CN102603649B - A kind of fluorescent probe compounds taking dibazol as guide's molecule and preparation method thereof - Google Patents
A kind of fluorescent probe compounds taking dibazol as guide's molecule and preparation method thereof Download PDFInfo
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- CN102603649B CN102603649B CN201110022177.8A CN201110022177A CN102603649B CN 102603649 B CN102603649 B CN 102603649B CN 201110022177 A CN201110022177 A CN 201110022177A CN 102603649 B CN102603649 B CN 102603649B
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- YTLQFZVCLXFFRK-UHFFFAOYSA-N C(c1nc2ccccc2[nH]1)c1ccccc1 Chemical compound C(c1nc2ccccc2[nH]1)c1ccccc1 YTLQFZVCLXFFRK-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a kind of fluorescent probe compounds taking dibazol as guide's molecule and preparation method thereof. This fluorescent probe compounds is using dibazol molecule as guide's molecule, by the method for molecule coupling, on dibazol molecule, introduce 5-dimethylamino-1-naphthalene sulfonyl chloride (DNS) as fluorescence labeling agent, form the new compound with fluorescence probe effect. This fluorescent probe compounds can emission wavelength at the green fluorescence of 480-580nm, and there is good cell-penetrating and biocompatibility, can be used for early clinical diagnosis and the study of pathogenesis of cardiovascular disease.
Description
Affiliated field
A kind of fluorescent probe compounds taking dibazol as guide's molecule and preparation method thereof, belongs to chemistry neckTerritory.
Background technology
Fluorescence labeling technology has important application as a kind of visual inactive labeling method. ItUtilization can emitting fluorescence material by physical absorption or chemical bonding effect, be combined with studied object, inspectionThereby survey photoluminescent property obtains the information of studied object. This technology can be used for environmental contaminants, amino acid, handThe detection of property molecule, nucleotides etc., highly sensitive, good stability, and also easy and simple to handle. Fluorescence labeling technologyAspect disease detection, there is very high potential using value, receive gradually in recent years people's concern, especially existThe earlier detection aspect of disease, has larger advantage compared with other means. In addition, at pharmaceutically active research, medicineThe aspects such as thing assay, drug effect effect identification, mechanism of drug action also have extraordinary effect.
What in fluorescence labeling technology, play a major role is fluorescence labeling compound, has special optionally glimmeringSignal compound is conventionally also referred to as fluorescent probe compounds. This compounds can be tied with specific target conventionallyClose, play the effect of leading mark. Utilize this performance of fluorescent probe compounds, can examine in early days in diseaseThe fields such as survey, pharmaceutically active research, pharmacological research obtain extensive use.
Laser scanning co-focusing microscope is a kind of widely used fluorescence microscope, and fluorescence imaging has directlySee, the performance of meticulous and fluorescent tracing, it can carry out stereoscan imaging to tissue, cell and subcellular fraction,In the research field such as life science and medical science, there is important application.
Cardiovascular disease is one of principal disease threatening human health, according to the World Health Organization (WHO) statistics,The whole world approximately has 1,200 ten thousand people to die from cardiovascular and cerebrovascular disease every year, accounts for 1/3 of total toll. The annual heart of ChinaVascular diseases died accounts for 40.7% of Died Of Disease total number of persons, and its ratio, far above mankind formidable enemy cancer, occupies eachFirst of the class cause of the death. The best opportunity of disease treatment in early days. Therefore, the early clinical diagnosis of cardiovascular disease particularlyImportant.
As background, the present invention is using cardiovascular disease therapies medicine---and dibazol, as guide's molecule, is selectedThe nontoxic 5-dimethylamino-1-naphthalene sulfonyl chloride (DNS) of cell, as fluorescence labeling agent, is passed through to chemical methodCarry out coupling reaction, prepared the new compound with fluorescence probe effect, early stage for cardiovascular diseaseDiagnosis.
Summary of the invention
Dibazol is one of clinical treatment medicine of high blood pressure, and this drug main is wanted vasoactive wall, to bloodPipe smooth muscle has direct relexation, peripheral vascular resistance is reduced and make blood pressure drops. The present invention adopts and clings toAzoles drug molecule, as guide's molecule, is selected the 5-dimethylamino-1-naphthalene sulfonyl chloride (DNS) nontoxic to cellAs fluorescence labeling agent, carry out coupling reaction by chemical method, prepare and there is the new of fluorescence probe effectType compound, this compound has good biocompatibility, and cytotoxicity is low, can be used for angiocardiopathyEarly diagnosis.
