washing will obtain target compound with recrystallizing methanol after the gained drying precipitate.
Experimental result shows, novel 1 of the 2-sulfydryl methyl phenyl ketone that contains of the present invention, 3, the 4-oxadiazole derivative has restraining effect to breast cancer cell MCF-7 and cutaneous squamous cell carcinoma cell A431, wherein A431 there is strong restraining effect, so 1,3 of the 2-sulfydryl methyl phenyl ketone that contains of the present invention, the 4-oxadiazole derivative can be applied to prepare anti-skin carcinoma medicine.
Embodiment
Further describe the present invention by following examples, but scope of the present invention is not subjected to any restriction of these embodiment.
Embodiment one: the preparation of 2-(5-(2-hydroxy-4-methyl phenyl)-1,3,4-oxadiazole-2-sulfo-)-1-methyl phenyl ketone (compound 1).
Get 1mmol 4-cresotinic acid and add the 50mL dehydrated alcohol, and add the vitriol oil of 5mL, backflow is spent the night.Underpressure distillation approximately remains 1/5th, adds 20mL water, uses ethyl acetate extraction, and successively with saturated NaHCO3 and saturated NaCl washing, uses at last anhydrous MgSO4 dry, and underpressure distillation can obtain 4-cresotinic acid ester; 4-cresotinic acid ester is dissolved in the dehydrated alcohol of 50mL, adds the hydrazine hydrate of 15ml, backflow is spent the night.With reacted solvent underpressure distillation, until there is not liquid to flow out, add entry, obtain 4-cresotinic acid hydrazides; Hydrazides is put in the round-bottomed flask of 50mL, be dissolved in the 30mL dehydrated alcohol, the dithiocarbonic anhydride of the molar masss such as adding, (potassium hydroxide) refluxed 24 hours under alkaline condition, recrystallization obtains a series of 2-sulfo-s-1,3,4 oxadiazole derivatives after the reacting coarse product drying; The 2-sulfo--1 of molar mass such as get, 3,4 oxadiazole derivatives and 2-bromoacetophenone drop into the round-bottomed flask of 25mL, and it is dissolved in 5mL 80% ethanol, stirring at room 4-6h, unnecessary solvent is removed in underpressure distillation, then will react crude extract and pour in the frozen water, leaves standstill 1-2h, filter, washing with using recrystallizing methanol after the gained drying precipitate, obtains target compound.White powder, productive rate 83%, fusing point: 196-198 ℃,
1H NMR (300MHz, CDCl
3-d
6) δ: 2.39 (d, J=6.03Hz, 3H); (4.98 s, 2H); (6.82 d, J=8.07Hz, 1H); (6.93 t, J=6.00Hz, 1H); (7.51-7.59 m, 3H); (7.65 t, J=7.50Hz, 1H); (8.05 t, J=4.50Hz, 2H); (9.73 s, 1H); MS (ESI): 327.37 (C
17H
15N
2O
3S, [M+H]
+) .Anal.Calcd for C
17H
14N
2O
3S:C, 62.56; H, 4.32; N, 8.58; Found:C, 62.48; H, 4.31; N, 8.62.
Embodiment two: the preparation of 2-(5-(4-(dimethylamino) phenyl)-1,3,4-oxadiazole-2-sulfo-)-1-methyl phenyl ketone (compound 2).
The preparation method is with embodiment one, and the 4-dimethylaminobenzoic acid replaces the 4-cresotinic acid, gets target compound.Faint yellow solid, productive rate 88%, fusing point: 203-204 ℃,
1H NMR (300MHz, CDCl
3-d
6) δ: 4.98 (s, 2H); (5.32 s, 6H); (7.55 t, J=7.50Hz, 4H); (7.67 t, J=7.32Hz, 1H); (7.91 d, J=8.61Hz, 2H); (8.05 d, J=7.68Hz, 2H) .MS (ESI): 340.41 (C
18H
18N
3O
2S, [M+H]
+) .Anal.Calcd for C
18H
17N
3O
2S:C, 63.70; H, 5.05; N, 12.38.Found:C, 63.64; H, 5.03; N, 12.44.
Embodiment three: the preparation of 2-(5-(2-hydroxyl-4-toluene)-1,3,4-oxadiazole-2-sulfo-)-1-methyl phenyl ketone (compound 3).
