CN103102283A - Preparation method of chalcone oxime compound and application of the same as novel immunosuppressant - Google Patents
Preparation method of chalcone oxime compound and application of the same as novel immunosuppressant Download PDFInfo
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- -1 chalcone oxime compound Chemical class 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000003018 immunosuppressive agent Substances 0.000 title claims abstract description 10
- 229960003444 immunosuppressant agent Drugs 0.000 title abstract description 4
- 230000001861 immunosuppressant effect Effects 0.000 title abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 30
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 150000003935 benzaldehydes Chemical class 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 5
- 229940124589 immunosuppressive drug Drugs 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000008062 acetophenones Chemical class 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 150000002923 oximes Chemical class 0.000 claims 1
- 210000001744 T-lymphocyte Anatomy 0.000 abstract description 11
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- GVSPXQVUXHMUMA-MDWZMJQESA-N (e)-3-(3,5-ditert-butyl-4-hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)\C=C\C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 GVSPXQVUXHMUMA-MDWZMJQESA-N 0.000 abstract 1
- IXQYPXRYRSEMAA-UHFFFAOYSA-N n-(1,3-diphenylprop-2-enylidene)hydroxylamine Chemical compound C=1C=CC=CC=1C(=NO)C=CC1=CC=CC=C1 IXQYPXRYRSEMAA-UHFFFAOYSA-N 0.000 abstract 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 11
- 239000013078 crystal Substances 0.000 description 10
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- WYECURVXVYPVAT-UHFFFAOYSA-N 1-(4-bromophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Br)C=C1 WYECURVXVYPVAT-UHFFFAOYSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000001506 immunosuppresive effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
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- SUYSQRHNTDVWKJ-UHFFFAOYSA-N 1,3-dichlorobenzene;formaldehyde Chemical compound O=C.ClC1=CC=CC(Cl)=C1 SUYSQRHNTDVWKJ-UHFFFAOYSA-N 0.000 description 2
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 238000011725 BALB/c mouse Methods 0.000 description 2
- 229910014265 BrCl Inorganic materials 0.000 description 2
- 206010062016 Immunosuppression Diseases 0.000 description 2
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 2
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- 230000010261 cell growth Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
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- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 1
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- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 244000309466 calf Species 0.000 description 1
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- 231100000060 cardiovascular toxicity Toxicity 0.000 description 1
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- 230000004663 cell proliferation Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 235000005513 chalcones Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
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- 231100000053 low toxicity Toxicity 0.000 description 1
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a chalcone oxime compound, which has a general formula as the following. Specifically, R1 can be a group as the following, and R2 can be a group as the following. The chalcone oxime derive provided in the invention has an obvious inhibitory effect on activated T cells, and has no significant inhibitory effect on unactivated T cells, so that the chalcone derivative involved in the invention can be applied in preparation of an immunosuppressant. The invention also discloses a preparation method of the chalcone oxime compound.
Description
Technical field
The present invention relates to phenyl styryl ketone oxime compounds and preparation method thereof and purposes as immunosuppressive drug.
Background technology
Immunosuppressor is a kind of important clinical medicine for medical procedure, and it is used for comprising treatment such as systemic lupus erythematous, rheumatoid arthritis and the psoriasis of graft-rejection and autoimmune disorder.The T lymphocyte has been brought into play indispensable effect in graft-rejection, make ciclosporin A (CsA), and tacrolimus (FK506's) and sirolimus (rapamycin) are shown one's talent as immunosuppressant treatment.Although immunosuppressive drug has been successfully used to the clinical treatment of organ transplantation and autoimmune disorder, its side effect comprises that liver toxicity, renal toxicity, malignant tumour, infection, Cardiovascular Toxicity etc. can not be ignored.Therefore, seek new adjusting immune response, and efficient, the needs of the immunosuppressive drug of the clinical application that the conduct of low toxicity is potential never stopped.
