CN115894407A - CIT fluorophore of 1-furan and thienyl-2-alkenyl-1-ketone containing nitrogen mustard and preparation method and application thereof - Google Patents
CIT fluorophore of 1-furan and thienyl-2-alkenyl-1-ketone containing nitrogen mustard and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a nitrogen mustard-containing CIT fluorophore of 1-furan and thienyl-2-alkenyl-1-ketone, a preparation method and application thereof, belonging to the field of medical intermediates, and having a molecular structure shown in a formula (I): whereinX is O or S; r is H, CH 3 And Cl. The preparation method comprises the following steps: 4- [ bis (beta-chloroethyl) amino]Benzaldehyde, acetyl-containing furan derivatives or acetyl-containing thiophene derivatives are uniformly mixed in a solvent, and then condensation reaction is carried out under the base catalysis condition to prepare the compound shown in the formula (I). Simultaneously discloses the application of the ICT fluorophore in cell fluorescence imaging and preparation of antitumor drugs. Also disclosed are antineoplastic agents comprising the ICT fluorophores. The ICT fluorophore obtained by the invention has strong pharmacological activity and wide development value in the field of antitumor drugs, and the preparation method of the ICT fluorophore provided by the invention is simple and easy to implement and convenient to popularize and use.
Description
Technical Field
The invention relates to the field of medical intermediates, in particular to a nitrogen mustard 1-furan, thienyl-2-alkenyl-1-ketone CIT fluorophore, and a preparation method and application thereof.
Background
In recent years, the development of fluorescent probes has become a booming research hotspot, and they are often used for biological process research in cancer treatment, such as real-time biomolecule imaging and diagnosis. Meanwhile, the research on the anti-cancer drugs with luminescent groups is well developed. These drugs have dual-action diseases: diagnosis and treatment. They can be used not only for real-time imaging but also as a therapeutic agent. However, many drugs lack effective luminophores. Although many fluorescent molecules are present, the stokes shift is small and the emission wavelength is generally short.
Nitrogen mustards are an important class of alkylated anticancer drugs that have been used in the treatment of a variety of solid tumors, and over the past several decades, a number of improvements have been made in the therapeutic efficacy due to the high reactivity and peripheral cytotoxicity of nitrogen mustards preparations. However, imaging and therapy applications of nitrogen mustard derivatives with luminophores are rare.
Therefore, how to provide a nitrogen mustard derivative with a luminophore and simultaneously apply the nitrogen mustard derivative to imaging and treatment is a technical problem which needs to be solved urgently by the technical personnel in the field.
Disclosure of Invention
The invention aims to provide a 1-furan, thienyl-2-alkenyl-1-ketone CIT fluorophore of nitrogen-containing mustard and a preparation method and application thereof, so as to solve the problems in the prior art.
In order to achieve the purpose, the invention provides the following scheme:
an ICT fluorophore for nitrogen-containing mustards, having a molecular structure represented by formula (I):
wherein X is O or S;
r is H or CH 3 。
Preferably, when X is O and acyl is attached to carbon number 2, R is H and/or CH 3 And substituted with carbon numbers 3, 4 and 5;
when the X is O and the acyl group is connected with the carbon number 3, the R is CH 3 And substituted with carbon numbers 2 and 5;
when the X is S and the acyl group is connected with the carbon No. 2, the R is CH 3 Or Cl, and substituted with carbon number 3, 4, or 5;
when the X is S and acyl is attached to carbon number 3, the R is H and is substituted on carbon number 2, 4 or 5.
A method for preparing an ICT fluorophore containing nitrogen mustard, which is characterized by comprising the following steps:
4- [ bis (beta-chloroethyl) amino ] benzaldehyde, acetyl-containing furan derivatives or acetyl-containing thiophene derivatives are uniformly mixed in a solvent, and then condensation reaction is carried out under the base catalysis condition, so as to prepare the compound shown in the formula (I).