The preparation method replaces the 4-cresotinic acid with embodiment one with 4-methoxyl group Whitfield's ointment, gets target compound.White powder, productive rate 83%, fusing point: 195 ℃,
1H NMR (300MHz, CDCl
3-d
6) δ: 3.89 (d, J=13.5Hz; 3H); (4.96 s, 2H); (5.35 s, 1H); (6.57 d, J=2.61Hz, 1H); (6.61 s, 1H), 7.54 (t, J=4.62Hz, 2H); 7.59 (d, J=2.61Hz; 1H); 7.66 (t, J=4.44Hz; 1H); 8.05 (d, J=2.39Hz; 2H) .MS (ESI): 343.37 (C
17H
15N
2O
4S, [M+H]
+) .Anal.Calcd for C
17H
14N
2O
4S:C, 59.74; H, 4.22; N, 8.18.Found:C, 59.66; H, 4.23; N, 8.21.
Embodiment four: the preparation of 2-(5-(2-amino piperidine)-1,3,4-oxadiazole-2-sulfo-)-1-methyl phenyl ketone (compound 4).
The preparation method replaces the 4-cresotinic acid with embodiment one with 2-amino-4-pyridine carboxylic acid, gets target compound.Pale yellow powder, productive rate 83%. fusing points: 208 ℃,
1H NMR (300MHz, CDCl
3-d
6) δ: 5.01 (s, 2H); (7.12 s, 1H); (7.23 d, J=5.76Hz, 1H); (7.54 t, J=4.62Hz, 3H); (7.66 s, 2H); 8.05 (d, J=2.11Hz; 3H) .MS (ESI): 313.25 (C
15H
13N
4O
2S, [M+H]
+) .Anal.Calcd for C
15H
12N
4O
2S:C, 57.68; H, 3.87; N, 17.94.Found:C, 57.59; H, 3.88; N, 17.98.
Embodiment five: the preparation of 2-(5-(2-Chloperastine-4-ethyl)-1,3,4-oxadiazole-2-sulfo-)-1-methyl phenyl ketone (compound 5).
The preparation method replaces the 4-cresotinic acid with embodiment one with the 2-chlorine apellagrin, gets target compound.White powder, productive rate 81%, fusing point: 165 ℃,
1H NMR (300MHz, CDCl
3-d
6) δ: 5.01 (s, 2H); (7.54 t, J=4.62Hz, 2H); (7.67 t, J=4.44Hz, 1H); (7.81 s, 1H); (7.90 s, 1H); 8.06 (d, J=4.50Hz; 2H); (8.57 s, 1H) .MS (ESI): 332.78 (C
15H
11ClN
3O
2S, [M+H]
+) .Anal.Calcd for C
15H
10ClN
3O
2S:C, 54.40; H, 3.04; N, 12.67; Found:C, 54.36; H, 3.05; N, 12.69.
Embodiment six: the preparation of 1-(4-bromobenzene)-2-(5-(2-hydroxyl-4-toluene)-1,3,4-oxadiazole-2-sulfo-) ethyl ketone (compound 6).
Get 1mmol 4-cresotinic acid and add the 50mL dehydrated alcohol, and add the vitriol oil of 5mL, backflow is spent the night.Underpressure distillation approximately remains 1/5th, adds 20mL water, uses ethyl acetate extraction, and uses successively saturated NaHCO
3With saturated NaCl washing, use at last anhydrous MgSO
4Drying, underpressure distillation can obtain 4-cresotinic acid ester; 4-cresotinic acid ester is dissolved in the dehydrated alcohol of 50mL, adds the hydrazine hydrate of 15ml, backflow is spent the night.With reacted solvent underpressure distillation, until there is not liquid to flow out, add entry, obtain 4-cresotinic acid hydrazides; Hydrazides is put in the round-bottomed flask of 50mL, be dissolved in the 30mL dehydrated alcohol, the dithiocarbonic anhydride of the molar masss such as adding, (potassium hydroxide) refluxed 24 hours under alkaline condition, recrystallization obtains a series of 2-sulfo-s-1,3,4 oxadiazole derivatives after the reacting coarse product drying; The 2-sulfo--1,3 of molar mass such as get, 4 oxadiazole derivatives and 2,4 '-dibromo-benzene ethyl ketone drops into the round-bottomed flask of 25mL, and it is dissolved in 5mL 80% ethanol, and stirring at room 4-6h, unnecessary solvent is removed in underpressure distillation, then will react crude extract pours in the frozen water, leave standstill 1-2h, filter, washing, with using recrystallizing methanol after the gained drying precipitate, obtain target compound.White powder, productive rate 84%, fusing point: 237-238 ℃,
1H NMR (300MHz, CDCl
3-d
6) δ: 2.38 (s, 3H); (4.91 s, 2H); (6.82 d, J=8.22Hz, 1H); (6.92 s, 1H); (7.58 d, J=8.04Hz, 1H); (7.60 d, J=8.40Hz, 2H); (7.92 d, J=8.40Hz, 2H); (9.70 s, 1H); MS (ESI): 406.27 (C
17H
14BrN
2O
3S, [M+H]
+) .Anal.Calcd for C
17H
13BrN
2O
3S:C, 50.38; H, 3.23; N, 6.91; Found:C, 50.43; H, 3.22; N, 6.89.
