CN103073538B - Application of 1,4-dihydropyridine derivative as NO fluorescent probe - Google Patents
Application of 1,4-dihydropyridine derivative as NO fluorescent probe Download PDFInfo
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- CN103073538B CN103073538B CN201210592781.9A CN201210592781A CN103073538B CN 103073538 B CN103073538 B CN 103073538B CN 201210592781 A CN201210592781 A CN 201210592781A CN 103073538 B CN103073538 B CN 103073538B
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- 0 CC1=C(C(O)OC)C(C(c2ccc(*)cc2O2)=CC2=O)C(C(OC)=O)=C(C)*1=C Chemical compound CC1=C(C(O)OC)C(C(c2ccc(*)cc2O2)=CC2=O)C(C(OC)=O)=C(C)*1=C 0.000 description 1
Abstract
The invention relates to the field of probes, in particular to an application of a 1,4-dihydropyridine derivative as a NO fluorescent probe. According to the invention, based on the specific effect of the 1,4-dihydropyridine derivative and nitric oxide, (aromatization, resulting in the changes of electronic structure distribution and molecular conformation in the probes) features of corresponding pyridine derivatives are produced, to realize the response of the fluorescent probe to nitric oxide. Based on the changes of the fluorescence in nature before and after the detection (changes in fluorescence emission intensity, fluorescence emission wavelength, fluorescence emission service life and the like), the detection for the nitric oxide is realized.
Description
Technical field
The present invention relates to molecular probe field, particularly, relate to the purposes of Isosorbide-5-Nitrae-dihydrogen pyridine derivative as NO fluorescent probe.
Background technology
Nitric oxide molecule (NO), as important messenger molecule a kind of in organism and neuromodulator, take part in the physiological function of multiple system.Evidence show nitrogen protoxide also with various diseases, as relevant in diabetes, parkinsonism and Alzheimer's disease etc.Therefore NO donor medicine is as potential cardiovascular, antitumor, novel anti-inflammatory and anti-alzheimer medicine, causes and pays close attention to widely.But NO is as gas radicals extremely unstable in vivo, the method therefore detecting NO is in vivo focus, the difficult point of of correlative study always.
" fluorescent probe " generally refers to and can optionally interact with other predetermined substance and its structure be changed, cause the compound that its photoluminescent property character such as () intensity, excitation/emission wavelength or fluorescence lifetimes changes, namely under certain condition can to the compound of predetermined substance generation specificity fluorescent response.Utilize this character, by fluorescence detection method to predetermined substance carry out qualitative, determine quantifier elimination.The class NO fluorescent molecular probe O-Phenylene Diamine class be most widely used at present, received much concern, due to the restriction by own structural characteristics and the mechanism of action, still there is much such as sensitivity by the impact of medium pH, the existence of autoxidation phenomenon, the problems such as specificity is high not, make it use and are restricted.
" Isosorbide-5-Nitrae-dihydrogen pyridine derivative " proposed by the invention can realize optionally interacting with nitrogen protoxide, recurring structure change (aromizing of molecular structure), thus causes its photoluminescent property to change (such as fluorescent emission intensity enhancing).
Summary of the invention
The object of this invention is to provide the purposes of Isosorbide-5-Nitrae-dihydrogen pyridine derivative as NO fluorescent probe.
In order to fundamentally solve the problem, " switch " unit that the present invention is fluorescent probe with Isosorbide-5-Nitrae-dihydrogen pyridine derivative, obtains corresponding fluorescent probe by introducing multiple luminescent dye molecule to No. 4 positions of Isosorbide-5-Nitrae-dihydropyridine ring.According to technical scheme of the present invention, wherein, its structure of Isosorbide-5-Nitrae-dihydrogen pyridine derivative is as shown in following formula I:
R
1=-CO
2et or F, Cl, Br, CN
R
2=luminescent dye molecule
R
3=H or Bn, Ph, Me, Et, Pr, i-Pr, CN
The invention provides the purposes of Isosorbide-5-Nitrae-dihydrogen pyridine derivative as NO fluorescent probe, wherein, multiple luminescent dye molecule is introduced in No. 4 positions to Isosorbide-5-Nitrae-dihydropyridine ring, and described luminescent dye molecule can be:
According to technical scheme of the present invention, utilize 1,4-dihydrogen pyridine derivative and nitric oxide production specific effect (aromizing, cause the structure distribution of electronics in probe molecule, the conformational change etc. of molecule), generate corresponding pyridine to spread out the character of class biology, realize fluorescent probe to nitric oxide production response.Realized nitric oxide production detection by the change (fluorescent emission intensity change, fluorescence emission wavelengths change, fluorescent emission lifetime change etc.) of photoluminescent property before and after detection effect.