Preferably, the molar ratio of the 4- [ bis (beta-chloroethyl) amino ] benzaldehyde, the acetyl-containing furan derivative or the acetyl-containing thiophene derivative to the base is 1:1: (1.0-2.0).
Preferably, the condensation reaction in the step (A) is carried out at a temperature of 0-110 ℃ for 5-24 hours.
Preferably, the solvent comprises one or more of methanol, ethanol, acetonitrile and toluene;
the base includes NaOH, KOH, na 2 CO 3 、K 2 CO 3 、CH 3 ONa、CH 3 OK、 CH 3 CH 2 ONa and CH 3 CH 2 One or more OK.
The acetyl-containing furan derivative comprises one of the following substances:
the acetyl-containing thiophene derivative comprises one of the following substances:
has the advantages that: the ICT fluorophore has the advantages of simple and feasible synthesis method, high yield, dual functions of cell fluorescence imaging and antitumor activity, and overcomes the defect that many nitrogen mustard drugs do not have fluorescence imaging. The ICT fluorophore has an emission wavelength of more than 516nm and a Stokes shift of 150nm, can be used as a good fluorescence imaging agent, and can effectively inhibit the proliferation, cloning and migration of tumor cells.
An application of an ICT fluorophore containing nitrogen mustard in cell fluorescence imaging.
An application of nitrogen mustard-containing ICT fluorophore in preparing antineoplastic medicines.
An application of nitrogen mustard ICT fluorophore in preparing medicine for inhibiting the growth of lung cancer cells.
An antineoplastic drug, an active ingredient of the antineoplastic drug comprising an ICT fluorophore of said nitrogen-containing mustard or a pharmaceutically acceptable salt thereof.
The invention discloses a nitrogen mustard-containing CIT fluorophore of 1-furan and thienyl-2-alkenyl-1-ketone, a preparation method and application thereof, which have longer emission wavelength and longer Stokes shift and can be effectively applied to subcellular imaging positioning. The invention shows strong pharmacological activity in the aspects of inhibiting cell proliferation, clone formation, migration and the like of lung cancer cells, and has wide research and development values in the field of antitumor drugs. The invention can be used for subcellular imaging localization and inhibition of proliferation of lung cancer cells, and also can inhibit clone formation and migration of lung cancer cells, and has a certain medical application prospect. Moreover, the preparation method of the fluorophore provided by the invention is simple and easy to implement, has low requirements on equipment, is easy to separate and purify a target compound, and is convenient to popularize and use.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed to be used in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings without inventive exercise.
FIG. 1 is a graph showing the ultraviolet absorption spectrum and fluorescence emission spectrum of the ICT fluorophore of the nitrogen-containing mustards obtained in examples 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 and 21 of the present invention;
FIG. 2 is a graph showing the in vitro anti-proliferative activity of the nitrogen-containing mustard of ICT fluorophores obtained in examples 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 and 21 of the present invention on lung cancer cells NCI-H460 and A549;
wherein, A is the in vitro anti-proliferation activity detection of the ICT fluorophore containing the nitrogen mustard on the lung cancer cell NCI-H460, and B is the in vitro anti-proliferation activity detection of the ICT fluorophore containing the nitrogen mustard on the lung cancer cell A549;
FIG. 3 shows the microscopic morphology of the cells after the fluorescence of the nitrogen-containing mustard ICT obtained in example 15 of the present invention acts on A549 cells;
FIG. 4 shows the sub-localization of the ICT fluorophore of the nitrogen-containing mustard obtained in example 15 of the present invention in A549 cells using CLSM imaging technique;
FIG. 5 is a graph showing the results of a cloning experiment in which A549 cells were incubated with the fluorescence of the nitrogen-containing mustard ICT obtained in example 15 of the present invention;
wherein A is a microscope photograph and B is a statistical chart;
FIG. 6 is a graph showing the results of a cell migration experiment in which A549 cells were incubated with an ICT fluorophore derived from a nitrogen-containing mustard of example 15 of the present invention;
wherein A is a microscope photograph and B is a statistical chart.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In order to make the aforementioned objects, features and advantages of the present invention more comprehensible, the present invention is described in detail with reference to the accompanying drawings and the detailed description thereof.
