CN108484523A - Benzo oxa- oxadiazole derivatives and its preparation method and application - Google Patents
Benzo oxa- oxadiazole derivatives and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of benzo oxa- oxadiazole derivatives and its preparation method and application, which is that NBD PZ first are obtained by the reaction by NBD Cl and piperazine；4 nitros 7 are obtained by the reaction by NBD PZ and acryloyl chloride again（N 1' acryloylpiperazines）2,1,3 benzo oxa- oxadiazoles.The benzo oxa- oxadiazole derivatives BGAS of the present invention has cysteine as fluorescence probe highly selective, it can specifically detect cysteine, especially there is quick detection result to the cysteine in water, also there is higher sensitivity simultaneously, so as to the detection applied to cysteine in living cells.
Description
Technical field
The invention belongs to technical field of analytical chemistry, and in particular to a kind of benzo oxa- oxadiazole derivatives and its preparation side
Method and application.
Background technology
Cysteine（Cysteine, Cys）And homocysteine（HomoCysteine, Hcy）It is to be expressed simultaneously in eukaryon
Intracellular contains sulfydryl（-SH）Amino acid, although their molecular structures are only there are one the difference of methylene, biological function is but
There were significant differences.Cys is one of necessary amino acid of human body, be participate in protein synthesis 20 in one kind in amino acid.Hcy
It is then not involved in the synthesis of protein, but related with many diseases, such as senile dementia, Parkinson disease, angiocardiopathy.
Not only there is fluorescence detection high sensitivity, detection to limit low, good selective, but also can be in living cells
Therefore Visual retrieval analyte is the most commonly used methods of current detection Cys and/or Hcy.
The fluorescence probe for being presently used for detection Cys and/or Hcy is broadly divided into two major classes：
（1）One kind is can to detect Cys and Hcy simultaneously.
This kind of fluorescence probe is obviously not suitable for the occasion for needing individually to detect Cys.
（2）It is another kind of, it is that can specifically detect Cys.
And it is existing can specific detection go out the fluorescence probe of Cys that there are sensitivity be not high, selectivity is bad, shine effect
The problems such as rate is low, permeability is poor, transporting is bad.
Invention content
It is an object of the invention to solve the above problems, provide one kind can specific detection go out cysteine and with height
Selectivity and highly sensitive benzo oxa- oxadiazole derivatives and its preparation method and application.
Realizing the technical solution of the object of the invention is：A kind of benzo oxa- oxadiazole derivatives, structure are as follows：
。
The preparation method of above-mentioned benzo oxa- oxadiazole derivatives is as follows：
1. by the chloro- 7- nitros -2,1,3- benzos oxa- oxadiazoles of 4-【Hereinafter referred to as NBD-Cl】4- nitros-are obtained by the reaction with piperazine
7- piperazine -2,1,3- benzo oxa- oxadiazoles【Hereinafter referred to as NBD-PZ】；
2. 4- nitros -7- is obtained by the reaction with acryloyl chloride in the NBD-PZ 1. obtained by step（N-1'- acryloylpiperazines）-2,1,
3- benzo oxa- oxadiazoles【Hereinafter referred to as BGAS】.
Specific synthetic route is as follows：
。
Above-mentioned steps 1. in, the molar ratio of the NBD-Cl and the piperazine is 1: 2~1: 5, preferably 1: 3.
1. above-mentioned steps carry out in organic solvent；The organic solvent is preferably methanol.
The reaction temperature of above-mentioned steps 1. is -5 DEG C~5 DEG C, preferably 0 DEG C.
Above-mentioned steps 2. in, the molar ratio of the NBD-PZ and the acryloyl chloride is 1: 10~1: 20.
2. above-mentioned steps carry out in organic solvent；The organic solvent is preferably dichloromethane.
2. above-mentioned steps carry out in the presence of basic catalyst；The basic catalyst is preferably triethylamine；Institute
The molar ratio for stating NBD-PZ and the triethylamine is 1: 5~1: 10.
The reaction temperature of above-mentioned steps 2. is room temperature（20 ± 5 DEG C, similarly hereinafter）.
Application of the above-mentioned benzo oxa- oxadiazole derivatives as fluorescence probe on specific detection cysteine.
The good effect that the present invention has：
（1）The benzo oxa- oxadiazole derivatives BGAS of the present invention has highly selective, energy as fluorescence probe to cysteine
It is enough specifically to detect cysteine, especially there is quick detection result to the cysteine in water, while also have compared with
High sensitivity, so as to the detection applied to cysteine in living cells.
