CN110642845B - Quinoline derivative and application thereof - Google Patents

Quinoline derivative and application thereof Download PDF

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CN110642845B
CN110642845B CN201910944286.1A CN201910944286A CN110642845B CN 110642845 B CN110642845 B CN 110642845B CN 201910944286 A CN201910944286 A CN 201910944286A CN 110642845 B CN110642845 B CN 110642845B
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ylidene
nadh
pyran
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姚宜山
李云峰
张黎明
秦炳杰
代威
冉玉华
鲁松松
王金柱
于广喜
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Abstract

The invention provides compounds of general formula (a) wherein the substituents are as defined in the specification. The invention also relates to the use of said compounds and their pharmaceutically acceptable addition salts for redox indicators and OFF-ON near-infrared fluorescent diagnostic reagents.

Description

Quinoline derivative and application thereof
Technical Field
The invention relates to quinoline or quinoline derivatives and application thereof.
Background
In the field of medical diagnostics, it is necessary in many cases to detect one or more analytes in a body fluid, for example a blood, interstitial fluid, urine, saliva or other type of body fluid sample. Examples of analytes to be detected are glucose, triglycerides, lactate, cholesterol or other types of analytes usually present in these body fluids. Depending on the concentration of the analyte, appropriate treatment may be selected, if desired.
Modern methods of analyte detection and measurement often rely on analyte-specific enzymes. Typically, a redox enzyme is used which transfers the redox equivalents to its substrate (reduction of the substrate) or, more typically, removes the redox equivalents from the substrate (oxidation of the substrate). Most redox enzymes require the presence of a redox coenzyme, such as NAD or NADP or its reduced form NADH or NADPH, from or to which redox equivalents are initially transferred by the enzyme. The redox equivalents removed from the analyte may then be transferred directly or indirectly to a redox indicator or electrode.
In general, devices and methods known to the skilled person use test elements comprising one or more test chemicals which, in the presence of the analyte to be detected, are capable of performing one or more detectable detection reactions, for example optically or electrochemically detectable detection reactions.
Redox indicators are compounds that change their absorption when undergoing a redox reaction. Most redox indicators known in the art show a red-shift, i.e. when oxidized, the band position is shifted to longer wavelengths in the absorption, reflection, transmission or emission spectrum, while there are only a few examples of redox indicators that show a red-shift when reduced. Redox indicators that exhibit a red-shift when reduced are particularly useful for colorimetric determination of analytes.
The compound of US5498542A undergoes a blue shift upon reduction that is difficult to measure. CN106573910A discloses a compound using cyanine as a fluorescent chromophore, which produces fluorescence with poor light stability and low photobleaching resistance. In addition, the emission wavelength is not in the near infrared region, the anti-interference capability is poor, and the method can not be applied to living body imaging. The compound DCI-MQH reported by anal. chem.2019,91,1368 is generated after being reduced by NAD (P) H, although the emission spectrum reaches the infrared region (660 nm) in a mixed solvent of water and DMSO and also realizes the imaging on the living body of a tumor-bearing mouse, the further application of the compound DCI-MQH in the in-vivo diagnosis is limited due to the low fluorescence quantum efficiency.
Therefore, there is a need in the art to provide a redox indicator having good fluorescence properties, an emission spectrum in the near infrared region, and the redox indicator can be applied to in vivo diagnosis.
Disclosure of Invention
The invention aims to solve the first technical problem of providing a compound with high fluorescence emission efficiency and an emission spectrum in a near infrared region.
In order to solve the technical problems, the invention adopts the technical scheme that:
a quinoline ring compound having the general structure of formula (a), or an acceptable acid addition salt thereof:
Figure GDA0002745494460000021
wherein R is1、R2、R3、R4Or R6Each independently selected from hydrogen, unsubstituted or substituted C1-C6Alkyl, said substitution being C1-C3Alkyl groups of (a); preferably, R1、R2、R3、R4、R6Is hydrogen;
R5selected from methyl, ethyl or benzyl; preferred R5Is methyl;
n is any one integer of 0 to 5, preferably 0, 1 or 2;
R9and R10Each independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, said substitution being C1-C3 alkyl, preferably, R9Is hydrogen, R10Is hydrogen, tert-butyl, methyl or isopropyl; or R9And R10Together form an aryl ring.
R7、R8Each independently selected from hydrogen, alkyl, halogen, nitro, sulfonate, -CN, -CO2H、-C(O)R11、-CO2R11、-C(O)NHR11、-C(O)NH2，R11Selected from alkyl, unsubstituted or substituted aryl, phenyl, said substitution being C1-C3 alkyl;
or R7And R8Together form an unsubstituted or substituted 5-membered ring; said substitution being optionally substituted by one or more carbonyl, phenyl or halo groups, preferably, R7And R8Together form a substituted 1, 3-pentanedione, more preferably, R7And R8Together form 1H-indene-1, 3(2H) -dione shown as the structure of (formula c),
Figure GDA0002745494460000031
y is selected from O, S, Se and Te;
x may be selected from triflate, sulphate, alkyl sulphonate, toluene sulphonate, phosphate, tetrafluoroborate, hexafluorophosphate, trifluoroacetate, perchlorate, chloride or nitrate. Preferably triflate (triflate).