According to research reports, the compound of chalcone has the multiple biological activitys such as anti-inflammatory, antiviral, anti-malarial, immunosuppression, and the T cell proliferation in immune response is had obvious restraining effect.Some oxime compounds also has certain immunosuppressive activity.Therefore, as the oxime derivatives of phenyl styryl ketone, its research aspect immunosuppression has larger potentiality equally.
Summary of the invention
The object of the present invention is to provide the novel phenyl styryl ketone oxime compounds of class and their preparation method and a purposes.
Technical scheme of the present invention is as follows:
1. a class phenyl styryl ketone oxime derivatives is characterized in that it has following general formula:
In formula: R
1-be:
R
2-be:
A kind of method for preparing above-mentioned oxime compounds, it is comprised of the following step:
Step 1. is in methanol solution, add the compound of corresponding acetophenones and the compound of corresponding benzaldehydes, the ratio of the amount of substance of the compound of acetophenones and the compound of benzaldehydes is 1: 1 left and right, the potassium hydroxide aqueous solution that adds again 6 moles every liter, the molar ratio of potassium hydroxide and methyl phenyl ketone are 2.5: 1, and stirring at room is until there is solid to form, with solid filtering, wash with frozen water and ice methyl alcohol again, the solid that obtains is dissolved in the anhydrous methanol recrystallization purifies
Solid after the purification that step 2. obtains step 1 is dissolved in pyridine, adds the oxammonium hydrochloride of 6 times of amount of substances, is heated with stirring to 60 ℃, cooling after reaction was spent the night 12 hours, the filtrate decompression evaporate to dryness washes the solid that obtains with water, use again the dehydrated alcohol recrystallization, obtain the compound of phenyl styryl ketone oximes.
Above-mentioned method for making, in described step 1, the consumption of methyl alcohol is that the compound of every mmole benzaldehydes adds 5ml.
Above-mentioned method for making, in described step 2, the consumption of pyridine is that every mmole oxammonium hydrochloride adds 1ml.
The T cell obvious restraining effect of phenyl styryl ketone oxime compounds of the present invention to activation, and to the restraining effect of non-activated T cell a little less than, therefore oxime compounds of the present invention can be used in the preparation immunosuppressive drug.
Embodiment
Embodiment one: the preparation of (2E)-1-(4-chloro-phenyl-)-3-(4-fluorophenyl) phenyl styryl ketone oxime (compound 1)
Add parachloroacetophenone (10mmol) and p-Fluorobenzenecarboxaldehyde (10mmol) in the 100ml single necked round bottom flask, add the dissolve with methanol of 50ml, then the potassium hydroxide aqueous solution (25mmol, 4.17mL) of 6 moles every liter that adds.The stirring at room reaction, then with solid filtering then is washed one time with ice methyl alcohol and frozen water to there being solid to produce, and obtains yellow solid.The solid that obtains is put into the beaker of 100ml, added dehydrated alcohol to dissolving fully, then filter after recrystallization, obtain yellow lenticular material 1-(4-chloro-phenyl-)-3-(4-fluorophenyl) phenyl styryl ketone.Again it is moved in the single necked round bottom flask of 100ml, add the oxammonium hydrochloride of 6 times of molar masss, be dissolved in pyridine (10ml).Be heated with stirring to 60 ℃, backflow is spent the night and was used later the thin layer chromatography detection reaction in 12 hours, until react completely, cooled and filtered, the filtrate decompression evaporate to dryness obtains yellow particulate state compound, then uses the dehydrated alcohol recrystallization after recrystallization, obtain yellow crystals shape material, i.e. target phenyl styryl ketone oxime compounds.Productive rate: 35%.Mp?150-152℃。
1H?NMR(300Hz，CDCl
3)：5.95-6.00(m，1H)；6.85(d，J＝8.76Hz，2H)；6.94(d，J＝8.79Hz，2H)；7.16(d，J＝8.61Hz，2H)；7,26(s，1H)；7.68(d，J＝8.79，2H).ESI-MS：277.05(C
15H
12ClFNO，[M+H]
+).Anal.Calcd?for?C
15H
12ClFNO：C，65.35；H，4.02；N，5.08.FOUND：C，65.21；H，4.20；N，5.21.
