CN112341411A - Rofexib-like derivative, organic fluorescent dye skeleton prepared from same and application of organic fluorescent dye skeleton - Google Patents

Rofexib-like derivative, organic fluorescent dye skeleton prepared from same and application of organic fluorescent dye skeleton Download PDF

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CN112341411A
CN112341411A CN202010746566.4A CN202010746566A CN112341411A CN 112341411 A CN112341411 A CN 112341411A CN 202010746566 A CN202010746566 A CN 202010746566A CN 112341411 A CN112341411 A CN 112341411A
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rofecoxib
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fluorescent dye
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谢立君
林风
江红
胡明
谢作旭
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Fujian Institute of Microbiology
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Abstract

The invention belongs to the technical field of biomedical materials, and particularly relates to a rofecoxib-like derivative, and further discloses an organic fluorescent dye skeleton prepared from the rofecoxib-like derivative and application of the organic fluorescent dye skeleton in the field of biological imaging. The rofecoxib-like series derivative is subjected to one-step condensation modification only on the basis of a COX-2 inhibitor rofecoxib structure by computational chemistry and quantum orbit theory conjecture technology, and a brand-new design strategy is adopted to synthesize and obtain a plurality of micromolecular fluorescent dyes with clinical development prospects and COX-2 inhibitor fluorescent probes, so that the photophysical and photochemical performances of the fluorescent dyes are effectively improved and improved on the basis of keeping strong COX-2 enzyme inhibition activity, the excellent fluorescent performance is shown, and a more ideal choice is provided for the design of the fluorescent dyes and probes in the future.

Description

Rofexib-like derivative, organic fluorescent dye skeleton prepared from same and application of organic fluorescent dye skeleton
Technical Field
The invention belongs to the technical field of biomedical materials, and particularly relates to a rofecoxib-like derivative, an organic fluorescent dye skeleton prepared from the rofecoxib-like derivative, and application of the rofecoxib-like derivative in the field of biological imaging.
Background
Fluorescent dyes are an important branch in dye chemistry, and especially in recent decades, fluorescent dyes and derivatives thereof have made many breakthrough progresses in the aspects of materials, biology, medicine and the like, and are gradually becoming a key research direction in dye chemistry. Among them, organic fluorescent dyes have ever-changing structures as an important class of fluorescent dyes. In essence, since the structure of organic fluorescent dye usually includes a mother nucleus capable of emitting fluorescence and a chromophore group capable of changing the fluorescence wavelength and enhancing fluorescence, with the rapid development of the subjects of analytical chemistry, bioscience, life science, medicine and the like, organic fluorescent dye has been widely applied to many aspects such as biomolecular labeling, enzyme analysis, environmental analysis, cell staining, clinical examination and diagnosis, and is an indispensable fluorescence signal reporter group in chemical, biological, environmental science and medical research.
The fluorescent probe is a molecule which effectively expresses a molecule recognition event through a fluorescent signal on the basis of the structural characteristics of a fluorescent dye, is established on the basis of organic combination of selective molecule recognition and a fluorescence technology, realizes the recognition of target molecules by utilizing a specific recognition reaction and obtains related information (such as species, concentration and the like) of the molecules, and further converts the molecule recognition information into a fluorescent signal which is easy to detect through a corresponding signal transmission mechanism, thereby realizing the recognition and detection of an analysis object. The fluorescent probe has the advantages of high sensitivity, good specificity, rapidness, accuracy, in-situ measurement and the like, and has been applied to the fields of nucleic acid, protein, cell detection, immunoassay and the like. Especially in recent years, along with the combination of a fluorescent probe technology with a laser scanning confocal microscopy technology, a two-photon fluorescence imaging technology, a living body imaging technology and the like, the detection is improved to a single cell level and a subcellular level, the real-time, dynamic and visual monitoring of active substances in living cells and tissues is effectively realized, the mystery of life is explored for people, and the process of understanding the life plays an important role; meanwhile, the method can also provide technical support for early diagnosis and treatment of diseases. Therefore, the construction and discovery of fluorescent probes, which are the main research contents in chemistry and biology, will certainly become a research hotspot in the world and the country. Therefore, the development of functional organic fluorescent dyes and fluorescent probes having practical value has become a subject of much attention.
At present, people have made great efforts on the optical property research and biological imaging application of organic fluorescent dyes and derivatives thereof, but most of the widely used commercial organic fluorescent dyes have different defects in photophysical and photochemical properties and the like, and cannot meet the requirements of current chemical and biological research and complex system analysis and detection. Therefore, the development of novel fluorescent dyes and the modification work of commercial fluorescent dyes have positive significance.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to provide an organic fluorescent dye skeleton-rofecoxib-like derivative and acceptable salts and isomers thereof with higher application value, wherein the substance shows excellent fluorescence characteristics, has strong recognition capability on specific COX-2 enzyme, and can be developed into a novel organic fluorescent dye by the structure of the substance and also has the condition of being directly developed into a fluorescent probe.
The second technical problem to be solved by the invention is to provide a preparation method and application of the rofecoxib-like derivative.
In order to solve the technical problems, the invention provides a rofecoxib-like derivative and acceptable salts and isomers thereof, wherein the derivative has a structure shown as the following formula (I):
Figure BDA0002608566220000021
wherein the content of the first and second substances,
ar is1、Ar2And Ar3Independently of one another, are selected from aromatic rings;
the R, R1And R2Independently of one another, from the group of pi-conjugated systems and/or from different types of electron-donating or electron-withdrawing groups. The electronic characteristics of each aromatic ring and substituent and the electronic push-pull system (pull-push system) constructed by the mutual synergistic effect can generate excellent fluorescence performance.
Specifically, Ar is1、Ar2And Ar3Independently of one another, are selected from the benzene rings, or, Ar is1、Ar2And Ar3Each independently selected from heteroaromatic rings.
Specifically, the R, R1And R2Independently of each other, from an electron donating group or an electron withdrawing group, or, R, R1And R2Independently of one another, from a pi-conjugated system with different types of substituents on the pi-conjugated system of electron donating groups or electron withdrawing groups.
Specifically, the electron donating group or the electron withdrawing group includes hydrogen, halogen, amino, carboxyl, cyano, trifluoromethanesulfonyl, trifluoromethoxy, methylsulfonyl, (C1-C6) alkyl, (C1-C4) alkylhydroxy, (C1-C4) alkoxy, (C1-C4) alkenyl, (C1-C4) alkynyl, N- (C1-C9) alkylamino, N-di (C1-C9) alkylamino, (C1-C4) alkylthio, (C1-C4) alkylsulfinyl, (C1-C4) alkylsulfonyl, (C1-C4) alkoxymethyl, (C1-C4) alkoxyethyl, (C1-C4) alkanoyl, carbamoyl, N- (C1-C4) ylcarbamoyl, N-di (C1-C4) alkylcarbamoyl or (C1-C3) alkylenedioxy, and the like.