In a preferred embodiment of the invention, the compounds of the invention are represented by any of the following structures:
Figure GDA0002745494460000041
or an acceptable addition salt thereof.
The compound of the invention can generate red shift of wavelength when being reduced; the pi acceptor group of the compounds of the invention is not reduced by the coenzymes NADH, NADPH, carbaNADH or carbaNADPH.
In addition, the compounds of the present invention or their acceptable salts form solvates, which may also be present in solvent-free form.
The invention also provides the use of the compounds of the invention as redox indicators.
The invention also provides application of the compound as a near-infrared fluorescent diagnostic reagent.
The reduction used in the case of the compounds of the invention involves the ring system gaining two electrons according to the following scheme:
Figure GDA0002745494460000051
thus, in the compounds of the invention, a polymethine type donor-acceptor dye is formed upon reduction. Thus, in one embodiment, the compounds of the invention are compounds that undergo a red-shift upon reduction. In one other embodiment, the reduced form of the compound (b) has an absorption maximum at a wavelength of 400 to 800 mm.
The compounds of the invention are compounds that undergo a red-shift upon reduction and the redox potential of the compounds makes them particularly suitable for accepting redox equivalents from reduced Nicotine Adenine Dinucleotide (NADH) or reduced Nicotinamide Adenine Dinucleotide Phosphate (NADPH). Furthermore, the compounds of the invention have at least one absorption maximum in the visible range, so that they are able to interfere with the visible spectrum and/or photometric determination of the redox state at wavelengths which are minimized or at least acceptable when obtaining interference from other compounds comprised in e.g. a blood sample. Some compounds of the invention also fluoresce upon reduction and therefore the reducing agent can be determined or detected by fluorescence spectroscopy or fluorescence imaging (see, e.g., r.freeman, r.gi11l, i.sheweky, m.kotler, u.banin, i.willner, angelwaldte chemie, 2009, 121, 315-.
Fluorometric determination of NADH
Change in fluorescence intensity upon reaction with NADH
mu.L of a 10mM solution of the indicator (E) -3- (2- (6- (tert-butyl) -4- (1, 3-dioxo-1H-inden-2 (3H) -ylidene) -4H-pyran-2-yl) -vinyl) -1-methylquinolinium trifluoromethanesulfonate (I) in DMSO, 1000uL of a 10mM PIPES buffer solution having a pH of 7, 1mM NADH solution in 0.5-4. mu.L of distilled water were mixed in a cuvette. The mixture was incubated at room temperature for 30 min. The fluorescence emission spectrum was recorded using an excitation wavelength of 571 nm.
4T1 tumor-bearing nude mice are selected for in vivo imaging experiments. And when the tumor size of the nude mouse reaches 10-12 mm, carrying out an in-vivo imaging experiment. Compound I solution with a concentration of 30 μ M was prepared, and 20 μ L volume was measured and injected by intratumoral injection. After injection, the small animal living body imaging system is used for carrying out living body imaging on the small animal living body imaging system within 5-150 min. Representative UV/Vis spectra of kinetics when two solutions of indicator (E) -3- (2- (6- (tert-butyl) -4- (1, 3-dioxo-1H-inden-2 (3H) -ylidene) -4H-pyran-2-yl) -vinyl) -1-methylquinolinium triflate (I) are treated with NADH (disodium salt, 20uM) or sodium ascorbate (asc, 20ul), respectively, in phosphate buffer at pH 7.
The indicator (E) -3- (2- (6- (tert-butyl) -4- (1, 3-dioxo-1H-inden-2 (3H) -ylidene) -4H-pyran-2-yl) -vinyl) -1-methylquinolinium trifluoromethanesulfonate (I) was subjected to in vivo imaging experiments in 4T1 tumor-bearing nude mice. And when the tumor size of the nude mouse reaches 10-12 mm, carrying out an in-vivo imaging experiment. The concentration was set at 30. mu.M, and the volume was 20. mu.L, and the injection was performed by intratumoral injection. After injection, the small animal living body imaging system is used for carrying out living body imaging on the small animal living body imaging system within 5-90 min.
To verify that NAD (P) H levels in tumor tissues were higher than in normal tissues, forelimb muscle tissue and tumor tissue of 4T1 tumor-bearing nude mice were injected with I (30. mu.M, 20. mu.L), respectively. After injection, the small animal living body imaging system is used for carrying out living body imaging on the small animal living body imaging system within 5-90 min.
Has the advantages that:
compared with DCI-MQH, some near-infrared dyes of the invention have the advantages that the fluorescence quantum efficiency is improved by 3-17 times when the emission spectrum is kept equivalent; some are emission spectra that are significantly red-shifted from about 60-100nm into the near infrared spectral range. The fluorescence quantum efficiency is obviously improved, the emission spectrum is obviously red-shifted, and the sensitivity in vivo detection is obviously improved. The lowest detection limits of compounds for NADH in aqueous solution were I (3.96nM), II (8.1nM), III (9.3nM), IV (10.1nM), V (7.0nM), VI (4.12nM), respectively, while the literature reports a detection limit for DCI-MQ of 12 nM.