（2）The detection method repeatability of the present invention is strong, and stability is good, and required condition is simple, and experimental situation is mild, yield
Preferably, mass production can be carried out in smaller input.
Description of the drawings
Fig. 1 is the fluorescence spectrum test result schematic diagram of test case 1.
Fig. 2 is the fluorescence spectrum test result schematic diagram of test case 2.
Fig. 3 is the fluorescence spectrum test result schematic diagram of test case 3.
Specific implementation mode
（Embodiment 1）
The chemical name of the benzo oxa- oxadiazole derivatives of the present embodiment is 4- nitros -7-（N-1'- acryloylpiperazines）-2,
1,3- benzo oxa- oxadiazoles, structure are as follows：
。
The preparation method of the benzo oxa- oxadiazole derivatives is as follows：
1., will be dissolved with the piperazine of 1.032g under 0 DEG C of ice bath（12mmol）Methanol solution be added drop-wise to dropwise dissolved with 0.798g's
NBD-Cl（4mmol）Methanol solution in, ice bath stirring react 30min, obtain red suspension.
After reaction, saturated sodium bicarbonate aqueous solution is added, continues after stirring 2min, filtering is washed 3 times with ice water,
Vacuum drying, obtains 0.558g red solid NBD-PZ, yield 56.0%.
1HNMR（600MHz,DSMO-d6）δ：8.52 (d, J=9.1Hz, 1H, ArH), 6.60 (d, J=9.2Hz, 1H, ArH),
4.23(s,2H,CH2),4.20(s,2H,CH2),3.91(s,2H,CH2),3.82(s,2H,CH2),1.07(s,1H,NH)。
2. under 0 DEG C of ice bath, by 0.249g steps 1. NBD-PZ obtained（1mmol）It is dissolved in anhydrous methylene chloride, by
1mL acryloyl chlorides are added dropwise to, then 1mL triethylamines are slowly added dropwise, are then slowly increased to room temperature, continue to be stirred to react 12h.
After reaction, solvent is removed under reduced pressure, column chromatography obtains 0.200g red granules BGAS, yield 66.0%.
1HNMR（600MHz,DSMO-d6）δ：8.51 (d, J=9.1Hz, 1H, ArH), 8.84 (dd, J1=10.4Hz,J2=
10.4Hz, 1H, CH), 6.61 (d, J=9.2Hz, 1H, ArH), 6.19 (dd, J1=2.3Hz,J2=2.2Hz,1H,CH),5.76(dd,
J1=2.3Hz,J2=2.2Hz,1H,CH),7.37(d,J=2.7Hz,1H),7.19(d,J=8.4Hz,1H),4.24(s,2H,CH2),
4.19(s,2H,CH2),3.92(s,2H,CH2),3.83(s,2H,CH2)。
（Test case 1）
The fluorescence spectrum test that this test case is BGAS and BGAS+Cys under different pH.
One, test condition：Hitachi's F-7000 sepectrophotofluorometers, voltage 500V, excitation wavelength 480nm, launch wavelength
For 480nm~700nm, slit 5nm × 5nm.
Two, respectively in different pH（3~12）Water/dimethyl sulfoxide (DMSO) mixed solution in be added embodiment 1 BGAS（Concentration
It is 1 μM）, measure fluorescence intensity, the result is shown in Figure 1.
As seen from Figure 1：With the variation of pH, BGAS fluorescence intensities keep stablizing, no significant change.
Three, respectively in different pH（3~12）Water/dimethyl sulfoxide (DMSO) mixed solution in be added embodiment 1 BGAS（Concentration
It is 1 μM）And Cys（A concentration of 10 μM）, fluorescence intensity is measured, as a result still sees Fig. 1.
As seen from Figure 1：It is added after Cys, with becoming larger for pH, fluorescence is clear and legible from nothing to strong process, and
Very strong fluorescence intensity is remained in 7~11 section.
Should the result shows that：BGAS is the fluorescence probe that can simulate physiological environment for intracellular Cys detections.
（Test case 2）
The fluorescence spectrum that this test case is BGAS and various concentration Cys is tested.
One, test condition is the same as test case 1.
Two, the BGAS of embodiment 1 is added in the water of pH=7.4/dimethyl sulfoxide (DMSO) mixed solution respectively（A concentration of 1 μM）
With the Cys of various concentration（0~3.5 μM）, fluorescence intensity is measured, as a result sees Fig. 2.
As seen from Figure 2：With the increase of semicystinol concentration, fluorescence intensity gradually increases, and presents fabulous
Linear relationship.
Should the result shows that：BGAS has higher sensitivity as fluorescence probe detection cysteine, and not only can be with
Qualitative detection can also quantitatively be detected by the linear relationship.