Embodiment two: the preparation of (2E)-1-(4-chloro-phenyl-)-3-(thiophene-2-yl) phenyl styryl ketone oxime (compound 2)
The preparation method is with embodiment one.Replace p-Fluorobenzenecarboxaldehyde with thiophene-2-formaldehyde, obtain yellow crystals shape target compound.Productive rate 30%.Mp?140-142℃.
1H?NMR(300Hz，CDCl
3)：6.83-6.70(m，1H)；6.97-7.03(m，1H)；7.09(d，J＝3.66Hz，1H)；7.29-7.34(t，J＝26.7Hz，1H)；7.39-7.48(m，5H).ESI-MS：264.02(C
13H
11ClNOS，[M+H]
+).Anal.Calcd?for?C
13H
10ClNOS：C，59.20；H，3.82；N，5.31.FOUND：C，60.12；H，3.76；N，5.44.
Embodiment three: the preparation of (2E)-1-(4-bromophenyl)-3-(thiophene-2-yl) phenyl styryl ketone oxime (compound 3)
The preparation method is with embodiment one.Replace parachloroacetophenone with parabromoacetophenone, replace p-Fluorobenzenecarboxaldehyde with thiophene-2-formaldehyde, obtain yellow crystals shape target compound.Productive rate 25%.Mp?129-132℃.
1H?NMR(300Hz，CDCl
3)：7.08-7.11(m，1H)；7.28(d，J＝10.26Hz，1H)；7.37-7.44(m，2H)；7.64(d，J＝8.43Hz，2H)；7.87(d，J＝8.58Hz，2H)；7.95(d，J＝15.36Hz，1H).ESI-MS：307.97(C
13H
11BrNOS，[M+H]
+).Anal.Calcd?for?C
13H
10BrNOS：C，50.66；H，3.27；N，4.54.FOUND：C，51.89；H，3.38；N，4.32.
Embodiment four: the preparation of (2E)-1-(4-bromophenyl)-3-(4-chloro-phenyl-) phenyl styryl ketone oxime (compound 4)
The preparation method is with embodiment one.Replace parachloroacetophenone with parabromoacetophenone, replace p-Fluorobenzenecarboxaldehyde with 4-chloro-benzaldehyde, obtain yellow crystals shape target compound.Productive rate 38%.Mp?166-170℃.
1H?NMR(300Hz，CDCl
3)：7.39-7.47(m，3H)；7.58(d，J＝6.57Hz，2H)；7.64-7.67(m，2H)；7.76(d，J＝15.75Hz，1H)；7.86-7.90(m，2H).ESI-MS：337.61(C
15H
12BrClNO，[M+H]
+).Anal.Calcd?for?C
15H
11BrClNO：C，53.52；H，3.29；N，4.16.FOUND：C，51.67；H，3.16；N，4.29.
Embodiment five: the preparation of (2E)-1-(4-bromophenyl)-3-(2,4 dichloro benzene base) phenyl styryl ketone oxime (compound 5)
The preparation method is with embodiment one.Replace parachloroacetophenone with parabromoacetophenone, replace p-Fluorobenzenecarboxaldehyde with 2,4 dichloro benzene formaldehyde, obtain yellow crystals shape target compound.Productive rate 34%.Mp?174-177℃.
1H?NMR(300Hz，CDCl
3)：7.16-7.20(m，1H)；7.60(d，J＝8.58Hz，4H)；7.80-7.83(m，4H).ESI-MS：372.06(C
15H
11BrCl
2NO，[M+H]
+).Anal.Calcd?for?C
15H
10BrCl
2NO：C，48.55；H，2.72；N，3.77.FOUND：C，48.64；H，2.83；N，3.62.