Preferably, the electron donating group or electron withdrawing group includes hydrogen, amino, cyano, trifluoromethanesulfonyl, methanesulfonyl, N- (C1-C9) alkylamino, N-di (C1-C9) alkylamino or (C1-C4) alkylthio and (C1-C4) alkylsulfinyl.
Specifically, the derivatives include compounds of the following structures:
Figure BDA0002608566220000031
Figure BDA0002608566220000041
specifically, the derivative comprises a salt, a solvate, an isomer, an ester or a precursor of the compound shown as the formula (I).
The invention also discloses a method for preparing the rofecoxib-like derivative, which comprises reacting the rofecoxib skeleton with the selected R as hydrogen radical or methoxy group structure to obtain a target compound;
Figure BDA0002608566220000042
in particular, compounds represented by (2a, 2b) and selected R2The aryl substituted alkyne compound is reacted with cuprous iodide and N, N-diisopropylethylamine to obtain the compound shown in the formula (I).
The invention also discloses the application of the rofecoxib-like derivative and acceptable salts and isomers thereof in preparing organic fluorescent dye frameworks.
The invention also discloses a composition containing the organic fluorescent dye or the probe, which comprises the rofecoxib-like derivative, acceptable salt and isomer thereof, and a biologically acceptable carrier or auxiliary material.
The invention also discloses application of the composition containing the organic fluorescent dye or the probe in the field of biological imaging.
The rofecoxib-like series derivative is prepared by performing one-step condensation modification on a COX-2 inhibitor rofecoxib structure by computational chemistry and quantum orbit theory conjecture technology, synthesizing a plurality of micromolecular fluorescent dyes with clinical development prospects and a COX-2 inhibitor fluorescent probe by adopting a brand-new design strategy, effectively improving and improving the photophysical and photochemical properties of the fluorescent dye on the basis of keeping strong COX-2 enzyme inhibition activity, showing excellent fluorescent properties including high quantum yield, large Stokes displacement, two-photon activity, near-infrared luminescence and the like, simultaneously having excellent properties which are not possessed by the traditional dye classical, overcoming a plurality of defects of the traditional dye, effectively solving the problems of poor stability, insufficient regulation and control sites, few selectable emission bands of the two-photon fluorescent dye and the like, provides a more ideal choice for the design of fluorescent dyes and probes in the future. The design concept of the probe completely breaks through the traditional fluorescent probe coupling strategy, effectively overcomes the defects of poor enzyme response, poor pharmacokinetics and the like of the traditional coupled probe, lays a solid foundation for successfully developing the novel near infrared NIR organic COX-2 fluorescent probe in the future, and indicates a new thought and direction for the design and development of other fluorescent probes aiming at different target positions. Meanwhile, the series of fluorescent dyes are simple in preparation method, provide a brand-new dye framework for the field of fluorescent dyes, and can be applied to probe design and development of early diagnosis of tumors.
The rofecoxib-like series derivatives are used as organic fluorescent dye framework materials, the fluorescence performance of a prepared fluorescent probe HXRF-1 is more outstanding compared with that of the existing coupled fluorescent probe, and partial compounds developed by the framework materials have the remarkable advantages of near infrared NIR luminous capacity, two-photon characteristics, large Stokes displacement, good light stability, strong quantum yield and the like; meanwhile, as the skeleton has enzyme recognition activity, part of fluorescent dye can be directly developed into fluorescence, the probe is a derivative of rofecoxib, the inhibition capability and the binding capability of the probe on COX-2 enzyme are slightly reduced compared with the rofecoxib, but compared with the traditional coupling COX-2 probe, the binding capability of the probe on the COX-2 enzyme is dozens of times stronger, the probe can quickly respond to the enzyme at ultralow concentration, and the probe has the advantage of strong protein binding force; in addition, because the rofecoxib is a classical COX-2 enzyme inhibitor, the rofecoxib is widely used as an anti-inflammatory drug in a large quantity, and as a rofecoxib derivative, the use dosage of a fluorescent dye and a probe is low, the rofecoxib derivative is free of cytotoxicity, and the rofecoxib derivative has good biological tissue compatibility; moreover, the series of derivatives can express COX-2 in a broad spectrum, and due to the fact that COX-2 is expressed in various cancers, if HXRF-1 can be successfully developed into a diagnostic reagent for early cancer, the diagnostic reagent can be used for early diagnosis of various types of cancers, and has a wide application range.
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In order that the present disclosure may be more readily and clearly understood, the following detailed description of the present disclosure is provided in connection with specific embodiments thereof and the accompanying drawings, in which,
FIG. 1 is a graph of the structural and parametric characteristics of the target compounds of examples 1-20;
FIG. 2 is a diagram showing the state of the compound of the present invention in powder and solution at white light and 365nm, respectively;
FIG. 3 is a graph of the fluorescence spectrum of a compound of the present invention;
FIG. 4 is a spectrum of fluorescence absorption and emission wavelengths for a compound of the present invention;
FIG. 5 shows the results of cytotoxicity assays for compounds of the present invention;
FIG. 6 is a graph showing the results of imaging capabilities of compounds of the present invention;
FIG. 7 shows the results of two-photon excitation performance of the compounds of the present invention;
FIG. 8 is a plot of the integrated emission coefficient as a function of excitation intensity for compounds of the present invention;
FIG. 9 shows different solvent effect results for compounds of the present invention;
FIG. 10 shows the results of a fluorescence emission wavelength tunability test of a compound of the present invention;
FIG. 11 shows the results of tunability tests of various substituents of compounds of the present invention;
FIG. 12 is an emission spectrum of different pyrrolidinyl substituent compounds of the present invention;
FIG. 13 is an emission spectrum of different hydroxy substituent compounds of the present invention;
FIG. 14 shows the results of aggregation-induced emission effects of the compounds of the present invention;
FIG. 15 shows the results of a cell fluorescence imaging experiment using the compound of the present invention.
Detailed Description
In the present invention, the groups "C1-C4 alkyl", "C1-4 alkyl", "(C1-C4) alkyl", etc., which have the same meaning, all represent straight-chain or branched alkyl groups having 1 to 4 carbon atoms, and others can be similarly understood.
In the context of the present invention, the group "C1-4 alkyl" includes that which is stated individually and in combination with other groups, and may be chosen, for example, from C1-3 alkyl, C1-2 alkyl. Likewise, C1-4 alkoxy may be selected from C1-3 alkoxy, C1-2 alkoxy, for example.
In the process of the invention for the synthesis of the compounds of formula I, the various starting materials used in the reaction are either prepared by the person skilled in the art on the basis of the prior knowledge, or can be prepared by methods known from the literature, or can be obtained commercially. The intermediates, starting materials, reagents, reaction conditions, etc. used in the above reaction schemes may be appropriately modified according to the knowledge of those skilled in the art. Alternatively, other compounds of formula I not specifically recited herein may also be synthesized by those skilled in the art according to the method of the second aspect of the invention.