（Test case 3）
This test case is that the fluorescence spectrum of BGAS and disturbance object are tested.
One, test condition is the same as test case 1.
Two, the BGAS of embodiment 1 is added in the water of pH=7.4/dimethyl sulfoxide (DMSO) mixed solution respectively（A concentration of 1 μM）
With different substances（Concentration is 5 μM）, fluorescence intensity is measured, as a result sees Fig. 3.
As seen from Figure 3：Fluorescence probe BGAS to Cys have it is highly selective, and for other chaff interferents hardly ring
It answers.
Claims (10)
1. a kind of benzo oxa- oxadiazole derivatives, structure are as follows：
。
2. the preparation method of benzo oxa- oxadiazole derivatives described in claim 1, it is characterised in that have steps of：①
4- nitro -7- piperazine -2,1,3- benzo oxa-s are obtained by the reaction by the chloro- 7- nitros -2,1,3- benzos oxa- oxadiazoles of 4- and piperazine
Oxadiazoles；2. 4- is obtained by the reaction with acryloyl chloride in the 4- nitro -7- piperazine -2,1,3- benzo oxa- oxadiazoles 1. obtained by step
Nitro -7-（N-1'- acryloylpiperazines）- 2,1,3- benzo oxa- oxadiazoles.
3. preparation method according to claim 2, it is characterised in that：Above-mentioned steps 1. in, chloro- nitro -2 7- 4-,
The molar ratio of 1,3- benzo oxa- oxadiazoles and the piperazine is 1: 2~1: 5.
4. preparation method according to claim 2, it is characterised in that：1. above-mentioned steps carry out in methanol solvate.
5. preparation method according to claim 2, it is characterised in that：The reaction temperature of above-mentioned steps 1. is -5 DEG C~5 DEG C.
6. preparation method according to claim 2, it is characterised in that：Above-mentioned steps 2. in, the 4- nitros -7- piperazines -
The molar ratio of 2,1,3- benzo oxa- oxadiazoles and the acryloyl chloride is 1: 10~1: 20.
7. preparation method according to claim 2, it is characterised in that：2. above-mentioned steps are carried out in dichloromethane solvent
's.
8. preparation method according to claim 2, it is characterised in that：2. above-mentioned steps are to carry out in the presence of triethyl amine
's；The molar ratio of the 4- nitros -7- piperazine -2,1,3- benzo oxa- oxadiazoles and the triethylamine is 1: 5~1: 10.
9. preparation method according to claim 2, it is characterised in that：The reaction temperature of above-mentioned steps 2. is room temperature.
10. benzo oxa- oxadiazole derivatives described in claim 1 are as fluorescence probe on specific detection cysteine
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110590801A (en) * | 2019-09-05 | 2019-12-20 | 中国药科大学 | Glutaminase small-molecule fluorescent probe and preparation method and application thereof |
| CN114213357A (en) * | 2021-12-24 | 2022-03-22 | 山西大学 | 7-nitro-1, 2, 3-benzooxadiazole derivative and synthetic method and application thereof |
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| WO2013155223A1 (en) * | 2012-04-10 | 2013-10-17 | The Regents Of The University Of California | Compositions and methods for treating cancer |
| CN106565694A (en) * | 2016-10-09 | 2017-04-19 | 北京化工大学 | NBD-organic amine fluorescence probe, and preparation method and application thereof |
| CN107417638A (en) * | 2017-05-04 | 2017-12-01 | 河南牧业经济学院 | A kind of glutathione and cysteine fluorescence probe based on 7 nitrobenzofurazans and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2013155223A1 (en) * | 2012-04-10 | 2013-10-17 | The Regents Of The University Of California | Compositions and methods for treating cancer |
| CN106565694A (en) * | 2016-10-09 | 2017-04-19 | 北京化工大学 | NBD-organic amine fluorescence probe, and preparation method and application thereof |
| CN107417638A (en) * | 2017-05-04 | 2017-12-01 | 河南牧业经济学院 | A kind of glutathione and cysteine fluorescence probe based on 7 nitrobenzofurazans and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110590801A (en) * | 2019-09-05 | 2019-12-20 | 中国药科大学 | Glutaminase small-molecule fluorescent probe and preparation method and application thereof |
| CN110590801B (en) * | 2019-09-05 | 2020-11-03 | 中国药科大学 | Glutaminase small-molecule fluorescent probe and preparation method and application thereof |
| CN114213357A (en) * | 2021-12-24 | 2022-03-22 | 山西大学 | 7-nitro-1, 2, 3-benzooxadiazole derivative and synthetic method and application thereof |
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