Embodiment six: the preparation of (2E)-1-(4-bromophenyl)-3-(4-fluorophenyl) phenyl styryl ketone oxime (compound 6)
The preparation method is with embodiment one.Replace parachloroacetophenone with parabromoacetophenone, replace p-Fluorobenzenecarboxaldehyde with p-Fluorobenzenecarboxaldehyde, obtain yellow crystals shape target compound.Productive rate 32%.Mp?180-184℃.
1H?NMR(300Hz，CDCl
3)：7.09-7.14(m，2H)；7.40(d，J＝15.54Hz，1H)；7.57-7.67(m，4H)；7.75-7.80(t，J＝7.86HZ，1H)；7.86-7.89(m，2H).ESI-MS：307.97(C
15H
12BrFNO，[M+H]
+).Anal.Calcd?for?C
15H
11BrFNO：C，56.27；H，3.46；N，4.37.FOUND：C，56.39；H，3.54；N，4.29.
Embodiment seven: the preparation of (2E)-1-(4-tolyl)-3-(4-fluorophenyl) phenyl styryl ketone oxime (compound 7)
The preparation method is with embodiment one.Replace parachloroacetophenone with p-methyl aceto phenone, replace p-Fluorobenzenecarboxaldehyde with p-Fluorobenzenecarboxaldehyde, obtain yellow crystals shape target compound.Productive rate 44%.Mp111-115℃.
1H?NMR(300Hz，CDCl
3)：2.42(s，3H)；6.94(d，J＝8.79Hz，2H)；7.35(d，J＝15.54Hz，1H)；7.59-7.65(m，4H)；7.79(d，J＝15.54Hz，1H)；7.88(d，J＝8.61Hz，2H).ESI-MS：256.29(C
16H
15FNO，[M+H]
+).Anal.Calcd?for?C
16H
14FNO：C，75.28；H，5.53；N，5.49.FOUND：C，75.11；H，5.42；N，5.57.
Embodiment eight: the preparation of (2E)-1-(4-tolyl)-3-(4-chloro-phenyl-) phenyl styryl ketone oxime (compound 8)
The preparation method is with embodiment one.Replace parachloroacetophenone with p-methyl aceto phenone, replace p-Fluorobenzenecarboxaldehyde with 4-chloro-benzaldehyde, obtain yellow crystals shape target compound.Productive rate 42%.Mp?144-146℃.
1HNMR(300Hz，CDCl
3)：2.41(s，3H)；6.75(d，J＝16.65Hz，1H)；7.24(d，J＝9.87Hz，2H)；7.29-7.44(m，6H)；7.63(d，J＝16.44Hz).ESI-MS：272.74(C
16H
15ClNO，[M+H]
+).Anal.Calcd?for?C
16H
14ClNO：C，70.72；H，5.19；N，5.15.FOUND：C，70.58；H，5.25；N，5.20.
Embodiment nine: the preparation of (2E)-1-(4-tolyl)-3-(2,4 dichloro benzene base) phenyl styryl ketone oxime (compound 9)
The preparation method is with embodiment one.Replace parachloroacetophenone with p-methyl aceto phenone, replace p-Fluorobenzenecarboxaldehyde with 2,4 dichloro benzene formaldehyde, obtain yellow crystals shape target compound.Productive rate 39%.Mp?152-156℃.
1H?NMR(300Hz，CDCl
3)：2.42(s，3H)；7.16-7.27(m，4H)；7.38-7.45(m，3H)；7.59(d，J＝16.65Hz，1H)；7.71(d，J＝9.51，1H).ESI-MS：307.19(C
16H
14Cl2NO，[M+H]
+).Anal.Calcd?for?C
16H
13Cl
2NO：C，62.76；H，4.28；N，4.57.FOUND：C，62.65；H，4.17；N，4.69.