The following examples of the invention:
the nuclear magnetic resonance hydrogen spectrum of the prepared compound is measured by BrukeraRx-300, and the mass spectrum is measured by Agilent 1100 LC/MSD;
all reagents used were analytically or chemically pure.
The structures and structural parameters of the target synthesis reactants in the following examples 1 to 20 are shown in FIG. 1 and Table 1, respectively, and the corresponding raw materials are selected according to the structures of the corresponding target compounds in each example and synthesized according to the method of the present application.
TABLE 1 structural formulas of the objective compounds in examples 1 to 20
Figure BDA0002608566220000061
Figure BDA0002608566220000071
In the following examples of the present invention, the synthesis of each of the target compounds is performed according to the following reaction equation, and those skilled in the art select appropriate starting materials 1a or 1b according to the structure of the target compound to perform the synthesis of the corresponding compound.
Figure BDA0002608566220000072
Example 1: compound 2a1((5Z) -5- (4-cyanophenylmethylene) -4- (4- (methylsulfonyl) phenyl) -3-phenylfuran-2 (5H) -one)
Figure BDA0002608566220000073
0.12g (0.0014mol) of piperidine is dripped into a methanol mixed solution of 0.4g (0.0013mol) of the compound 1a or 1b and 0.0026mol of aromatic aldehyde, the reaction is stirred for 12 hours at room temperature and a black room, the reaction liquid is detected, the reaction is finished, and the product 0.28g (89%) of light yellow solid powder is obtained by cooling, suction filtration and methanol washing.
The nuclear magnetic data of the obtained compound are:1H-NMR(400MHz,DMSO-d6)δ8.04(d,J＝8.5Hz,2H), 7.96(d,J＝8.6Hz,2H),7.88(d,J＝8.6Hz,2H),7.67(d,J＝8.5Hz,2H),7.35–7.31(m,5H), 6.16(s,1H),3.28(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.77,149.99,149.06,142.31, 138.10,135.11,133.20,131.37,130.90,129.95,129.93,129.72,129.07,128.95,128.19,127.59, 119.23,111.32,111.12,43.78.HR-MS(ESI):calcd for C25H17NNaO4S:450.0776([M+Na]+) 450.0772, found. It can be seen that the product structure is correct.
Example 2: compound 2a2((5Z) -5- (benzylidene) -4- (4- (methylsulfonyl) phenyl) -3-phenylfuran-2 (5H) -one)
Figure BDA0002608566220000081
This example, compound 2a2, was synthesized in the same manner as example 1, starting from compound 1a to give a yellow powder with a calculated product yield of 86%.
The nuclear magnetic data of the obtained compound are:1H-NMR(400MHz,DMSO-d6)δ8.04(d,J＝8.7Hz,2H), 7.79(d,J＝7.4Hz,2H),7.67(d,J＝8.8Hz,2H),7.47–7.39(m,3H),7.38–7.27(m,2H), 6.06(s,1H),3.28(s,3H).13C-NMR(101MHz,DMSO-d6)δ168.12,149.44,147.98,142.21, 135.46,133.47,131.02,130.88,129.87,129.65,129.51,129.22,129.02,128.15,126.28,113.39, 43.79.HR-MS(ESI):calcd for C24H18NaO4S:425.0823([M+Na]+) 425.0817, found. It can be seen that the product structure is correct.
Example 3: 2a3((5Z) -5- (4-methanesulfonylbenzylidene) -4- (4- (methanesulfonyl) phenyl) -3-phenylfuran-2 (5H) -one)
Figure BDA0002608566220000082
This example, compound 2a3, was synthesized in the same manner as example 1, starting from compound 1a to give a yellow powder with a calculated product yield of 88%.
The nuclear magnetic data of the obtained compound are:1H-NMR(400MHz,DMSO-d6)δ8.09–8.00(m,4H),7.96 (d,J＝8.5Hz,2H),7.68(d,J＝8.5Hz,2H),7.39–7.25(m,5H),6.19(s,1H),3.28(s,3H), 3.22(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.86,149.90,149.12,142.30,140.78,138.35, 135.14,131.42,130.92,129.73,129.70,129.11,129.08,128.97,128.19,127.99,127.97,127.55, 111.10,43.79.HR-MS(ESI):calcd for C25H20NaO6S2:503.0599([M+Na]+) 503.0588, found. It can be seen that the product structure is correct.
Example 4: 2a4((5Z) -5- (2, 6-dimethylbenzylidene) -4- (4- (methylsulfonyl) phenyl) -3-phenylfuran-2 (5H) -one)
Figure BDA0002608566220000083
This example, compound 2a4, was synthesized in the same manner as example 1, starting from compound 1a to give a yellow powder with a calculated product yield of 68%.
The nuclear magnetic data of the obtained compound are:1H-NMR(400MHz,DMSO-d6)δ8.06(d,J＝8.3Hz,2H), 7.70(d,J＝8.3Hz,2H),7.56(d,J＝8.1Hz,2H),7.45–7.40(m,3H),7.37–7.30(m,5H), 6.16(s,1H),3.28(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.42,149.96,147.27,142.50, 134.78,134.66,134.65,131.57,130.88,130.78,130.09,129.82,129.11,128.91,128.73,128.65, 128.33,107.79,43.72.HR-MS(ESI):calcd for C24H16Cl2NaO4S:493.0044([M+Na]+) 493.0034, found. It can be seen that the product structure is correct.
Example 5: 2a5((5Z) -5- (2, 6-dichlorobenzylidene) -4- (4- (methylsulfonyl) phenyl) -3-phenylfuran-2 (5H) -one)
Figure BDA0002608566220000091
This example, compound 2a5, was synthesized in the same manner as example 1, starting from compound 1b to give a yellow powder with a calculated product yield of 73%.
The nuclear magnetic data of the obtained compound are:1H-NMR(400MHz,DMSO-d6)δ8.04(d,J＝8.6Hz,2H), 7.73(d,J＝8.6Hz,2H),7.37–7.27(m,5H),7.21–7.01(m,3H),6.38(s,1H),3.27(s,3H), 2.20(s,6H).13C-NMR(101MHz,DMSO-d6)δ168.00,148.43,148.07,142.27,136.87,135.43, 132.01,130.82,129.76,129.70,129.05,128.17,127.89,127.25,112.78,43.75,20.90.HR-MS (ESI):calcd for C26H22NaO4S:453.1136([M+Na]+) 453.1125, found. As a result, the product was found to be cakingThe structure is correct.
Example 6: 2a6((5Z) -5- (4-hydroxybenzylidenee) -4- (4- (methylsulfonyl) phenyl) -3-phenylfuran-2 (5H) -one)
Figure BDA0002608566220000092
This example, compound 2a6, was synthesized in the same manner as example 1, starting from compound 1a to give a yellow powder with a calculated product yield of 89%.