TABLE 1 absorption and emission spectra, relative fluorescence quantum efficiency of Compounds I (H) -VI (H) in different solvents
Figure GDA0002745494460000071
[a]Maximum absorption [ b ]]Maximum emissionc]Relative fluorescence quantum efficiency (measured in DMSO solution (1X 10)- 6M), assume DCM (P)yranenitrile) Is 1.)
Wherein I (H), II (H), III (H), IV (H), V (H), VI (H) and DCI-MQ (H) correspond to the reduced forms of compounds I (H) -VI (H) and DCI-MQ, respectively
Drawings
FIG. 1 is a graph showing the change in absorbance of a mixed solution after reacting Compound (I) with NADH within 10 minutes
FIG. 2 is a graph showing the change in fluorescence intensity of a mixed solution after reacting Compound (I) with NADH within 10 minutes (excitation wavelength 571nm)
FIG. 3 is a graph showing a calibration curve of the fluorescence intensity of NADH in the concentration range of 0 to 25um
FIG. 4 is a graph of representative UV-Vis spectra of kinetics of treatment of indicator compound (I) with NADH or sodium ascorbate, respectively
FIG. 5 fluorescence intensity of Compound (I) for in vivo imaging
FIG. 6 fluorescence intensity in tumor tissue (F) and fluorescence intensity in normal muscle tissue (F)0) Ratio of F/F0
Detailed Description
All reagents and solvents were commercial and no further purification was required. Cell count kit-8 (CCK-8) was from Dojindo (Japan). Lipidure-coat 96 well plates from Amsbio (UK). PBS buffer was from Thermo Fisher Scientific.1H and13CNMR spectra were recorded on a JNM-ECA 400M spectrometer using Tetramethylsilane (TMS) as an internal standard and referenced to solvent signal at room temperature. HRMS (high resolution mass spectrometry), sample dissolved in MeOH and electrospray ionization time-light (ESI-ToF) mass spectrometry by direct analysis in positive ion mode, flow injection (injection volume 5 μ L) on Waters Q-ToF Premier instrument. The fluorescence spectrum was measured on a Hitachi F-4600 spectrophotometer. The absorption spectra were measured on a Shimadzu UV-2600UV-Visible spectrophotometer. Confocal fluorescence imaging was performed using a Nikon A1R microscope with a 60 x oil immersion objective. Cytotoxicity was determined on a Bio Tek Instruments, Inc (Highland Park, Winooski, VT 05404-0998, USA). Animal experiments were performed with a Berthold Technologies NightOWL LB 983 fluorescence imaging in vivo system.
Example 1
(E) Synthesis of (E) -2- (2- (tert-butyl) -6- (2- (quinolin-3-yl) vinyl) -4H-pyran-4-ylidene) -1H-indene-1, 3(2H) -dione (I-1)
Figure GDA0002745494460000081
To a solution of 3-quinolinecarboxaldehyde (500mg, 3.18mmol) in 20ml of anhydrous acetonitrile was added 2- (2-tert-butyl-6-methyl-pyran-4-ylidene) -indan-1, 3-dione (1.12g, 3.82mmol) and 0.3ml piperidine. The mixture was heated to 85 ℃ under argon blanket and refluxed for 20 h. And after the reaction is finished, filtering to obtain a crude product solid. The crude product was washed with cold acetonitrile and dried to yield finally 800mg (58.1%) of compound I-1.
1HNMR(400MHz，CDCl3):(ppm)9.13(d，1H，J＝2.4Hz)，8.56(d，1H，J＝1.6Hz)，8.45(d，1H，J＝1.6Hz)，8.31(d，1H，J＝2.0Hz)，8.15(d，1H，J＝8.4Hz)，7.89(d，1H，J＝7.6Hz),7.76-7.80(m，3H)，7.58-7.68(m，3H)，7.54(d，1H，J＝16.4Hz)，7.12(d，1H，J＝16.4Hz)，1.48(s，9H).
13CNMR(100MHz，DMSO-d6):190.4，190.2，178.0，164.7，158.0，149.3，147.9，140.2，140.0，135.9，135.2，135.0，131.3，131.1，129.7，128.5,128.4,128.3,127.6,127.2,126.8，126.6，122.6，115.5，112.7，35.5，31.9(3C).
ESI-HRMS：[M+H]+434.1678.