According to the specific embodiment of the present invention citing, described Isosorbide-5-Nitrae-dihydrogen pyridine derivative is coumarins and derivative thereof, and in this example, NO probe is that structural formula is such as formula 1e.And 1c, 1d are coumarins fluorescent agent, they are actually the precursor of NO probe 1e, structurally have certain common ground with 1e, and 1f is the product generated after NO probe 1e and NO acts on, and is the coumarins fluorescent agent with extremely strong fluorescence.
Its synthetic route is:
Accompanying drawing explanation
Fig. 1, a show the ultra-violet absorption spectrum of 4-methylcoumarin 1c, and b shows 4-methylcoumarin 1c fluorescence spectrum.
Fig. 2, a show the ultra-violet absorption spectrum of 4-aldehyde radical coumarin 1 d, and b shows the fluorescence spectrum of 4-aldehyde radical coumarin 1 d.
Fig. 3, a are based on the ultra-violet absorption spectrum of the nitric oxide fluorescent probe (1e) of fluorescent coumarin dye molecule, and b shows the fluorescence spectrum before 1e and NO effect.
Fig. 4, a show the ultra-violet absorption spectrum of the product (1f) after the nitric oxide fluorescent probe of fluorescent coumarin dye molecule and Effect of Nitric Oxide, the fluorescence spectrum of b display effect product (1f).
Fig. 5, a show fluorescent probe (1e, solid line) and Effect of Nitric Oxide product (1f, dotted line) ultra-violet absorption spectrum contrast, and b shows fluorescent probe (1e solid line) and contrasts with the fluorescence spectrum of NO effect product (1f, dotted line).
Embodiment
Resorcino in following embodiment, 9-aldehyde radical anthracene, tonka bean camphor are all purchased from Beijing Reagent Company, and reagent is all purchased from Beijing Chemical Plant.
Embodiment 1 is based on the synthesis of the coumarin derivatives of Hantzsch fat synthesis method
1, the synthesis (7-hydroxy-4-methyl-2H-chromen-2-one) of 1b
By 11g(100mmol) Resorcino, 13mL (100mmol) methyl aceto acetate, 52mL H
3pO
4add in round-bottomed flask, stirred at ambient temperature 12h, solution yellowing paste, poured into by yellow paste in large water gaging, suction filtration, obtains Off-white solid.Pure white solid is obtained by recrystallization from ethyl acetate/petroleum ether.
1H NMR(400Hz CDCl
3)δppm:10.50(s,1H),7.60(d,1H,J=8.7Hz),6.82(q,1H,J=2.3Hz),6.70(d,1H,J=2.3Hz),6.12(d,1H,J=0.9Hz),2.36(d,3H,J=0.9Hz).
2, the synthesis (7-methoxy-4-methyl-2H-chromen-2-one7-methoxyl group-4-methylcoumarin) of 1c
3.5g (22mmol) 1b 30mL acetone is dissolved, is added 6.03g (43.2mmol) K
2cO
3, stir 10min, then add 3.12g (22mmol) CH
3i, back flow reaction 6h, stop heating, heat filtering.Filtrate is spin-dried for, obtains white solid, ethyl alcohol recrystallization.
1H NMR(400Hz CDCl
3)δppm:7.49（d,1H,J=4.8Hz），6.86（q,1H,J=2.5Hz），6.81（d,1H,J=2.4Hz），6.13（d,1H,J=0.9Hz），3.87（s,3H），2.40（d,3H,J=1.0Hz）
3, the synthesis (7-methoxy-2-oxo-2H-chromene-4-carbaldehyde) of 1d
By 0.95g(5mmol) 1c, 30mL dimethylbenzene adds in round-bottomed flask, and stir and heat, making it dissolve gradually.Add 0.55g(5mmol again) SeO
2, after back flow reaction 4h, then add 0.55g(5mmol) and SeO
2, continue back flow reaction 4h, stop heating, recover room temperature, have yellow solid to separate out, suction filtration, solid recrystallized from acetonitrile, obtains yellow needle-like crystals.