The starting materials in the examples of the present invention were all purchased from commercial sources.
Example 1
An ICT fluorophore for a nitrogen-containing mustard having the molecular structure shown below in compound 3 a:
the preparation method of the compound 3a comprises the following steps:
4- [ bis (beta-chloroethyl) amino]Benzaldehyde (1 mol), 2-acetylfuran (1 mol) and CH 3 ONa (1.5 mmol) was added to methanol (160 mL) and reacted at 60 ℃ for 5 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to obtain compound 3a. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Characterization data: 1 H NMR(600MHz,DMSO-d 6 )δ:8.02(d,J＝1.90Hz, 1H,Furan-H),7.71～7.65(overlapped,4H,CH,Furan-H,ArH),7.45(d,J ＝15.61Hz,1H,CH),6.83(d,J＝8.89Hz,2H,ArH),6.76(dd,J＝1.90, 3.55Hz,1H,Furan-H),3.84～3.76(overlapped,8H,CH 2 ). 13 C NMR(150 MHz,DMSO-d 6 )δ:177.19,153.77,149.19,148.15,143.86,131.38, 123.36,118.70,117.35,113.04,112.40,52.24,41.53.HR-MS(ESI)m/z: Calcd for C 17 H 18 Cl 2 NO 2 [M+H] + 338.0715,found 338.0716。
example 2
An ICT fluorophore for a nitrogen mustard having the molecular structure shown in compound 3a of the formula:
the preparation method of the compound 3a comprises the following steps:
4- [ bis (beta-chloroethyl) amino]Benzaldehyde (1 mol), 2-acetylfuran (1 mol) and NaOH (1.5 mol) were added to ethanol (160 mL) and reacted at room temperature for 24 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 3a. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Example 3
An ICT fluorophore for a nitrogen mustard having the molecular structure shown in compound 3b of the formula:
the preparation method of the compound 3b comprises the following steps:
reacting 4- [ bis (. Beta. -chloroethyl) amino group]Benzaldehyde (1 mol), 5-methyl-2-acetylfuran (1 mol), CH 3 ONa (1.5 mol) was added to methanol (160 mL) and reacted at 60 ℃ for 5 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 3b. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Characterization data: 1 H NMR(600MHz,DMSO-d 6 )δ:7.68(d,J＝8.90Hz, 2H,ArH),7.64～7.60(overlapped,2H,Furan-H,CH),7.40(d,J＝15.52Hz, 1H,CH),6.83(d,J＝8.90Hz,2H,ArH),6.40(dd,J＝0.90Hz,3.44Hz, 1H,Furan-H),3.84～3.76(overlapped,8H,CH 2 ). 13 C NMR(150MHz, DMSO-d 6 )δ:176.43,158.21,152.68,149.03,143.16,131.23,123.47, 120.54,117.49,112.37,109.73,52.24,41.54,14.19.HR-MS(ESI)m/z: Calcd for C 18 H 20 Cl 2 NO 2 [M+H] + 352.0871,found 352.0873。
example 4
An ICT fluorophore for a nitrogen mustard having the molecular structure shown in compound 3b of the formula:
the preparation method of the compound 3b comprises the following steps:
4- [ bis (beta-chloroethyl) amino]Benzaldehyde (1 mol), 5-methyl-2-acetylfuran (1 mol) and NaOH (1.5 mol) were added to ethanol (160 mL) and reacted at room temperature for 24 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 3b. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Example 5
An ICT fluorophore for a nitrogen-containing mustard having the molecular structure shown below as compound 3 c:
the preparation method of the compound 3c comprises the following steps:
4- [ bis (beta-chloroethyl) amino]Benzaldehyde (1 mol), 2, 5-dimethyl-3-acetylfuran (1 mol), CH 3 ONa (1.5 mol) was added to methanol (160 mL) and reacted at 60 ℃ for 5 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 3c. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Characterization data: 1 H NMR(600MHz,DMSO-d 6 )δ:7.67(d,J＝8.90Hz, 2H,ArH),7.54(d,J＝15.53Hz,1H,CH),7.24(d,J＝15.53Hz,1H,CH), 6.81(d,J＝8.90Hz,2H,ArH),6.73(s,J＝3.44Hz,1H,Furan-H), 3.82～3.77(overlapped,8H,CH 2 ). 13 C NMR(150MHz,DMSO-d 6 )δ: 185.25,156.86,150.01,149.01,143.22,131.27,123.60,123.02,120.15, 112.42,106.76,52.30,41.59,14.54,43.51.HR-MS(ESI)m/z:Calcd for C 19 H 22 Cl 2 NO 2 [M+H] + 366.1028,found 366.1026。
example 6
An ICT fluorophore for a nitrogen-containing mustard having the molecular structure shown below as compound 3 c:
the preparation method of the compound 3c comprises the following steps:
4- [ bis (beta-chloroethyl) amino]Benzaldehyde (1 mol), 2, 5-dimethyl-3-acetylfuran (1 mol) and NaOH (1.5 mol) were added to ethanol (160 mL) and reacted at room temperature for 24 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 3c. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Example 7
An ICT fluorophore for a nitrogen-containing mustard having the molecular structure shown below in compound 3 d:
the preparation method of the compound 3d comprises the following steps:
reacting 4- [ bis (. Beta. -chloroethyl) amino group]Benzaldehyde (1 mol), 2-acetylthiophene (1 mol), CH 3 ONa (1.5 mol) was added to methanol (160 mL) and reacted at 60 ℃ for 5 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 3d. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Characterization data: 1 H NMR(600MHz,DMSO-d 6 )δ:8.25(d,J＝3.78Hz, 1H,thiophene-H),8.00(d,J＝4.88Hz,1H,CH),7.74(d,J＝8.88Hz,2H, ArH),7.67(d,J＝15.54Hz,1H,CH),7.61(d,J＝15.54Hz,1H,CH), 7.29(dd,J＝3.78,4.88Hz,1H,thiophene-H),6.84(d,J＝8.88Hz,2H, ArH),3.83～3.78(overlapped,8H,CH 2 ). 13 C NMR(150MHz,DMSO-d 6 ) δ:181.92,149.30,146.68,144.29,135.15,133.13,131.57,129.29, 123.52,117.40,112.47,52.31,41.62.HR-MS(ESI)m/z:Calcd for C 17 H 18 Cl 2 NOS[M+H] + 354.0486,found 354.0488。
example 8
An ICT fluorophore for a nitrogen mustard having the molecular structure shown in compound 3d of the formula:
the preparation method of the compound 3d comprises the following steps:
4- [ bis (beta-chloroethyl) amino]Benzaldehyde (1 mol), 2-acetylthiophene (1 mol) and NaOH (1.5 mol) were added to ethanol (160 mL) and reacted at room temperature for 24 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 3d. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Example 9
An ICT fluorophore for a nitrogen mustard having the molecular structure shown below for compound 3 e:
the preparation method of the compound 3e comprises the following steps:
reacting 4- [ bis (. Beta. -chloroethyl) amino group]Benzaldehyde (1 mol), 3-methyl-2-acetyl thiophene (1 mol), CH 3 ONa (1.5 mol) was added to methanol (160 mL) and reacted at 60 ℃ for 5 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give 3e. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Characterization data: 1 H NMR(600MHz,DMSO-d 6 )δ:8.72(d,J＝2.22Hz, 1H,thiophene-H),7.72(d,J＝8.88Hz,2H,ArH),7.76～7.63(overlapped, 3H,thiophene-H,CH),7.58(d,J＝15.38Hz,1H,CH),6.84(d,J＝8.88 Hz,2H,ArH),3.83～3.78(overlapped,8H,CH 2 ). 13 C NMR(150MHz, DMSO-d 6 )δ:183.29,149.07,144.05,143.85,133.62,131.37,137.83, 137.63,123.59,118.65,112.36,52.24,41.55.HR-MS(ESI)m/z:Calcd for C 17 H 18 Cl 2 NOS[M+H] + 354.0486,found 354.0490。