The nuclear magnetic data of the obtained compound are:1H-NMR(600MHz,DMSO-d6)δ10.08(s,1H),8.02(d,J＝ 8.0Hz,2H),7.68–7.59(m,4H),7.32–7.23(m,5H),6.81(d,J＝8.4Hz,2H),5.95(s,1H), 3.27(s,3H).13C-NMR(151MHz,DMSO-d6)δ168.27,159.54,149.57,145.74,142.10,135.77, 133.20,130.84,129.54,129.32,128.96,128.09,124.65,124.50,116.57,114.29,43.80.HR- MS(ESI):calcd for C24H18O5SNa:441.0773([M+Na]+) 441.0784, found. It can be seen that the product structure is correct.
Example 7: 2a7((5Z) -5- (3-hydroxybenzylidene) -4- (4- (methylsulfonyl) phenyl) -3-phenylfuran-2 (5H) -one)
Figure BDA0002608566220000101
This example, compound 2a7, was synthesized in the same manner as example 1 starting from compound 1a to give a pale yellow powder with a calculated product yield of 86%.
The nuclear magnetic data of the obtained compound are:1H-NMR(600MHz,DMSO-d6)δ9.63(s,1H),8.03(d,J＝ 7.1Hz,2H),7.66(d,J＝7.1Hz,2H),7.37–7.26(m,6H),7.19(t,J＝7.2Hz,1H),7.12(d,J ＝7.0Hz,1H),6.76(d,J＝7.6Hz,1H),5.94(s,1H),3.28(s,3H).13C-NMR(151MHz,DMSO- d6)δ168.15,158.13,149.47,147.80,142.18,135.49,134.51,130.87,130.38,129.64,129.26, 129.00,128.13,126.13,122.58,117.33,117.00,113.68,43.80.HR-MS(ESI):calcd for C24H18NaO5S:441.0773([M+Na]+) 441.0764, found. It can be seen that the product structure is correct.
Example 8: 2a8((5Z) -5- (2-hydroxybenzylidene) -4- (4- (methylsulfonyl) phenyl) -3-phenylfuran-2 (5H) -one)
Figure BDA0002608566220000102
This example, compound 2a8, was synthesized in the same manner as example 1, starting from compound 1a to give a yellow powder with a calculated product yield of 91%.
The nuclear magnetic data of the obtained compound are:1H-NMR(600MHz,DMSO-d6)δ10.09(s,1H),8.05(d,J＝ 7.6Hz,2H),8.01(d,J＝7.8Hz,1H),7.67(d,J＝7.6Hz,2H),7.34–7.26(m,5H),7.18(t,J ＝7.6Hz,1H),6.91(t,J＝7.5Hz,1H),6.86(d,J＝8.0Hz,1H),6.32(s,1H),3.30(s,3H).13C- NMR(151MHz,DMSO-d6)δ168.24,156.76,149.58,147.22,142.30,135.83,131.61,130.94, 130.83,129.59,129.49,129.37,128.99,128.10,125.47,120.39,120.28,116.20,107.74, 43.68.HR-MS(ESI):calcd for C24H18NaO5S:441.0773([M+Na]+) 441.0763, found. It can be seen that the product structure is correct.
Example 9: 2a9((5Z) -5- (2-hydroxy-5-fluorobenzylidene) -4- (4- (methylsulfonyl) phenyl) -3-phenylfuran-2 (5H) -one)
Figure BDA0002608566220000103
This example, compound 2a9, was synthesized in the same manner as example 1, starting from compound 1a to give a yellow powder with a calculated product yield of 82%.
The nuclear magnetic data of the obtained compound are:1H-NMR(600MHz,DMSO-d6)δ10.14(s,1H),8.05(d,J＝ 7.6Hz,2H),7.73(d,J＝10.1Hz,1H),7.66(d,J＝7.5Hz,2H),7.36–7.22(m,5H),7.06(t,J ＝8.3Hz,1H),6.91–6.82(m,1H),6.25(s,1H),3.30(s,3H).13C-NMR(151MHz,DMSO-d6) δ167.94,156.61,155.06,153.14,149.30,147.97,142.38,135.58,130.80,129.65,129.61, 129.18,129.03,128.15,126.15,121.10,121.05,118.21,118.05,117.23,117.18,116.06,115.90, 106.48,43.67.HR-MS(ESI):calcd for C24H18FO5S:437.0853([M+H]+) 437.0851, found. It can be seen that the product structure is correct.
Example 10: 2a10((5Z) -5- (2-hydroxy-3-methoxybenzylidene) -4- (4- (methylsulfonyl) phenyl) -3-phenylfuran-2 (5H) -one)
Figure BDA0002608566220000111
This example, compound 2a10, was synthesized in the same manner as example 1, starting from compound 1a to give a pale yellow powder with a calculated product yield of 81%.
The nuclear magnetic data of the obtained compound are:1H-NMR(600MHz,DMSO-d6)δ9.10(s,1H),8.05(d,J＝ 8.0Hz,2H),7.68(d,J＝8.0Hz,2H),7.62(d,J＝7.9Hz,1H),7.33–7.26(m,5H),6.95(d,J ＝7.8Hz,1H),6.85(t,J＝8.0Hz,1H),6.35(s,1H),4.03(q,J＝6.8Hz,2H),3.30(s,3H),1.28 (t,J＝6.9Hz,3H).13C-NMR(151MHz,DMSO-d6)δ168.23,149.61,147.35,147.17,146.44, 142.32,130.84,129.58,129.50,129.36,129.00,128.07,122.39,120.71,120.04,114.75,107.78, 64.84,43.67,15.08.HR-MS(ESI):Calcd for C26H22NaO6S:485.1034([M+Na]+) 485.1020, found. It can be seen that the product structure is correct.
Example 11: 2a11((5Z) -5- (2-hydroxy-5-chlorobenzylidene) -4- (4- (methylsulfonyl) phenyl) -3-phenylfuran-2 (5H) -one)
Figure BDA0002608566220000112
This example, compound 2a11, was synthesized in the same manner as example 1, starting from compound 1a to give a yellow powder with a calculated product yield of 73%.
The nuclear magnetic data of the obtained compound are:1H-NMR(600MHz,DMSO-d6)δ10.44(s,1H),8.05(d,J＝ 7.7Hz,2H),7.97(s,1H),7.66(d,J＝7.8Hz,2H),7.36–7.26(m,5H),7.23(d,J＝8.7Hz, 2H),6.88(d,J＝8.7Hz,2H),6.22(s,1H),6.22(s,3H).13C-NMR(151MHz,DMSO-d6)δ 167.98,155.56,149.29,148.06,142.39,135.56,130.92,130.80,129.65,129.62,129.16, 129.04,128.15,126.20,123.65,121.97,117.87,105.98,43.67.HR-MS(ESI):calcd for C24H17ClNaO5S:475.0377([M+Na]+) 475.0372, found. It can be seen that the product structure is correct.
Example 12: 2a12((5Z) -5- (4- (dimethylamino) benzylidene) -4- (4- (methylsulfonyl) phenyl) -3-phenylfuran-2 (5H) -one)
Figure BDA0002608566220000121
This example, compound 2a12, was synthesized in the same manner as example 1, starting from compound 1a or 1b to give a yellow powder with a calculated product yield of 86%.