Example 2
(E) Synthesis of (E) -2- (2- (tert-butyl) -6- (2- (quinolin-6-yl) vinyl) -4H-pyran-4-ylidene) malononitrile (II-1)
Figure GDA0002745494460000091
To a solution of 3-quinolinecarboxaldehyde (500mg, 3.18mmol) in 50ml of anhydrous acetonitrile, 2- (2- (tert-butyl) -6-methyl-4H-pyran-4-ylidene) malononitrile (817mg, 3.82mmol) and 0.3ml of piperidine were added. The mixture was heated to 85 ℃ under argon blanket and refluxed for 20 h. And after the reaction is finished, filtering to obtain a crude product solid. The crude product was washed with cold acetonitrile and dried to yield 776mg (69.1%) of the title compound.
1HNMR(400MHz，DMSO):(ppm)9.11(d，1H，J＝2.4Hz),8.30(d，1H，J＝2.0Hz)，8.13(d，1H，J＝8.4Hz)，7.88(d，1H，J＝7.6Hz)，7.73-7.83(m，1H)，7.69-7.59(m，1H)，7.55(d，1H，J＝16.4Hz)，6.98(d，1H，J＝16.4Hz)，6.78(d,1H,＝2.0Hz),6.60(d,1H,＝2.0Hz),1.41(s，9H).
13CNMR(400MHz，DMSO):178.9,178.0,164.7,149.3,147.9,135.9,131.1,129.7,128.5,128.4,128.3,127.6,127.2,122.6,115.5,112.5(2C),90.8,70.1,35.5,31.9(3C)
ESI-HRMS:[M+H]+354.1532
Example 3
(E) Synthesis of (E) -2- (2- (2- (quinolin-3-yl) vinyl) -4H-chromen-4-ylidene) -1H-indene-1, 3(2H) -dione (III-1)
Figure GDA0002745494460000092
To a solution of 3-quinolinecarboxaldehyde (500mg, 3.18mmol) in 50ml of anhydrous acetonitrile were added 2- (2-methyl-4H-en-4-ylidene) -1H-indene-1, 3(2H) -dione (1.1g, 3.82mmol) and 0.3ml piperidine. The mixture was heated to 85 ℃ under argon blanket and refluxed for 20 h. And after the reaction is finished, filtering to obtain a crude product solid. The crude product was washed with cold acetonitrile and dried to yield 1.078g (79.38%) of compound III.
1H NMR(400MHz，DMSO):(ppm)9.17(s，1H)，8.78(s，1H)，8.70(d，1H，J＝3.6Hz)，8.35(s，1H)，8.14(d，1H，J＝8.0Hz)，8.01-7.37(m，11H),7.19((d，1H，J＝16.0Hz)
13C NMR(400MHz，DMSO):190.5,190.3,149.3,149.2,147.9,141.7,140.2,140.0,135.9,135.2,135.0,131.1,129.7,129.4,128.6,128.5,128.4,128.3,127.6,127.3,127.2,126.8,126.6,125.5,122.8,122.6,115.5,112.1
ESI-HRMS:[M+H]+428.1209.
Example 4
(E) Synthesis of (E) -2- (2- (2- (quinolin-3-yl) vinyl) -4H-chromen-4-ylidene) malononitrile (IV-1)
Figure GDA0002745494460000101
3-Quinolinecarboxaldehyde (500mg, 3.18mmol) was dissolved in 50ml of anhydrous acetonitrile, and then 2- (2-methyl-4H-pyran-4-ylidene) malononitrile (794mg, 3.82mmol) and 0.3ml of piperidine were added thereto. The mixture was heated to 85 ℃ under argon blanket and refluxed for 20 h. And after the reaction is finished, filtering to obtain a crude product solid. The crude product was washed with cold acetonitrile and dried to yield finally 888.5mg (80.5%) of the title compound.
1HNMR(400MHz，CDCl3):(ppm)＝9.16(d，1H，J＝2.4Hz)，8.95(dd，1H，J＝4.0，1.2Hz)，8.36(d，1H，J＝1.6Hz)，8.15(d，1H，J＝8.8Hz)，7.91(d，1H，J＝8.0Hz)，7.86-7.70(m，3H)，7.70-7.56(m，2H)，7.54-7.44(m，1H)，7.08(d，1H，J＝16.0Hz)，6.98(s，1H).
13CNMR(100MHz，DMSO-d6):177.8,153.7,147.9,149.3,149.2,135.9,131.1,129.7,129.4,128.6,128.5,128.4,128.3,127.6,127.2,125.5,122.8,122.6,115.9,115.7,115.5,112.1,63.3
ESI-HRMS:[M+H]+348.1059.
Example 5
Synthesis of 2- (2- (tert-butyl) -6- ((1E, 3E) -4- (quinolin-3-yl) but-1, 3-dien-1-yl) -4H-pyran-4-ylidene) malononitrile (V-1)
Figure GDA0002745494460000111
(E) -3- (quinolin-3-yl) acrolein (581.9mg, 3.2mmol) was dissolved in 50ml of anhydrous acetonitrile, and then 2- (2-methyl-4H-pyran-4-ylidene) malononitrile (794.0mg, 3.8mmol) and 0.3ml of piperidine were added thereto. The mixture was heated to 85 ℃ under argon blanket and refluxed for 20 h. And after the reaction is finished, filtering to obtain a crude product solid. The crude product was washed with cold acetonitrile and dried to yield finally 964.6mg (80.0%) of the title compound.