The object of the invention is to utilize the special compatibility of dibazol drug molecule and VSMC, logicalCross chemical means and in molecular backbone structure, introduce fluorescence chromophoric group, the noval chemical compound of preparation had both been retained and bloodThe good affinity of pipe smooth muscle cell, has again fluorescence tone-on-tone effect. Adopt this compound to make fluorescence labeling,Utilize Imaging-PAM to carry out stereoscan imaging to fluorescently-labeled cell, can reach cardiovascular focus is hadThe object of effect imaging, for cardiovascular disease early stage _ _ clinical diagnosis and study of pathogenesis provide experimental basis.
In the present invention, adopt hypertension therapeutic medicine---the dibazol conduct that directly acts on vascular smooth muscleGuide's molecule, adopts non-toxic organic fluorescent dye 5-dimethylamino-1-naphthalene sulfonyl chloride (DNS) as fluorescenceIndicate agent, carry out coupling by methodology of organic synthesis, the synthetic compound with fluorescence probe effect making new advances.
Technical scheme of the present invention:
The structural formula of dibazol is:
The structural formula of 5-dimethylamino-1-naphthalene sulfonyl chloride (DNS) is:
A kind ofly taking dibazol as the preparation method of the fluorescent probe compounds of guide's molecule be dibazol and 5-Dimethylamino-1-naphthalene sulfonyl chloride is taking mol ratio as 1.5～1.0: 1.0 mix after, taking carrene asSolvent, NaOH is as de-proton agent, and tetra-n-butyl ammonium bromide cooks phase transfer catalyst, controls temperature and exists15～45 DEG C, stirring reaction 8～16 hours, after separation and purification, can make a kind of apparent for yellowishThe fluorescent probe compounds of the green-emitting fluorescence of look. Its chemical reaction process is as follows:
Adopt prepared fluorescent probe compounds in this way, its productive rate can reach 75% conventionally. Adopt nuclear-magnetismResonance method characterizes the structure of this fluorescent probe compounds, and its basic characteristics are:(1)1H-NMR(400MHz，CDCl3)：δ(ppm)：8.49-8.52(d，1H)，8.09-8.11(d，1H)，7.93-7.95(m，1H)，7.75-7.78(m，2H)，7.28-7.42(m，4H)，7.15-7.19(m，6H)，4.56(s，2H)，2.86(s，6H)。(2)13C-NMR(100Mz，CDCl3)：δ(ppm)：153.44，152.04，141.68，135.43，134.15，133.87，132.04，129.80，129.45，129.15，129.00，128.66，128.33，126.77，124.98，124.57，122.84，120.30，117.78，115.73，113.92，45.34，35.47。
Adopt mass spectrometry method to analyze, be characterized in MS:m/z442.1578[M+H]+。
Further carry out fluoroscopic examination, be characterized in, excitation wavelength is 220～410nm, emission peak symmetry,Can transmitting green fluorescence, maximum emission wavelength is at 527nm place.
Brief description of the drawings
Fig. 1 is the fluorescence emission spectrogram of the prepared fluorescent probe compounds of the present invention, and concentration is1×10-6The ethanolic solution of mol, the excitation wavelength adopting is 365nm, spectrum data shows, its maximum sending outEjected wave length is at 527nm place.
Fig. 2, after the prepared fluorescent probe compounds of the present invention dyes to living cells, utilizes laser to sweepRetouch the design sketch that Laser Scanning Confocal Microscope carries out cell imaging. A is light field scintigram, and b is confocal fluorescent figure,C is stacking chart.
Detailed description of the invention
Embodiment 1:
In 50mL round-bottomed flask, add 5mL carrene, 20mg tetra-n-butyl ammonium bromide, 30mgNaOH, controls temperature at 35 DEG C, adds while stirring 0.11g dibazol. By 0.081g5-dimethylaminoBase-1-naphthalene sulfonyl chloride (DNS) is dissolved in 10mL carrene, is placed in constant pressure funnel, slowly splashes intoState round-bottomed flask, constant temperature stirs after 12 hours and stops reacting.
Above-mentioned product is washed successively to organic layer anhydrous slufuric acid with HCl, the distilled water of distilled water, 1MSodium dried overnight. Decompression distillation is removed after organic solvent, with Preparative TLC chromatogram (TLC) (ethyl acetate/oil=1: 3) separation and purification, product extracts from silica gel with carrene and ethanol, and Vacuum Concentration obtainsFaint yellow solid be required fluorescent probe compounds.