Embodiment seven: the preparation of 1-(4-bromobenzene)-2-(5-(4-(dimethylamino) phenyl)-1,3,4-oxadiazole-2-sulfo-) ethyl ketone (compound 7).
Aminobenzoic acid substitution 4-cresotinic acid gets target compound.White powder, productive rate 85%, fusing point: 197-198 ℃,
1H NMR (300MHz, CDCl
3-d
6) δ: 3.55 (s, 6H); (4.97 s, 2H); (7.51 d, J=8.22Hz, 2H); (7.67 d, J=8.40Hz, 2H); (7.92 d, J=8.43Hz, 4H) .MS (ESI): 419.31 (C
18H
17BrN
3O
2S, [M+H]
+) .Anal.Calcd for C
18H
16BrN
3O
2S:C, 55.69; H, 4.44; N, 6.49.Found:C, 55.65; H, 4.45; N, 6.45.
Embodiment eight: the preparation of 1-(4-bromobenzene)-2-(5-(2-hydroxyl-4-toluene)-1,3,4-oxadiazole-2-sulfo-) ethyl ketone (compound 8).
The preparation method replaces the 4-cresotinic acid with embodiment six with the 4-methoxybenzoic acid, gets target compound.White powder, productive rate 86%, fusing point: 229-230 ℃,
1H NMR (300MHz, CDCl
3-d
6) δ: 3.89 (d, J=7.64Hz, 3H); (4.98 s, 2H); (5.35 s, 1H); (6.58 t, J=6.40Hz, 2H); (7.59 d, J=8.61Hz, 1H); (7.68 d, J=8.58Hz, 2H); (7.92 d, J=8.61Hz, 2H) .MS (ESI): 422.27 (C
17H
14BrN
2O
4S, [M+H]
+) .Anal.Calcd for C
17H
13BrN
2O
4S:C, 48.47; H, 3.11; N, 6.65.Found:C, 48.42; H, 3.12; N, 6.61.
Embodiment nine: the preparation of 2-(5-(2-amino piperidine-4-ethyl)-1,3,4-oxadiazole-2-sulfo-)-1-(4-bromobenzene) ethyl ketone (compound 9).
The preparation method replaces the 4-cresotinic acid with embodiment six with the amino 4-pyridine carboxylic acid of 2-, gets target compound.Yellow powder, productive rate 87%, fusing point: 200 ℃,
1H NMR (300MHz, CDCl
3-d
6) δ: 4.98 (s, 2H); (7.18 d, J=9.15Hz, 1H); (7.35 d, J=8.80Hz, 1H); (7.59 d, J=8.61Hz, 2H); (7.68 d, J=8.43Hz, 1H); (7.76 d, J=8.58Hz, 1H); (7.92 d, J=8.61Hz, 2H); (8.14 d, J=5.67Hz, 1H) .MS (ESI): 392.24 (C
15H
12BrN
4O
2S, [M+H]
+) .Anal.Calcd for C
15H
11BrN
4O
2S:C, 46.05; H, 2.83; N, 14.32.Found:C, 46.01; H, 2.82; N, 14.37.
Embodiment ten: the preparation of 1-(4-bromobenzene)-2-(5-(2-Chloperastine-4-ethyl)-1,3,4-oxadiazole-2-sulfo-) ethyl ketone (compound 10).