The nuclear magnetic data of the obtained compound are:1H-NMR(600MHz,DMSO-d6)δ8.01(d,J＝7.8Hz,2H), 7.69–7.59(m,4H),7.27(s,5H),6.72(d,J＝8.0Hz,2H),5.93(s,1H),3.28(s,3H),2.96(s, 3H).13C-NMR(151MHz,DMSO-d6)δ168.36,151.30,149.38,144.54,141.98,136.09,132.94, 130.83,129.89,129.43,129.01,128.91,128.07,122.88,120.95,115.33,112.50,43.81.HR- MS(ESI):calcd for:446.1426([M+H]+),found:446.1419.Chemical Formula:C26H24NO4s Exact Mass: 446.1426. It can be seen that the product structure is correct.
Example 13: 2a13((5Z) -4- (4- (methylsulfonyl) phenyl) -3-phenyl-5- (4- (pyrrol-1-yl) benzylidene) furan-2 (5H) -one)
Figure BDA0002608566220000122
This example, compound 2a13, was synthesized in the same manner as example 1, starting from compound 1a to give a red powder with a calculated product yield of 78%.
The nuclear magnetic data of the obtained compound are:1H-NMR(600MHz,DMSO-d6)δ8.01(d,J＝8.0Hz,2H), 7.63(d,J＝6.9Hz,4H),7.34–7.18(m,5H),6.57(d,J＝8.6Hz,2H),5.92(s,1H),3.31–3.20 (m,7H),1.96–1.89(m,4H).13C-NMR(151MHz,DMSO-d6)δ168.38,149.37,148.80, 144.19,141.96,136.17,135.30,133.15,130.83,129.98,129.40,128.91,128.06,122.49, 120.50,115.71,112.56,47.77,43.81,25.48.HR-MS(ESI):calcd for C28H25NNaO4S:472.1577 ([M+H]+) 472.1574, found. It can be seen that the product structure is correct.
Example 14: 2a14((5Z) -5- (4- (4-methylpiperazin-1-yl) benzylidene) -4- (4- (methylsulfonyl) phenyl) -3-phenylfuran-2 (5H) -one)
Figure BDA0002608566220000131
This example, compound 2a14, was prepared according to the same procedure as example 1, starting from compound 1a or 1b to give an orange powder with a calculated product yield of 72%.
The nuclear magnetic data of the obtained compound are:1H-NMR(600MHz,DMSO-d6)δ8.01(s,2H),7.63(d,J＝ 7.7Hz,2H),7.27(s,5H),6.95(s,2H),5.94(s,1H),3.30–3.19(m,8H),2.38(s,3H),2.17(s, 3H).13C-NMR(151MHz,DMSO-d6)δ168.29,151.71,149.41,145.29,142.03,135.92,132.73, 130.83,129.72,129.48,129.16,128.93,128.08,123.68,123.29,123.07,114.81,114.63,54.88, 47.11,46.27,43.81；HR-MS(ESI):calcd for C29H29N2O4S:501.1848([M+H]+) 501.1834, found. It can be seen that the product structure is correct.
Example 15: 2a15((5Z) -4- (4- (methylsulfonyl) phenyl) -3-phenyl-5- (2- (pyrrol-1-yl) benzylidene) furan-2 (5H) -one)
Figure BDA0002608566220000132
This example, compound 2a15, was synthesized in the same manner as example 1, starting from compound 1a to give a yellow powder with a calculated product yield of 71%.
The nuclear magnetic data of the obtained compound are:1H-NMR(400MHz,DMSO-d6)δ8.05(d,J＝8.7Hz,2H), 7.85(d,J＝9.9Hz,1H),7.69(d,J＝8.7Hz,2H),7.37–7.28(m,5H),7.25–7.14(m,1H), 6.99–6.86(m,2H),6.02(s,1H),3.28(s,3H),3.11–2.98(m,4H),1.75–1.71(m,4H).13C- NMR(101MHz,DMSO-d6)δ168.33,150.35,149.54,146.56,142.22,136.02,131.62,130.70, 130.66,129.47,129.43,129.03,128.07,124.92,123.07,120.63,116.88,112.36,52.68,43.75, 24.96.HR-MS(ESI):calcd for C25H20NaO6S:471.0878([M+Na]+) 471.0863, found. It can be seen that the product structure is correct.
Example 16: 2a16((Z) -4- (4- (methylsulfonyl) phenyl) -5- (2-morpholinobenzylidene) -3-phenylfuran-2 (5H) -one)
Figure BDA0002608566220000133
This example, compound 2a16, was synthesized in the same manner as example 1, starting from compound 1a to give a yellow powder with a calculated product yield of 76%.
The nuclear magnetic data of the obtained compound are:1H-NMR(600MHz,DMSO-d6)δ8.10(d,J＝7.3Hz,2H), 8.01(d,J＝7.3Hz,1H),7.71(d,J＝7.3Hz,2H),7.38–7.28(m,6H),7.17(t,J＝6.9Hz,1H), 7.08(d,J＝7.6Hz,1H),6.18(s,1H),3.43(s,4H),3.27(s,3H),2.77(s,4H).13C-NMR(151 MHz,DMSO-d6)δ168.24,152.57,149.80,148.03,142.25,136.15,131.15,131.02,130.79, 129.63,129.46,129.28,129.08,128.16,126.58,125.38,123.96,119.79,109.59,66.94,53.20, 43.85.HR-MS(ESI):calcd for C28H25NNaO5S:510.1351([M+Na]+),found:510.1357. it can be seen that the product structure is correct.
Example 17: 2a17((Z) -4- (4- (methylsulfonyl) phenyl) -5- (4-morpholinylbenzylidene) -3-phenylfuran-2 (5H) -one)
Figure BDA0002608566220000141
This example, compound 2a17, was synthesized in the same manner as example 1, starting from compound 1a to give a red powder with a calculated product yield of 89%.
The nuclear magnetic data of the obtained compound are:1H-NMR(400MHz,DMSO-d6)δ8.02(d,J＝8.5Hz,2H), 7.67(d,J＝9.1Hz,2H),7.63(d,J＝8.6Hz),7.32–7.25(m,5H),6.97(d,J＝9.2Hz,2H), 5.95(s,1H),3.71–3.66(m,4H),3.28(s,3H),3.23–3.19(m,4H).13C-NMR(101 MHz,DMSO-d6)δ168.29,151.84,149.43,145.47,142.04,135.89,132.68,130.84,129.68, 129.50,129.21,128.95,128.09,123.89,123.56,114.69,114.50,66.41,47.45,43.80.HR-MS (ESI):calcd for C28H26NO5S:488.1532([M+H]+) 488.1523, found. It can be seen that the product structure is correct. Example 18: 2b1((Z) -5- (4-hydroxybenzylidene) -3- (4-methoxyphenyl) -4- (4- (methylsulfonyl) phenyl) furan-2 (5H) -one)
Figure BDA0002608566220000142
This example, compound 2b1, was synthesized in the same manner as example 1 starting from compound 1b to give a yellow powder with a calculated product yield of 89%.