Embodiment ten: the research of phenyl styryl ketone oxime compounds immunosuppressive activity
Adopt MTT[3-(4,5)-two methyl-2-thiazole-(2,5)-phenyl bromination tetrazole is blue] method measures oxime compounds to T cell and the non-activated T cell minimum inhibitory concentration (minimal inhibitory concentration, MIC) of activation.Adopt the method for flow cytometer and immunoblotting to carry out the mechanism of action detection to the best compound of immunocompetence.
(1) animal is prepared: available from Jiangsu Province's Experimental Animal Center 6 to 8 age in week female BALB/c mouse.Under 21 ± 2 ℃, mouse keep freely eating food and water, and kept for 12 little time/cycle secretly.Laboratory Animal Welfare and experimental arrangement are to carry out in strict accordance with laboratory animal guide (science and China, technical division in 2006) the ethics rules guide relevant with Nanjing University.Reduce to full capacity the misery of animal and reduce the quantity of using animal.
(2) cell is prepared with reagent: separate lymph-node cell from BALB/c mouse at 37 ℃, in the air of 5.0% carbonic acid gas humidification, cultivate in being aided with 1640 substratum of 10% foetal calf serum.Anti-CD3, anti-CD28 murine antibody is available from BD Pharmingen.Annexin V-FITC/PI test kit is available from the U.S. biotechnology of crystalline substance.Anti-caspase-3 antibody and the anti-PARP antibody of splitting is available from Santa Cruz biotech company.Anti--ribose antibody is available from Cell Signaling Technology, Inc..Every other chemical obtains Sigma chemical industry company limited.
(3) cell proliferation experiment: lymph-node cell is with 5 * 10
5The density of individual/plate is cultivated in 96 holes, with the compound of different concns with the anti-CD28 Co stituation of anti-CD3/, continue 72h.4h before cultivating end, every hole adds 20 μ l MTT, and the multiplicative stage begins.After end, after removing supernatant liquor, add 20 μ l DMSO Rong Xie formazan crystallizations.With the absorbancy under enzyme linked immunosorbent assay instrument test 540nm.
(4) cell toxicity test: with cell with 5 * 10
5The density in individual/hole adds in 96 orifice plates, then adds the compound of gradient concentration to cultivate 72h.The every hole of 4h adds the MTT of 20 μ l before finishing cultivation.And then add the DMSO Rong Xie formazan crystal of 200 μ l.Survey at last the absorbance of 540nm.
(5) statistical study
All experiments have all repeated 3-5 time, all obtain similar result.These two experimental group P values are tested with two tail student t-checks.It is 0.05 that significance level fixes on the P value.If applicable, data report is mean+SD (SD).
The calculating of inhibiting rate: the inhibiting rate of Growth of Cells calculates according to following formula:
Growth inhibition ratio=(1-survival rate) * 100%=[1-(OD
Experiment-OD
Blank)/(OD
Contrast-OD
Empty In vain)] * 100% (OD
ExperimentThe average optical of expression testing drug group, OD
ContrastThe average optical of expression control group, OD
BlankThe average optical of expression control group).
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 on typical curve.
The inhibition IC of T cell to activation of phenyl styryl ketone oxime compounds of the present invention
50Value sees Table 1, to the inhibition CC of non-activated T cell
50Value sees Table 2.