The preparation method replaces the 4-cresotinic acid with embodiment six with the 2-chlorine apellagrin, gets target compound.White powder, productive rate 79%, fusing point: 177 ℃,
1H NMR (300MHz, CDCl
3-d
6) δ: 5.01 (s, 2H); (7.54 t, J=4.62Hz, 2H); (7.67 t, J=4.44Hz, 2H); (7.90 s, 1H); (8.06 d, J=4.5Hz, 1H); (8.57 s, 1H) .MS (ESI): 411.67 (C
15H
10BrClN
3O
2S, [M+H]
+) .Anal.Calcd for C
15H
9BrClN
3O
2S:C, 43.87; H, 2.21; N, 10.23.Found:C, 43.76; H, 2.22; N, 10.27.
Embodiment 11: contain 2-and dredge 1,3 of benzoylformaldoxime, 4-oxadiazole derivative antitumor activity
1. experiment material and method
1.1 medicine and reagent
Adopting MTT[3-(4,5)-two methyl-2-thiazole-(2,5)-phenyl bromination tetrazole blue] method measures and contains 1,3 of 2-sulfydryl methyl phenyl ketone, and the 4-oxadiazole derivative is to the 503nhibiting concentration of MCF-7 and A431, i.e. IC
50
(1) preparation of nutrient solution (every liter): 1. suspension cell: RPMI-1640 cultivates one bag in powder (10.4g), new-born calf serum 100ml, penicillin solution (200,000 U/ml) 0.5ml, Streptomycin sulphate solution (200,000 U/ml) 0.5ml, after adding the tri-distilled water dissolving, the NaHCO with 5.6%
3Solution transfers pH value to 7.2-7.4, is settled at last 1000ml.Filtration sterilization.2. attached cell: the same, add again NaHCO
32.00g, HEPES2.38g.
(2) preparation of D-Hanks damping fluid (every liter): NaCl 8.00g, KCl 0.40g, Na2HPO
412 H
2O 0.06g, KH
2PO
40.06g, NaHCO
30.35g.Autoclaving.
(3) preparation of trypsin solution: utilizing the D-Hanks damping fluid to be made into concentration is 0.5% trypsin solution.Filtration sterilization.
(4) preparation of experiment liquid: specimen is made into storing solution with a small amount of tri-distilled water dissolving, general 10 times of preparation storing solutions by the experiment maximum concentration.Different according to compound dissolution, available tri-distilled water directly dissolves, or with a small amount of DMSO hydrotropy, adds the tri-distilled water dissolving again.The concentration of DMSO in nutrient solution is unsuitable excessive, and the final concentration of DMSO generally is no more than 0.05%-0.1% in the every porocyte suspension after the dosing.Storing solution is stored in-20 ℃ of refrigerators for subsequent use.
(5) cultivation of MCF-7 and A431: be the adherent growth cell, cellar culture (contains 10% calf serum, 100U/ml Streptomycin sulphate) in the RPMI-1640 nutrient solution, put 37 ℃, 5% CO
2Cultivate in the incubator, went down to posterity once every 3-4 days.Discard first original fluid when going down to posterity, again with the washing of D-Hanks damping fluid; Then use 0.5% tryptic digestion about 30 seconds, add a small amount of fresh medium and stop digestion; Piping and druming makes attached cell split away off from the culturing bottle wall; Pipette in right amount to the fresh culture bottle, replenish again fresh medium to original volume (nutrient solution volume be about culturing bottle capacity 1/10).
(6) cell is hatched: the above-mentioned tumour cell in the vegetative period of taking the logarithm, transferring concentration of cell suspension is 2 * 10
4Individual/ml.Every hole adds cell suspension 100 μ l in 96 well culture plates, puts 37 ℃, 5%CO
2Cultivate 24h in the incubator.After cultivating 24h, add liquid by design respectively.
(7) dosing: will test liquid and join respectively in each hole according to the concentration gradient of ultimate density, each concentration is established 6 parallel holes.Experiment is divided into drug test group (the test medicine that adds respectively different concns), control group (only add nutrient solution and cell, do not add the test medicine) and blank group (only add nutrient solution, do not add cell and test medicine).96 orifice plates after the dosing are placed 37 ℃, 5%CO
2Cultivate 48h in the incubator.
(8) mensuration of survivaling cell: in having cultivated 96 orifice plates behind the 48h, every hole adds MTT 40 μ l (being made into the MTT of 2.5mg/ml with 40 μ l PBS).Behind 37 ℃ of placement 4h, remove supernatant liquor.Every hole adds 100 μ l extracting solutions (10%SDS-5% isopropylcarbinol-0.01M HCl).37 ℃ of overnight incubation, last, utilize automatic microplate reader to detect the optical density(OD) (OD value) in each hole at 570nm wavelength place.