The nuclear magnetic data of the obtained compound are:1H-NMR(600MHz,DMSO-d6)δ10.04(s,1H),8.03(d,J＝ 7.2Hz,2H),7.64(s,4H),7.23(d,J＝8.1Hz,2H),6.87(d,J＝8.0Hz,2H),6.80(d,J＝7.7Hz, 2H),5.88(s,1H),3.70(s,3H),3.28(s,3H).13C-NMR(151MHz,DMSO-d6)δ168.48,160.12, 159.36,147.75,145.87,142.00,136.12,133.02,130.89,130.82,128.16,124.74,124.04, 121.69,116.53,114.54,113.41,55.72,43.83.HR-MS(ESI):calcd for C25H20NaO6S:471.0878 ([M+Na]+) 471.0868, found. It can be seen that the product structure is correct.
Example 19: 2b2((Z) -5- (3-hydroxybenzylidene) -3- (4-methoxyphenyl) -4- (4- (methylsulfonyl) phenyl) furan-2 (5H) -one)
Figure BDA0002608566220000151
This example, compound 2b2, was synthesized in the same manner as example 1 starting from compound 1b to give a yellow powder with a calculated product yield of 86%.
The nuclear magnetic data of the obtained compound are:1H-NMR(600MHz,DMSO-d6)δ9.61(s,1H),8.04(d,J＝ 7.9Hz,2H),7.66(d,J＝7.9Hz,2H),7.31(s,1H),7.25(d,J＝8.4Hz,2H),7.18(t,J＝7.8Hz, 1H),7.09(d,J＝7.6Hz,1H),6.88(d,J＝8.4Hz,2H),6.74(d,J＝7.9Hz,1H),5.87(s,1H), 3.70(s,3H),3.28(s,3H).13C-NMR(151MHz,DMSO-d6)δ168.35,160.34,158.11,147.92, 147.56,142.08,135.88,134.61,131.04,130.85,130.35,128.21,125.58,122.43,121.41,117.14, 116.91,114.58,112.83,55.75,43.84.HR-MS(ESI):calcd for C25H20NaO6S:471.0878 ([M+Na]+) 471.0871, found. It can be seen that the product structure is correct.
Example 20: 2b3((Z) -5- (2-hydroxybenzylidene) -3- (4-methoxyphenyl) -4- (4- (methylsulfonyl) phenyl) furan-2 (5H) -one)
Figure BDA0002608566220000152
This example, compound 2b3, was synthesized in the same manner as example 1, starting from compound 1b to give a yellow powder with a calculated product yield of 78%.
The nuclear magnetic data of the obtained compound are:1H-NMR(600MHz,DMSO-d6)δ10.05(s,1H),8.06(d,J＝ 8.0Hz,2H),8.00(d,J＝7.7Hz,1H),7.67(d,J＝8.0Hz,2H),7.24(d,J＝8.5Hz,2H),7.17 (t,J＝7.5Hz,1H),6.91–6.83(m,4H),6.26(s,1H),3.70(s,3H),3.31(s,3H).13C-NMR(151 MHz,DMSO-d6)δ168.45,160.24,156.61,147.70,147.34,142.19,136.20,131.38,130.97, 130.82,128.18,124.96,121.52,120.50,120.25,116.16,114.57,106.90,55.74,43.72.HR-MS (ESI):calcd for C25H20NaO6S:471.0878([M+Na]+) 471.0863, found. It can be seen that the product structure is correct.
Examples of the experiments
1. In the state of solution
The powder and solution states of the above compounds 2a1-2a17 and 2b1-2b3 at white light and 365nm were observed, respectively, and the powder and solution state diagrams and fluorescence spectrum diagrams of the above compounds 2a1-2a17 and 2b1-2b3 at white light and 365nm are shown in fig. 2 (a) - (t), respectively.
It is noted that each compound was dissolved in dimethyl sulfoxide (0.1mM) to prepare a solution, and the black background of the left part of the photograph was taken under a hand-held ultraviolet lamp, while the back part of the photograph was taken with the naked eye under normal lighting conditions.
As can be seen, most compounds show strong fluorescence characteristics under the irradiation of an ultraviolet 365nm ultraviolet lamp in a solid state. In the solution state, most compounds also exhibit similar fluorescent properties.
2. Normalized absorption and fluorescence emission spectra
The fluorescence spectra of the compounds 2a1-2a17 and 2b1-2b3 prepared as described above were measured, and the results are shown in (a) to (t) of FIG. 3, respectively.
The fluorescence absorption and emission wavelength spectra of the compounds 2a1-2a17 and 2b1-2b3 prepared above are shown in (a) and (b) of FIG. 4, respectively.
The fluorescence parameters of the above prepared compounds 2a1-2a17 and 2b1-2b3 are shown in Table 2 below.
TABLE 2 fluorescence parameters of Compounds 2a1-2a17 and 2b1-2b3
Dye λmax(nm)a λmax(nm)b Stokes shift[c] Фf d
2a1 365 455 90 0.38
2a2 364 462 98 0.26
2a3 361 453 92 0.06
2a4 329 449 120 0.03
2a5 335 471 136 0.04
2a6 394 541 148 0.23
2a7 372 483 111 0.02
2a8 387 556 169 0.01
2a9 394 580 186 <0.01
2a10 382 664 282 0.01
2a11 394 587 193 0.03
2a12 474 661 187 0.11
2a13 487 656 169 0.18
2a14 454 649 195 0.18
2a15 432 680 248 0.25
2a16 391 677 286 0.94
2a17 446 652 206 0.40
2b1 398 537 139 <0.01
2b2 386 500 114 0.03
2b3 385 530 145 0.02
a. C, unit of nm.d.phi.f: solid state fluorescence quantum yield was determined using an FLS980 spectrometer (Edinburgh).
It can be seen that the compounds in the near infrared region show higher fluorescence quantum yields, with 2a16 up to 0.94 quantum yield. The fluorescent dye has the potential of becoming a commercial fluorescent dye due to the high quantum yield.
3. Cytotoxicity assays
The rofecoxib-like derivative is used as a novel organic fluorescent dye, the tissue compatibility and the biological toxicity of the organic fluorescent dye are one of indexes to be studied firstly, and in the experimental example, in-vitro cytotoxic activity detection is carried out on the compounds 2a12, 2a13 and 2a16 with excellent fluorescent characteristics.