It is 1 × 10 that prepared fluorescent probe compounds is made into concentration with ethanol dissolving-6The solution of mol,Adopt the light wave that excitation wavelength is 365nm to excite, can observe green fluorescence, its maximum emission wavelength is527nm。
Imaging by prepared fluorescent probe compounds dilute solution for KB cell, solution concentration is joined by instituteBe 2.5 × 10-6M. Fluorescent staining condition is: KB cell is with containing 2.5 × 10-6The solution of this compound of M is 5%CO2, 95% air, temperature is to hatch 15min under the environment of 37 DEG C, then shows by confocal fluorescentMicro mirror is observed. Laser Scanning Confocal Microscope excitation wavelength is 405nm, collects the signal of emitting fluorescence 480-580nm.Imaging effect as shown in Figure 2.
Claims (2)
1. the fluorescent probe compounds taking dibazol as guide's molecule, is characterized in that: the compound with following formula structure
2. the fluorescent probe compounds preparation method of claim 1, is characterized in that: dibazol and 5-dimethylamino-1-naphthalene sulfonylAfter chlorine mixes taking mol ratio as 1.5-1.0:1.0, taking carrene as solvent, NaOH is as de-proton agent, tetra-n-butylAmmonium bromide cooks phase transfer catalyst, controls temperature at 15-45 DEG C, stirring reaction 8-16 hour, and after separation and purification,Make a kind of apparent fluorescent probe compounds for flaxen green-emitting fluorescence.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110022177.8A CN102603649B (en) | 2011-01-20 | 2011-01-20 | A kind of fluorescent probe compounds taking dibazol as guide's molecule and preparation method thereof |
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| CN201110022177.8A CN102603649B (en) | 2011-01-20 | 2011-01-20 | A kind of fluorescent probe compounds taking dibazol as guide's molecule and preparation method thereof |
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| CN102603649A CN102603649A (en) | 2012-07-25 |
| CN102603649B true CN102603649B (en) | 2016-05-25 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55110937A (en) * | 1979-02-19 | 1980-08-27 | Yuki Gosei Yakuhin Kogyo Kk | Method of fluometric quantative analysis of amino acid, peptide or protein using sodium n-chloro-1- dimethylaminonaphthalene-5-sulfonamide |
| CN1863817A (en) * | 2003-09-10 | 2006-11-15 | 沃尼尔·朗伯有限责任公司 | Antibodies to M-CSF |
| CN1956738A (en) * | 2004-01-09 | 2007-05-02 | 辉瑞大药厂 | Antibodies to MAdCAM |
| CN101015531A (en) * | 2005-09-26 | 2007-08-15 | 刘凤鸣 | Sustained release preparation of dibazole |
| WO2010021697A2 (en) * | 2008-08-18 | 2010-02-25 | Pfizer Inc. | Antibodies to ccr2 |
-
2011
- 2011-01-20 CN CN201110022177.8A patent/CN102603649B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55110937A (en) * | 1979-02-19 | 1980-08-27 | Yuki Gosei Yakuhin Kogyo Kk | Method of fluometric quantative analysis of amino acid, peptide or protein using sodium n-chloro-1- dimethylaminonaphthalene-5-sulfonamide |
| CN1863817A (en) * | 2003-09-10 | 2006-11-15 | 沃尼尔·朗伯有限责任公司 | Antibodies to M-CSF |
| CN1956738A (en) * | 2004-01-09 | 2007-05-02 | 辉瑞大药厂 | Antibodies to MAdCAM |
| CN101015531A (en) * | 2005-09-26 | 2007-08-15 | 刘凤鸣 | Sustained release preparation of dibazole |
| WO2010021697A2 (en) * | 2008-08-18 | 2010-02-25 | Pfizer Inc. | Antibodies to ccr2 |
Non-Patent Citations (1)
| Title |
|---|
| 以5-二甲氨基萘磺酰氯为荧光探针的功能膜制备;尹艺青;《惠州大学学报（自然科学版）》;20011231;第21卷(第4期);第48-51页 * |
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Address after: Box No. 487 No. 86 341000 Jiangxi University of Science and Technology Jiangxi city of Ganzhou province Zhanggong District Hongqi Avenue Applicant after: Gan Nan Normal College Address before: 341000 Ganzhou economic and Technological Development Zone, Jiangxi Applicant before: Gan Nan Normal College |
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