1HNMR(400MHz，DMSO):(ppm)9.11(d，1H，J＝2.4Hz),8.30(d，1H，J＝2.0Hz)，8.13(d，1H，J＝8.4Hz)，7.88(d，1H，J＝7.6Hz)，7.73-7.83(m，1H)，7.69-7.59(m，1H),6.98(d，1H，J＝16.4Hz)，6.80(dd，1H，J1＝16.0Hz,J2＝16.4Hz),6.65(dd，1H，J1＝16.0Hz,J2＝15.8Hz),6.51(d，1H，J＝15.8Hz),6.78(d,1H,＝2.0Hz),6.60(d,1H,＝2.0Hz),1.41(s，9H).
13CNMR(400MHz，DMSO):178.9,178.0,164.7,149.3,147.9,135.9,131.1,129.7,128.5,128.4,128.3,127.6,127.2,122.6,115.5,112.6,112.4,90.8,70.1,35.5,31.9(3C)
ESI-HRMS:[M+H]+380.1687
Example 6
Synthesis of 2- (2- (tert-butyl) -6- ((1E, 3E) -4- (quinolin-3-yl) but-1, 3-dien-1-yl) -4H-pyran-4-ylidene) -1H-indene-1, 3(2H) -dione (VI-1)
Figure GDA0002745494460000121
(E) -3- (quinolin-3-yl) acrolein (581.9mg, 3.2mmol) was dissolved in 50ml of anhydrous acetonitrile, to which was then added 2- (2-tert-butyl-6-methyl-pyran-4-ylidene) -indan-1, 3-dione (1.12g, 3.8mmol) and 0.3ml piperidine. The mixture was heated to 85 ℃ under argon blanket and refluxed for 20 h. And after the reaction is finished, filtering to obtain a crude product solid. The crude product was washed with cold acetonitrile and dried to yield finally 1102.0mg (75.0%) of the title compound.
1HNMR(400MHz，CDCl3):(ppm)9.13(d，1H，J＝2.4Hz)，8.56(d，1H，J＝1.6Hz)，8.45(d，1H，J＝1.6Hz)，8.31(d，1H，J＝2.0Hz)，8.15(d，1H，J＝8.4Hz)，7.76-7.80(m，3H)，7.62-7.64(m，3H)，7.54(d，1H，J＝16.4Hz)，7.12(dd，1H，J1＝16.4Hz,J2＝16.0Hz)，7.08(dd，1H，J＝16.0Hz,J2＝15.6Hz),6.86(d，1H，J＝15.6Hz)，1.48(s，9H).
13CNMR(100MHz，DMSO-d6):190.4，190.2，178.0，164.7，158.0，149.3，147.9，142.6,140.2，140.0，135.9，135.2，135.0，131.3，131.2,131.1，129.7，128.5，128.4，128.3，127.6，127.2，126.8，126.6，122.4，115.5，112.7，35.5，31.9(3C).
ESI-HRMS：[M+H]+460.1838.
Example 7
(E) Synthesis of (E) -3- (2- (6- (tert-butyl) -4- (1, 3-dioxo-1H-inden-2-ylidene) -4H-pyran-2-yl) vinyl) -1-methylquinolinium trifluoromethanesulfonate (I)
Figure GDA0002745494460000131
2- (2-tert-butyl-6- (2-quinolin-3-yl-vinyl) -pyran-4-ylidene) -indan-1, 3-dione (300mg, 0.69mmol) was dissolved in 10ml of anhydrous dichloromethane, and then methyl trifluoromethanesulfonate (313.5. mu.L, 2.77mmol) was added to the solution, followed by reaction under argon atmosphere at room temperature for 10 hours. And after the reaction is finished, filtering to obtain a crude product solid. The crude product was washed with cold dichloromethane and dried to yield 340mg (82.2%) of the title compound.
1H NMR(400MHz，DMSO-d6):(ppm)＝10.03(s，1H)，9.61(s.1H)，8.52(d，1H，J＝8.8Hz)，8.45(d，1H，J＝1.6Hz)，8.38(d，1H，J＝7.6Hz)，8.33(d，1H，J＝1.6Hz)，8.28(dd，1H，J＝7.9，7.2Hz)，7.75(s，2H)，7.66-7.72(m，4H)，4.66(s.3H)，1.46(s.9H).
13CNMR(100MHz，DMSO-d6):191.8，174.8，159.7，150.4，148.2，144.5(2C)，140.5，140.4，138.0(2C)，136.3，134.5，131.1(2C)，129.7，129.4，125.5(2C)，121.9，121.8，119.8，119.1(TfO-)，110.4，109.0，103.0，46.2，37.3(3C).
ESI-HRMS：[M-OTf]+448.1910.