The method comprises the following steps: selecting cell lines such as RAW 264.7 and HeLa cells, and measuring the tumor cell line of the target compound by MTT methodThe rate of inhibition of cell growth. A. Selecting logarithmic growth human tumor cells, trypsinizing, preparing 40000/mL cell suspension with 10% calf serum RPMI1640 culture solution, inoculating in 96-well culture plate, and culturing at 37 deg.C with 5% CO2And culturing for 24 h. B. The experimental group was replaced with a new culture medium containing 5ng/mL of the test sample, and the control group was set at 37 ℃ with 5% CO2And (5) culturing for 3 d. C. The supernatant was discarded, 100. mu.L of 0.5mg/mL MTT was added, and the mixture was cultured for 4 hours. The supernatant was discarded, 200. mu.L of DMSO was added to dissolve the MTT precipitate, and the mixture was mixed well and the optical density at 544nm was measured.
The results of the cytotoxicity test of the compounds 2a12, 2a13 and 2a16 prepared above are shown in (a) and (b) of fig. 5. Wherein (a) in FIG. 5 is the result of cytotoxicity measured by MTT method after HeLa cells were cultured at 37 ℃ for 24 hours in compounds 2a12, 2a13 and 2a16 at concentrations of 3.125-12.5. mu.M, respectively; FIG. b shows the results of cytotoxicity in MTT assay of Raw 264.7 cells cultured at 37 ℃ for 24 hours in compounds 2a12, 2a13 and 2a16 at concentrations of 3.125 to 12.5. mu.M, respectively.
Therefore, the compound has low cytotoxicity and strong biocompatibility, and lays a foundation for successfully developing organic fluorescent dyes and organic fluorescent probes.
4. Compound membrane permeability fluorescence imaging experiment
The above compounds 2a2, 2a10 and 2a16 were subjected to a transmembrane capacity fluorescence imaging experiment, and HeLa cells were treated for 2h (magnification X40, λ ex:405 nm; Green λ em: 500-550 nm; Red λ em: 570-1000nm) in compounds 2a2, 2a10 and 2a16 at a concentration of 5. mu.M, respectively.
The results of the imaging capabilities of compounds 2a2, 2a10, and 2a16 are shown in fig. 6.
Therefore, in the derivative disclosed by the invention, the compounds with three different emission wavelengths have stronger membrane permeation capability, and a way is paved for successfully developing the compounds into novel organic fluorescent dyes and novel organic fluorescent probes in the later period.
5. Two-photon fluorescence characteristics
In this example, compounds 2a1 and 2a17 were used as examples, and the two-photon fluorescence characteristics of the compounds were tested, and the two-photon excitation performance of compounds 2a1 and 2a17 is shown in (a) and (b) of fig. 7, respectively. Wherein (a) in fig. 7 is a photoluminescence spectrum of compound 2a1 under excitation of 730nm, and (b) in fig. 7 is a photoluminescence spectrum of compound 2a17 under excitation of 900 nm; two-photon absorption and photoluminescence process schematic (right), 730nm/900nm pulsed laser excited strong blue emission of 2a1/2a17 (bottom).
Further, the emission as a function of excitation intensity for compounds 2a1 and 2a17 are shown in (a) and (b) of fig. 8, respectively.
It can be seen that the organic fluorescent dye discovered in the present invention exhibits strong two-photon characteristics, as demonstrated by the two-photon phenomenon of the organic dyes such as compounds 2a1 and 2a17 in fig. 7 and 8 above, through multiple experiments. The two-photon characteristic enables the novel fluorescent dye to have stronger biological imaging application value, enables the novel fluorescent dye to be in a near infrared region at both excitation wavelength and emission wavelength, has strong tissue penetration capacity, and lays a solid foundation for developing biological imaging and diagnostic reagents in the future.
6. Solvent effect of compound
The above compounds 2a13, 2a14, 2a16 and 2a17 were tested for different solvent effects, and the test results are shown in fig. 9 (a) - (d), respectively. The polar test solvents are DCM, Tol, DMF, DMSO and EtOH respectively, and are prepared into solutions with the concentration of 0.1M, the emission spectra of each target compound in different solvents are recorded respectively, and images are shot by a handheld ultraviolet lamp (365 nm).
Therefore, the series of organic fluorescent dye compounds developed by the invention have compound solvent effect, show different emission spectrum characteristics under different polar solvents, and have the potential of being developed into fluorescent probes for sensing microenvironment change in organisms.
7. Fluorescent dye fluorescence emission wavelength tunability
The fluorescence emission wavelength tunability tests were performed on compounds 2a1, 2a2, 2a3, 2a6, 2a8, 2a9, 2a12, 2a13, 2a16 and 2b3, respectively, and the results are shown in fig. 10. Therefore, the series of organic fluorescent dye compounds discovered by the invention have strong adjustability of emission wavelength.
Taking 2a1, 2a2, 2a3, 2a6, 2a12 and 2a13 as examples respectively, the adjustability of the fluorescence property is tested by analyzing the substituents by changing the types of the substituents, and the test result is shown in FIG. 11. Therefore, the type of the substituent of the compound is changed, so that the series of compounds show the capability of emitting wavelength from blue light to near infrared, the structure-fluorescence relation between the structure and fluorescence can be constructed through analyzing the type of the substituent and the Hammett equation, and powerful scientific guidance and basis are provided for developing a more superior fluorescence probe in the later period.
8. Effect of substituent position on fluorescence emission wavelength and fluorescence intensity
Taking compounds 2a16 and 2a17 as examples, emission spectra of compounds containing pyrrolidinyl group (i.e. substituents at ortho-position and para-position of benzene ring) were investigated, and the results are shown in FIG. 12.
Taking compound 2a1-2a3 as an example, the influence of OH groups at different positions of the Ar3 benzene ring on the fluorescence emission performance is studied, wherein (a) in FIG. 13 is the influence result of the OH group structures at different positions on the emission spectrum, and (b) in FIG. 13 is the influence result of the OH group structures at different positions on the fluorescence intensity.
Therefore, the fluorescence characteristics can be obviously influenced by the structures of the compounds with the same substituent and different substitution positions; for example, the compounds 2a16 and 2a17 are morpholine substituted compounds, and the ortho substitution effect enables the emission wavelength to be red-shifted and the fluorescence quantum yield to be obviously improved; similarly, the compounds 2b1, 2b2 and 2b3 also show the same phenomenon, and the emission wavelength and fluorescence intensity of the compounds are changed due to different positions of hydroxyl groups, so that guidance is provided for further development of the novel organic fluorescent dye.
9. Aggregation induced emission effect (AIE)
From the introduction of the AIE concept to the present time, over 80 countries and regions have entered the world over 1500 international teams, and in 2016, AIE materials and related research were highlighted by magazines and media such as nature, new york times, and CNBC (american global finance and television channel). In The scientific news deep analysis long text of "The nanolight revolution is coming" (The nanolight recycling communication), published in nature, AIE nanomaterials (AIE dots) are listed as one of four large nanomaterial systems that support The coming nanolight revolution. At present, most intellectual property rights of commercial fluorescent probes are controlled by foreign enterprises, such as a provider of a bioluminescent labeling and detecting product in the United states, the bioluminescent labeling and detecting product for the living beings is expensive and high in profit, only 2012 years later, the annual output value of the whole company is up to 38 hundred million dollars, and the earning rate is more than 29%; in addition, most of the current commercial fluorescent probes are not very efficient. Therefore, it is very important to develop materials and technologies with AIE performance advantages, and to make AIE material systems and breakthroughs thereof in the application field contribute to the improvement of the quality of life of people and the improvement of medical conditions.