The inhibition IC of T cell to activation of the listed oxime compounds of table 1 the present invention
50Value (μ M) and to the inhibition CC of non-activated T cell
50Value
CsA: positive control
Claims (5)
1. a class phenyl styryl ketone oxime derivatives is characterized in that it has following general formula:
In formula: R
1-be:
R
2-be:
2. method for preparing above-mentioned phenyl styryl ketone oxime compounds is characterized in that it is comprised of the following step:
Step 1. is in methanol solution, add the compound of corresponding acetophenones and the compound of corresponding benzaldehydes, the ratio of the amount of substance of the compound of acetophenones and the compound of benzaldehydes is 1: 1 left and right, the potassium hydroxide aqueous solution that adds again 6 moles every liter, the molar ratio of potassium hydroxide and methyl phenyl ketone are 2.5: 1, and stirring at room is until there is solid to form, with solid filtering, wash with frozen water and ice methyl alcohol again, the solid that obtains is dissolved in the anhydrous methanol recrystallization purifies
Solid after the purification that step 2. obtains step 1 is dissolved in pyridine, adds the oxammonium hydrochloride of 6 times of amount of substances, is heated with stirring to 60 ℃, cooling after reaction was spent the night 12 hours, the filtrate decompression evaporate to dryness washes the solid that obtains with water, use again the dehydrated alcohol recrystallization, obtain the compound of phenyl styryl ketone oximes.
3. method for making according to claim 2, it is characterized in that: in described step 1, the consumption of methyl alcohol is that the compound of every mmole benzaldehydes adds 5ml.
4. method for making according to claim 2, it is characterized in that: in described step 2, the consumption of pyridine is that every mmole oxammonium hydrochloride adds 1ml.
5. the application of phenyl styryl ketone 9 oxime derivate described according to claim in the preparation immunosuppressive drug.
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| PL424469A1 (en) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oxime of 2,4-dimethoxy-4'-phenylchalcone and (Z)-oxime of 2,4-dimethoxy-4'-phenylchalcone and method for obtaining them simultaneously |
| PL424471A1 (en) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oxime of 4-ethoxy-4'-phenylchalcone and (Z)-oxime of 4-ethoxy-4'-phenylchalcone and method for obtaining them simultaneously |
| PL424477A1 (en) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oxime of 4-chloro-4'-phenylchalcone and (Z)-oxime of 4-chloro-4'-phenylchalcone and method for obtaining them simultaneously |
| PL424476A1 (en) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oxime of 4'-phenyl-4-carboxychalcone and (Z)-oxime of 4'-phenyl-4-carboxychalcone and method for obtaining them simultaneously |
| PL424475A1 (en) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oxime of 4-ethyl-4'-phenylchalcone and (Z)-oxime of 4-ethyl-4'-phenylchalcone and method for obtaining them simultaneously |
| PL424474A1 (en) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oxime of 4'-phenyl-4-fluorochalcone and (Z)-oxime of 4'-phenyl-4-fluorochalcone and method for obtaining them simultaneously |
| PL424472A1 (en) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oxime of 4'-phenyl-4-nitrochalcone and (Z)-oxime of 4'-phenyl-4-nitrochalcone and method for obtaining them simultaneously |
| PL424473A1 (en) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oxime of 4'-phenyl-4-methylchalcone and (Z)-oxime of 4'-phenyl-4-methylchalcone and method for obtaining them simultaneously |
| PL424479A1 (en) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oxime of 4-phenyl-2-methylchalcone and (Z)-oxime of 4'-phenyl-2-methylchalcone and method for obtaining them simultaneously |
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| PL424478A1 (en) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oxime of 4-bromo-4'-phenylchalcone and (Z)-oxime of 4-bromo-4'-phenylchalcone and method for obtaining them simultaneously |
| PL424480A1 (en) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oxime of 4'-phenyl-2-methoxychalcone and (Z)-oxime of 4'-phenyl-2-methoxychalcone and method for obtaining them simultaneously |
| PL424695A1 (en) * | 2018-02-27 | 2019-09-09 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oxime of 4'-phenyl-4-methoxychalcone and (Z)-oxime of 4'-phenyl-4-methoxychalcone and method for obtaining them simultaneously |
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| PL424471A1 (en) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oxime of 4-ethoxy-4'-phenylchalcone and (Z)-oxime of 4-ethoxy-4'-phenylchalcone and method for obtaining them simultaneously |
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