UV-Vis(DMSO)：λmax452 nm; after reduction with NADH: lambda [ alpha ]max＝571nm。
Example 8
(E) Synthesis of (E) -3- (2- (6- (tert-butyl) -4- (dicyanomethylidene) -4H-pyran-2-yl) vinyl) -1-methylquinolin-1-ium trifluoromethanesulfonate (II)
Figure GDA0002745494460000132
(E) -2- (2- (tert-butyl) -6- (2- (quinolin-6-yl) vinyl) -4H-pyran-4-ylidene) malononitrile (250mg, 0.71mmol) was dissolved in 15ml of anhydrous dichloromethane, and then methyl trifluoromethanesulfonate (320. mu.L, 2.83mmol) was added to the solution, followed by reaction at room temperature for 10 hours under argon atmosphere. And after the reaction is finished, filtering to obtain a crude product solid. The crude product was washed with cold dichloromethane and dried to yield finally 345mg (94.26%) of the title compound.
1H NMR(400MHz，DMSO-d6):(ppm)10.03(s，1H)，9.94(d，1H，J＝1.6Hz)，8.54(d，1H，J＝8.8Hz)，8.42(d，1H，J＝7.6Hz)，8.31(t，1H，J＝8.0Hz)，8.10(t，1H，J＝8.0Hz)，7.84(d，1H，J＝16.0Hz)，7.77(d，1H，J＝16.0Hz)，6.94(d，1H，J＝2.0Hz)，6.56(d，1H，J＝2.0Hz)，4.65(s，3H)，1.41(s，9H).
13CNMR(100MHz，DMSO-d6):173.5，158.3，156.9，150.6，144.3，138.2，136.5，131.3，131.2，131.0，129.6，129.4，124.7，119.9，119.1(TfO-)，115.5，115.4，109.4，102.9，59.1，46.3，37.1，27.9.
ESI-HRMS:[M-TfO]+368.1756.
UV-Vis(DMSO)：λmax360 nm; after reduction with NADH: lambda [ alpha ]max＝533nm。
Example 9
(E) Synthesis of (III) -3- (2- (4- (1, 3-dioxo-1, 3-dihydro-2H-inden-2-ylidene) -4H-chromen-2-yl) vinyl) -1-methylquinolinium trifluoromethanesulfonate
Figure GDA0002745494460000141
(E) -2- (2- (2- (quinolin-3-yl) vinyl) -4H-chromen-4-ylidene) -1H-indene-1, 3(2H) -dione (III-1) (200mg, 0.47mmol) was dissolved in 15ml of anhydrous dichloromethane, and after that, methyl trifluoromethanesulfonate (212. mu.L, 1.87mmol) was added to the solution, followed by reaction at room temperature for 10 hours under argon atmosphere. And after the reaction is finished, filtering to obtain a crude product solid. The crude product was washed with cold dichloromethane and dried to yield finally 180mg (65.07%) of the title compound.
1HNMR(400MHz，DMSO-d6):(ppm)9.96(s，1H)，9.51(s，1H)，8.74(dd，1H，J＝8.0，1.2Hz)，8.54(d，1H，J＝8.8Hz)，8.41(d，1H，J＝7.6Hz)，8.31(td，1H，J＝8.8，1.2Hz)，8.09(t，1H，J＝7.2Hz)，7.93-8.01(m，2H)，7.85(d，1H，J＝16.0Hz)，7.77(dd，1H，J＝4.6，0.8Hz)，7.67(td，1H，J＝8.0，1.2Hz)，7.03(s，1H)，4.66(s，3H).
13CNMR(100MHz，DMSO-d6):156.6，153.1，152.3，150.4，144.4，138.2，136.5，131.8，131.3，131.2，129.6，129.4，127.1，125.3，125.1，119.9，119.5，119.1(TfO-)，117.5，117.1，116.0，109.0，63.1，46.4.
ESI-HRMS:[M-TfO]+442.1436
UV-Vis(DMSO)：λmax486 nm; after reduction with NADH: lambda [ alpha ]max＝650nm。
Example 10
Synthesis of ((E) -3- (2- (4- (dicyanomethylene) -4H-chromen-2-yl) vinyl) -1-methylquinolin-1-ium trifluoromethanesulfonate (IV)
Figure GDA0002745494460000151
Synthesis of compound IV: (E) -2- (2- (2- (quinolin-3-yl) vinyl) -4H-chromen-4-ylidene) malononitrile (IV-1) (180mg, 0.52mmol) was dissolved in 15ml of anhydrous dichloromethane, and then methyl trifluoromethanesulfonate (235. mu.L, 2.07mmol) was added to the solution, followed by reaction at room temperature for 10 hours under argon atmosphere. IV (230mg, 0.45mmol) was obtained. And after the reaction is finished, filtering to obtain a crude product solid. The crude product was washed with cold dichloromethane and dried to yield finally 230mg (87.07%) of the title compound.