The Aggregation Induced Emission (AIE) effect of compound 2a16 was tested, and the results are shown in FIG. 14, in which (a) in FIG. 14 is the fluorescence intensity value at different excitation wavelengths, and (b) in FIG. 14 is the fluorescence intensity value at different water content.
As can be seen, the compound 2a16 prepared by the invention shows aggregation-induced emission effect (AIE), and can overcome aggregation quenching effect (ACQ) in traditional organic fluorescent dyes.
10. Ability to recognize cancer cells
Taking compound 2a16 as an example, the series of compounds of the present invention were tested for their ability to recognize cancer cells, and the results of the tests are shown in FIG. 15 by fluorescence imaging experiments on cells. Therefore, the compound 2a16 provided by the invention has the capability of identifying HeLa cancer cells, the novel organic fluorescent dye can be used as a novel fluorescent dye skeleton and developed into a novel commercialized fluorescent dye, and the novel organic fluorescent dye is expected to be developed into a novel cancer early diagnosis reagent due to the strong targeting capability of COX-2 enzyme.
11. Prediction of excitation and emission spectra of compounds using TDDFT
The excitation and emission spectra of compounds 2a2, 2a6 and 2a12 were tested using the TDDFT (Time-Dependent sensitivity Functional Theory) model,
we used the Gaussian 09 software package to predict the absorption and emission spectra of compounds 2a2, 2a 62 a12 in DMSO solvent at the level of B3 LYP/6-311 + + G (2d, p) according to the time-density functional theory (TDDFT). The solvent effect of DMSO was simulated by using the default IEFPCM model. The difference between the LUMO and HOMO molecular orbital energies in the ground state is used to calculate the maximum absorption wavelength. The emission spectrum is a wavelength corresponding to an energy difference between the first excited state and the second excited state calculated according to the Franck-Condon principle. The calculated spectra are shown in table 3.
Table 3 excitation and emission spectra results for the compounds
Figure BDA0002608566220000191
It can be seen that compared with the experimental values, the theoretical values are closer to the measured values, which fully indicates that the absorption and emission spectrum values of the compound can be predicted more accurately by using the energy orbit calculation.
12. Using calculations to mimic the binding capacity of a compound to the enzyme COX-2
Compounds 2a12-2a17 were tested for their ability to bind to COX-2 enzyme and the results are shown in Table 4 below.
Experimental crystal structures of COX-2 complexes were obtained from a protein database (PDB: 5 KIR). The molecular model of the compound was constructed from Discovery Studio 3.5. Proteins and ligands add polar hydrogen atoms and their partial charge through AutoDockTools 1.5.6. Molecular docking was performed by AutoDock 4.2. The grid points are set to 50 at the x, y, z axes. The number of runs of Dock is set to 20 all other parameters are kept at default values.
TABLE 4 binding free energy results
Figure BDA0002608566220000192
Therefore, a plurality of compounds in the near infrared region show stronger binding capacity with COX-2, so that the compounds have great potential to become COX-2 fluorescent probes. In conclusion, the rofecoxib-like series compound as a novel organic fluorescent dye not only shows excellent fluorescence characteristics, such as two-photon characteristics, near-infrared luminescence, large Stokes shift, high quantum yield and the like; meanwhile, through a cell fluorescence imaging experiment, the compound 2a16 has the capacity of identifying HeLa cancer cells and has the strong targeting capacity of COX-2 enzyme, and the novel organic fluorescent dye not only can be used as a novel fluorescent dye skeleton to be developed into a novel commercial fluorescent dye, but also is expected to be developed into a novel cancer early diagnosis reagent, so that the novel organic fluorescent dye has great application value.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Variations and modifications in other variations may occur to those skilled in the art based upon the foregoing description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.

Claims (10)

1. A rofecoxib-like derivative having a structure represented by the following formula (i):
Figure FDA0002608566210000011
wherein the content of the first and second substances,
ar is1、Ar2And Ar3Independently of one another, are selected from aromatic rings;
the R, R1And R2Independently of one another, from the group of pi-conjugated systems and/or different types of electron-donating or electron-withdrawing groups.
2. The rofecoxib-like derivative of claim 1, wherein Ar is Ar1、Ar2And Ar3Independently of one another, are selected from the benzene rings, or, Ar is1、Ar2And Ar3Independently of one another, from heteroaromatic rings.
3. The rofecoxib-like derivative of claim 1, wherein R, R is present1And R2Independently of each other, from an electron donating group or an electron withdrawing group, or, R, R1And R2Independently of one another, from a pi-conjugated system with different types of substituents on the pi-conjugated system of electron donating groups or electron withdrawing groups.
4. Rofecoxib-like derivatives according to any of claims 1 to 3, wherein the electron donating or withdrawing group comprises hydrogen, halogen, amino, carboxy, cyano, trifluoromethanesulfonyl, trifluoromethoxy, methylsulfonyl, (C1-C6) alkyl, (C1-C4) alkylhydroxy, (C1-C4) alkoxy, (C1-C4) alkenyl, (C1-C4) alkynyl, N- (C1-C9) alkylamino, N-di (C1-C9) alkylamino, (C1-C4) alkylthio, (C1-C4) alkylsulfinyl, (C1-C4) alkylsulfonyl, (C1-C4) alkoxymethyl, (C1-C4) alkoxyethyl, (C1-C4) alkylacyl, carbamoyl, N- (C1-C4) ylcarbamoyl, N, N-di (C1-C4) alkylcarbamoyl or (C1-C3) alkylenedioxy, and the like.
5. The rofecoxib-like derivative according to any one of claims 1-4, wherein the derivative comprises a compound having the structure:
Figure FDA0002608566210000012
Figure FDA0002608566210000021
Figure FDA0002608566210000031
6. the rofecoxib-like derivative according to any one of claims 1-5, wherein the derivative comprises a salt, solvate, isomer, ester or precursor of a compound having formula (I).
7. A process for the preparation of a rofecoxib-like derivative according to any of claims 1 to 6, comprising the step of reacting a rofecoxib skeleton compound having a structure wherein R is selected from the group consisting of hydrogen and methoxy to obtain the target compound;
Figure FDA0002608566210000032
8. use of rofecoxib-like derivatives according to any of claims 1 to 6, and acceptable salts, isomers thereof for the preparation of organic fluorescent dye matrices.
9. A composition comprising an organic fluorescent dye or probe, comprising the rofecoxib-like derivative of any one of claims 1-6, or an acceptable salt or isomer thereof, and a biologically acceptable carrier or excipient.
10. Use of the composition comprising an organic fluorescent dye or probe according to claim 9 in the field of bioimaging or in the field of other materials.
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