1H NMR(400Hz CDCl
3)δppm:10.07（s,1H），8.49（d,1H,5.00），6.93（q,1H,2.52），6.86（d,1H,2.48），6.71（s,1H），3.89（s,3H）。
4, the synthesis (dimethyl-4-(7-methoxy-2-oxo-2H-chromen-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate) of 1e
0.3g (1 is added in the 250mL round-bottomed flask that reflux condensing tube, drying tube are housed, 47mmol) 1d, 1.07(9.2mmol) methyl acetoacetate, 0.15g (9.2mmol) ammoniacal liquor, 30mL ethanol, stir and back flow reaction 4h, stop heating, be cooled to room temperature, boil off part ethanol, by solution left standstill in ice-water bath, obtain pure yellow crystals 1e.
1H NMR(400Hz CDCl
3)δppm:8.12(d,1H,J=9.08),6.93(d,1H,J=2.5Hz),6.91(d,1H,J=2.5Hz),6.79(d,1H,J=2.5Hz),6.24(s,1H),5.35(s,1H),3.88(s,3H),3.51(s,6H),2.35(s,6H).
5, the synthesis (dimethyl-4-(7methoxy-2-oxo-2H-chromen-4-yl)-2,6-dimethylpyridine-3,5-dicarboxylate) of 1f
In a little reaction flask, add 0.02g1e, dissolve with 1mL methylene dichloride, add excessive nitrite sodium, under stirring, drip dilute hydrochloric acid gradually, after reaction for some time, solution saturated common salt water washing 3 times, then use dichloromethane extraction organic phase, after anhydrous sodium sulfate drying, except desolventizing, obtain pure white solid 1f.
1H NMR(400Hz CDCl
3)δppm:6.88(d,1H,J=8.8Hz),6.78(d,1H,J=2.4Hz),6.69(q,1H,J=2.4Hz),6.01(s,1H),3.81(s,3H),3.50(s,6H),2.62(s,6H).
The ultraviolet of embodiment 2, coumarin derivatives and fluorescent probe, photoluminescent property research
1, coumarin derivatives self ultraviolet, photoluminescent property:
As shown in Figure 1, solvent is ethanol, ultra-violet absorption spectrum (Fig. 1 a, c=1.0 × 10 of 4-methylcoumarin 1c
-4molL
-1, ε=1.81 × 10
4) and 4-methylcoumarin 1c(Fig. 1 b, c=1.0 × 10
-6molL
-1, λ
ex=323nm, λ
em=384nm) fluorescence spectrum.
As shown in Figure 2, ultra-violet absorption spectrum (Fig. 2 a, c=1.0 × 10 of 4-aldehyde radical coumarin 1 d
-4molL
-1, ε=2.22 × 10
4) and fluorescence spectrum (Fig. 2 b, c=1.0 × 10 of 4-aldehyde radical coumarin 1 d
-6molL
-1, λ
ex=324nm, λ
em=389nm), solvent is ethanol.
As shown in Figure 1 and Figure 2, the photoluminescent property impact of substituting groups different on No. 4 positions of 7-methoxyl group-tonka bean camphor on himself is not remarkable.
2, based on ultraviolet, the photoluminescent property of the nitric oxide fluorescent probe (1e) of fluorescent coumarin dye molecule and the product (1f) with Effect of Nitric Oxide thereof:
Be illustrated in figure 3 ultra-violet absorption spectrum (Fig. 3 a, c=1.0 × 10 of the nitric oxide fluorescent probe (1e) based on fluorescent coumarin dye molecule
-4molL
-1, ε=2.12 × 10
3), and 1e), and with NO effect before fluorescence spectrum (c=1.0 × 10
-6molL
-1, λ
ex=334nm, λ
em=411nm), solvent is ethanol.As shown in the figure, No. 4 positions that 7-methoxyl group-tonka bean camphor is spread out to Isosorbide-5-Nitrae-dihydropyridine by the scion grafting of C-C key, cause its uv-absorbing to reduce (Fig. 3 a), the fluorescence sharp-decay (almost cancellation completely) (Fig. 3 b) of luminescent dye molecule simultaneously, showing as probe molecule does not almost have fluorescence.