1H NMR(400MHz,DMSO):(ppm)9.96(s,1H),9.51(s,1H),8.74(dd,1H,J＝8.0,1.2Hz),8.54(d,1H,J＝8.8Hz),8.41(d,1H,J＝7.6Hz),8.31(td,1H,J＝8.8,1.2Hz),8.09(t,1H,J＝7.2Hz),7.93-8.01(m,2H),7.85(d,1H,J＝16.0Hz),7.77(dd,1H,J＝4.6,0.8Hz),7.67(td,1H,J＝8.0,1.2Hz),7.03(s,1H),4.66(s,3H).
13C NMR(400MHz,DMSO):156.6,153.1,152.3,150.4,144.4,138.2,136.5,131.8,131.3,131.2,129.6,129.4,127.1,125.3,125.1,119.9,119.5,117.5,117.1,116.0,109.0,63.1,46.4.
ESI-HRMS:[M-TfO]+362.1286.
UV-Vis(DMSO)：λmax422 nm; after reduction with NADH: lambda [ alpha ]max＝584nm。
Example 11
Synthesis of 3- ((1E, 3E) -4- (6- (tert-butyl) -4- (dicyanomethylene) -4H-pyran-2-yl) but-1, 3-dien-1-yl) -1-methylquinolin-1-ium trifluoromethanesulfonate (V)
Figure GDA0002745494460000161
2- (2- (tert-butyl) -6- ((1E, 3E) -4- (quinolin-3-yl) but-1, 3-dien-1-yl) -4H-pyran-4-ylidene) malononitrile (V-1) (269.2mg, 0.71mmol) was dissolved in 15ml of anhydrous dichloromethane, and after that, methyl trifluoromethanesulfonate (320. mu.L, 2.83mmol) was added to the solution, followed by reaction at room temperature for 10 hours under argon shield. And after the reaction is finished, filtering to obtain a crude product solid. The crude product was washed with cold dichloromethane and dried to yield 366.2mg (95.0%) of the title compound.
1H NMR(400MHz，DMSO-d6):(ppm)10.00(s，1H)，9.92(d，1H，J＝1.6Hz)，8.54(d，1H，J＝8.8Hz)，8.40(d，1H，J＝7.6Hz)，8.28(t，1H，J＝8.0Hz)，8.10(t，1H，J＝8.0Hz)，7.82(d，1H，J＝16.0Hz)，7.77(dd，1H，J1＝16.0Hz,J2＝15.6Hz)，7.65(dd，1H，J1＝15.6Hz,J2＝15.4Hz),7.50(d，1H，J＝15.4Hz),6.94(d，1H,J＝2.0Hz)，6.56(d，1H，J＝2.0Hz)，4.63(s，3H)，1.41(s，9H).
13CNMR(100MHz，DMSO-d6):173.1，158.0，156.4，150.2，144.0，141.1,138.0，136.3，131.3，131.2，131.1,131.0，129.4，129.2，124.4，119.6，119.1(TfO-)，115.8，115.4，109.1，102.7，59.0，46.0，37.0，27.7.
ESI-HRMS:[M-TfO]+394.1916.
UV-Vis(DMSO)：λmax420 nm; after reduction with NADH: lambda [ alpha ]max＝573nm。
Example 12
Synthesis of 3- ((1E, 3E) -4- (6- (tert-butyl) -4- (1, 3-dioxo-1H-inden-2 (3H) -ylidene) -4H-pyran-2-yl) but-1, 3-dien-1-yl) -1-methylquinolin-1-ium trifluoromethanesulfonate (VI)
Figure GDA0002745494460000171
2- (2- (tert-butyl) -6- ((1E, 3E) -4- (quinolin-3-yl) but-1, 3-dien-1-yl) -4H-pyran-4-ylidene) -1H-indene-1, 3(2H) -dione (VI-1) (316.7mg, 0.69mmol) was dissolved in 10ml of anhydrous dichloromethane, after which methyl trifluoromethanesulfonate (313.5. mu.L, 2.77mmol) was added to the solution and reacted at room temperature for 10H under argon protection. And after the reaction is finished, filtering to obtain a crude product solid. The crude product was washed with cold dichloromethane and dried to yield 365.5mg (85.0%) of the title compound.
1H NMR(400MHz，DMSO-d6):(ppm)＝10.00(s，1H)，9.59(s.1H)，8.52(d，1H，J＝8.8Hz)，8.45(d，1H，J＝1.6Hz)，8.40(d，1H，J＝7.6Hz)，8.33(d，1H，J＝1.6Hz)，8.28(dd，1H，J＝7.9，7.2Hz)，7.75(s，2H)，7.62-7.70(m，6H)，4.64(s,3H)，1.43(s,9H).
13CNMR(100MHz，DMSO-d6):191.6，174.7，159.8，150.4，148.4，144.5(2C)，142.6,140.5，140.1，138.0(2C)，136.1，134.4，132.3,131.1(2C)，129.9，129.4，125.5(2C)，121.9，121.7，119.4，119.1(TfO-)，110.4，108.0，102.0，46.0，37.1(3C).
ESI-HRMS：[M-OTf]+474.2062.