Half-inhibition concentration (IC
50) be defined as the drug level when the survival of 50% tumour cell.According to the optical density(OD) (OD value) of measuring, make the typical curve of inhibitory rate of cell growth, try to achieve its corresponding drug level at typical curve.
Table 1.Compound 1-10 is to the restraining effect of MCF-7 and A431 cell
Claims (4)
1. a class contains 1,3 of 2-sulfydryl methyl phenyl ketone, and the 4-oxadiazole derivative is characterized in that it has following general formula:
R in the formula
1For:
R in the formula
2For:
——H
——Br。
2. one kind prepares above-mentioned 1,3 of the 2-sulfydryl methyl phenyl ketone that contains, and the method for 4-oxadiazole derivative is characterized in that it is comprised of the following step:
Step 1: get the 1mmol carboxylic acid and add the 50mL dehydrated alcohol, and add the vitriol oil of 5mL, backflow 12h.Underpressure distillation approximately remains 1/5th, adds 20mL water, uses ethyl acetate extraction, and uses successively saturated NaHCO
3With saturated NaCl washing, use at last anhydrous MgSO
4Drying, underpressure distillation can obtain target compound.
Step 2: the ester that produces in the step 1 is dissolved in the dehydrated alcohol of 50mL, and adds the hydrazine hydrate of 15ml, backflow is spent the night.With reacted solvent underpressure distillation, until there is not liquid to flow out, add entry, obtain hydrazides.
Step 3: get in the round-bottomed flask that the hydrazides that obtains in the 1mmol step 2 joins 50mL, be dissolved in the 30mL dehydrated alcohol, add equimolar dithiocarbonic anhydride, (potassium hydroxide) refluxed 24 hours under alkaline condition, recrystallization obtains a series of 2-sulfo-s-1 after the reacting coarse product drying, 3,4 oxadiazole derivatives.
Step 4: get 1mmol step 3 gained 2-sulfo--1,3,4 oxadiazole derivatives and etc. molar mass 2-bromoacetophenone/2,4 '-dibromo-benzene ethyl ketone adds the round-bottomed flask of 25mL, and be dissolved in 5mL 80% ethanol, stirring at room 4-6h, unnecessary solvent is removed in underpressure distillation, then will react crude extract and pour in the frozen water, leave standstill 1-2h, filter, washing will obtain target compound with recrystallizing methanol after the gained drying precipitate.
3. 1,3 of 2-sulfydryl methyl phenyl ketone, the preparation method of 4-oxadiazole derivative of containing according to claim 2.
4. 1,3 of the 2-sulfydryl methyl phenyl ketone that contains claimed in claim 1, the application of 4-oxadiazole derivative in the preparation antitumor drug.
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| CN1660824A (en) * | 2004-12-08 | 2005-08-31 | 贵州大学 | 2-substitution-5-(3,4,5-trialkoxy phenyl)-1,3,4-ramification of thiadiazoles and preparation method and biological activity |
| WO2009078587A2 (en) * | 2007-12-14 | 2009-06-25 | Korea Research Institute Of Bioscience And Biotechnology | Composition for prevention and treatment of cancer containing triazolyl-thio-ethanone derivatives inhibiting activity of protein phosphatases or pharmaceutically acceptable salts thereof as an active ingredient |
| CN101723912A (en) * | 2009-11-13 | 2010-06-09 | 天津理工大学 | 2-[5-(2-hydroxyphenyl)-1,3,4-oxadiazole-2-thioether]-1-acetophenone compounds |
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| CN1660824A (en) * | 2004-12-08 | 2005-08-31 | 贵州大学 | 2-substitution-5-(3,4,5-trialkoxy phenyl)-1,3,4-ramification of thiadiazoles and preparation method and biological activity |
| WO2009078587A2 (en) * | 2007-12-14 | 2009-06-25 | Korea Research Institute Of Bioscience And Biotechnology | Composition for prevention and treatment of cancer containing triazolyl-thio-ethanone derivatives inhibiting activity of protein phosphatases or pharmaceutically acceptable salts thereof as an active ingredient |
| CN101723912A (en) * | 2009-11-13 | 2010-06-09 | 天津理工大学 | 2-[5-(2-hydroxyphenyl)-1,3,4-oxadiazole-2-thioether]-1-acetophenone compounds |
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