Be illustrated in figure 4 ultra-violet absorption spectrum (Fig. 4 a, c=1.0 × 10 of the product (1f) after based on the nitric oxide fluorescent probe of fluorescent coumarin dye molecule and Effect of Nitric Oxide
-4molL
-1, ε=1.16 × 10
4); And with fluorescence spectrum (c=1.0 × 10 of NO effect product (1f)
-6molL
-1, λ
ex=330nm, λ
em=427nm), solvent is ethanol.As shown in the figure, after fluorescent probe (1e) and Effect of Nitric Oxide, its uv-absorbing obviously strengthens, and the fluorescence of probe molecule sharply increases (increased value >10 doubly) (Fig. 3 b) simultaneously.
3, based on the nitric oxide fluorescent probe (1e) of fluorescent coumarin dye molecule and contrast with the ultraviolet of Effect of Nitric Oxide product (1f), photoluminescent property:
Fig. 5 shows fluorescent probe (1e, solid line) and Effect of Nitric Oxide product (1f, dotted line) ultra-violet absorption spectrum contrast (Fig. 5 a), and, fluorescent probe (1e solid line) and NO effect product (1f, dotted line) fluorescence spectrum contrast (Fig. 5 b), solvent is ethanol.As shown in the figure, after fluorescent probe (1e) and Effect of Nitric Oxide, its uv-absorbing obviously strengthens, and the fluorescence of probe molecule sharply increases (increased value >10 doubly) (Fig. 3 b) simultaneously.The result of this Experimental Comparison shows 1,4-dihydropyridine can realize specificly-response to nitrogen protoxide, there is aromizing (being become the pyridine structure of aromaticity from nonaro-maticity dihydropyridine structure), cause the electronic structure of logical fluorescent probe molecule, the change of distribution thus, cause photoluminescent property change (from basic unstressed configuration to stronger fluorescence) of probe (crossing covalent linkage connection fluorescence dye-Isosorbide-5-Nitrae-dihydropyridine to obtain).This principle can be used for development of new nitric oxide fluorescent probe, in situ detection, the imaging of cell intracellular nitric oxide will be can be used for, by the generation to NO in organism, conduction and the effect in biological function regulates thereof, and the research of the relevant aspect such as medical diagnosis on disease, new drug development provides effective research means, detection method.
Claims (1)
1.1,4-dihydrogen pyridine derivative, as the purposes of NO fluorescent probe, is characterized in that, the structural formula of described Isosorbide-5-Nitrae-dihydrogen pyridine derivative is as follows:
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| CN103319465B (en) * | 2013-06-25 | 2016-02-17 | 北京师范大学 | A kind of strange ester derivative of the Chinese and Synthesis and applications thereof |
| US9383644B2 (en) | 2014-09-18 | 2016-07-05 | Heraeus Precious Metals North America Daychem LLC | Sulfonic acid derivative compounds as photoacid generators in resist applications |
| US9477150B2 (en) | 2015-03-13 | 2016-10-25 | Heraeus Precious Metals North America Daychem LLC | Sulfonic acid derivative compounds as photoacid generators in resist applications |
| CN107056759B (en) * | 2016-06-21 | 2021-03-23 | 北京师范大学 | Novel quaternary ammonium salt fluorescent probe and application thereof |
| CN106317029B (en) * | 2016-08-22 | 2018-11-27 | 山东禾本堂生物科技有限公司 | One kind containing polyether chain dihydrogen pyridine derivatives and its preparation and application |
| CN107353892A (en) * | 2017-07-13 | 2017-11-17 | 长春海谱润斯科技有限公司 | A kind of hot activation delayed fluorescence material and its organic electroluminescence device |
| CN109608427B (en) * | 2018-12-29 | 2020-06-30 | 山东师范大学 | Two-photon fluorescent probe for qualitatively detecting nitric oxide concentration and synthesis method and application thereof |
| CN115181094B (en) * | 2022-08-08 | 2024-01-30 | 南京医科大学 | Pyridine-substituted coumarin derivative, preparation method thereof and application of pyridine-substituted coumarin derivative in preparation of pH fluorescent probe |
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| US20100055735A1 (en) * | 2006-11-03 | 2010-03-04 | Philip Stewart Low | Ex vivo flow cytometry method and device |
| CN101671555A (en) * | 2009-10-14 | 2010-03-17 | 大连理工大学 | Nitric oxide fluorescent probe based on ruthenium (II) complex and application thereof |
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