UV-Vis(DMSO)：λmax488 nm; after reduction with NADH: lambda [ alpha ]max＝656nm
the-O-compounds obtained in examples 1 to 6 were reacted with Na, respectively2S,Na2Se,Na2Te was prepared by substitution reaction in a suitable solvent to give the compounds of Table 2 substituted with-S-, -Se-, -Te-for-O-.
TABLE 2
Figure GDA0002745494460000172
Figure GDA0002745494460000181
Figure GDA0002745494460000191
Figure GDA0002745494460000201
Figure GDA0002745494460000211
In analogy to examples 7-12, the quaternary ammonium salts of the corresponding compounds were obtained by reacting the compounds from examples 1-6 and table 2 with various triflate alkylating agents, as shown in table 3. The reaction temperature and time can generally vary within wide limits. The product is precipitated by crystallization from a suitable solvent and, if desired, the anion can be modified by conventional procedures, for example using ion exchange resins.
TABLE 3
Figure GDA0002745494460000212
Figure GDA0002745494460000221
Figure GDA0002745494460000231
Figure GDA0002745494460000241
Figure GDA0002745494460000251
Figure GDA0002745494460000261
Detection of NADH:
the following were mixed in a cuvette: 100uL of indicator (E) -3- (2- (6- (tert-butyl) -4- (1, 3-dioxo-1H-inden-2 (3H) -ylidene) -4H-pyran-2-yl) vinyl) -1-methylquinolinium trifluoromethanesulfonate (III) in DMSO at 10mM, 1000. mu.L of 50mM phosphate buffer, pH7, 10. mu.L of NADH in distilled water at 10 mM. The change in absorbance and the fluorescence intensity at 571nm excitation wavelength of the above solution were recorded within 10min as shown in FIGS. 1 and 2.
As shown in FIG. 3, representative UV/Vis spectra of kinetics when a solution of indicator (E) -3- (2- (6- (tert-butyl) -4- (1, 3-dioxo-1H-inden-2 (3H) -ylidene) -4H-pyran-2-yl) -vinyl) -1-methylquinolinium triflate (I) (2. mu.L, 10mM) is treated with NADH (0.5-4. mu.L, 1mM) in a phosphate buffer at pH7, respectively, the mixture is incubated at room temperature for 30min, a curve of change in fluorescence intensity is recorded using excitation at 571nm, and a calibration curve (R) of fluorescence intensity of NADH in a concentration range of 0-25um is determined2＝0.9811)。
4T1 tumor-bearing nude mice are selected for in vivo imaging experiments. And when the tumor size of the nude mouse reaches 10-12 mm, carrying out an in-vivo imaging experiment. Compound I solution with a concentration of 30 μ M was prepared, and 20 μ L volume was measured and injected by intratumoral injection. After injection, the small animal living body imaging system is used for carrying out living body imaging on the small animal living body imaging system within 5-150 min. Representative UV/Vis spectra of kinetics when two solutions of indicator (E) -3- (2- (6- (tert-butyl) -4- (1, 3-dioxo-1H-inden-2 (3H) -ylidene) -4H-pyran-2-yl) -vinyl) -1-methylquinolinium triflate (I) are treated with NADH (disodium salt, 20uM) or sodium ascorbate (asc, 20ul), respectively, in phosphate buffer at pH 7. As can be seen from FIG. 4, the fluorescence intensity in tumors gradually increased with time, and the reaction product of compound (I) with NADH and ascorbic acid began to gradually decay after 10min to a maximum.
As shown in FIG. 5, the indicator (E) -3- (2- (6- (tert-butyl) -4- (1, 3-dioxo-1H-inden-2 (3H) -ylidene) -4H-pyran-2-yl) vinyl) -1-methylquinolinium trifluoromethanesulfonate (I) was subjected to in vivo imaging experiments in 4T1 tumor-bearing nude mice. And when the tumor size of the nude mouse reaches 10-12 mm, carrying out an in-vivo imaging experiment. The concentration was set at 30. mu.M, and the volume was 20. mu.L, and the injection was performed by intratumoral injection. After injection, the small animal living body imaging system is used for carrying out living body imaging on the small animal living body imaging system within 5-90 min. As can also be seen in FIG. 5, no extravasation of the tumor was observed after the compound (I) entered the tumor, indicating that the product of its reaction with NADH was stably present in the tumor tissue.
To verify that NAD (P) H levels in tumor tissues were higher than in normal tissues, forelimb muscle tissue and tumor tissue of 4T1 tumor-bearing nude mice were injected with I (30. mu.M, 20. mu.L), respectively. After injection, the small animal living body imaging system is used for carrying out living body imaging on the small animal living body imaging system within 5-90 min. As shown in FIG. 6, the fluorescence intensity (F) in tumor tissue and the fluorescence intensity (F) in normal muscle tissue were observed within 90min0) The ratio of (a) to (b) is between 2.7 and 4.1. Thus, it could be demonstrated that NAD (P) H levels are higher in tumor tissues than in normal tissues.

Claims (2)

1. A compound of formula I:
Figure FDA0002745494450000011
2. use of a compound according to claim 1 in the manufacture of a medicament for use as a redox indicator.
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