example 10
An ICT fluorophore for a nitrogen mustard having the molecular structure shown below for compound 3 e:
the preparation method of the compound 3e comprises the following steps:
reacting 4- [ bis (. Beta. -chloroethyl) amino group]Benzaldehyde (1 mol), 3-methyl-2-acetylthiophene (1 mol) and NaOH (1.5 mol) were added to ethanol (160 mL) and reacted at room temperature for 24 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give 3e. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Example 11
An ICT fluorophore for a nitrogen mustard having the molecular structure shown below for compound 3 f:
the preparation method of the compound 3f comprises the following steps:
reacting 4- [ bis (. Beta. -chloroethyl) amino group]Benzaldehyde (1 mol), 4-methyl-2-acetylfuran (1 mol), CH 3 ONa (1.5 mol) was added to methanol (160 mL) and reacted at 60 ℃ for 5 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 3f. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Characterization data: 1 H NMR(600MHz,DMSO-d 6 )δ:8.05(d,J＝5.24Hz, 1H,thiophene-H),7.70(d,J＝15.30Hz,1H,CH),7.65(d,J＝8.88Hz, 2H,ArH),7.52(d,J＝15.30Hz,1H,CH),7.28(d,J＝5.28Hz,1H, thiophene-H),6.85(d,J＝8.88Hz,2H,ArH),3.83～3.78(overlapped,8H, CH 2 ). 13 C NMR(150MHz,DMSO-d 6 )δ:181.15,149.58,145.49,137.88, 133.21,131.51,131.12,126.90,123.12,118.21,112.55,52.23,41.46. HR-MS(ESI)m/z:Calcd for C 17 H 17 Cl 3 NOS[M+H] + 388.0096,found 388.0010。
example 12
An ICT fluorophore for a nitrogen-containing mustard having the molecular structure shown below as compound 3 f:
the preparation method of the compound 3f comprises the following steps:
4- [ bis (beta-chloroethyl) amino]Benzaldehyde (1 mol), 4-methyl-2-acetylfuran (1 mol) and NaOH (1.5 mol) were added to ethanol (160 mL) and reacted at room temperature for 24 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 3f. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Example 13
An ICT fluorophore for a nitrogen-containing mustard having the molecular structure of compound 3g of the formula:
the preparation method of the compound 3g comprises the following steps:
4- [ bis (beta-chloroethyl) amino]Benzaldehyde (1 mol), 5-methyl-2-acetylfuran (1 mol), CH 3 ONa (1.5 mol) was added to methanol (160 mL) and reacted at 60 ℃ for 5 hours. However, the device is not suitable for use in a kitchenThen, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give 3g of the compound. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Characterization data: 1 H NMR(600MHz,DMSO-d 6 )δ:8.30(d,J＝1.43Hz, 1H,thiophene-H),7.98(d,J＝1.43Hz,1H,thiophene-H),7.71(d,J＝ 8.88Hz,2H,ArH),7.65(d,J＝15.30Hz,1H,CH),7.60(d,J＝15.30Hz, 1H,CH),6.81(d,J＝8.88Hz,2H,ArH),3.81～3.73(overlapped,8H,CH 2 ). 13 C NMR(150MHz,DMSO-d 6 )δ:181.13,149.57,146.69,145.32, 132.39,131.86,129.99,125.15,123.44,116.61,112.48,52.29,41.63. HR-MS(ESI)m/z:Calcd for C 17 H 17 Cl 3 NOS[M+H] + 388.0096,found 388.0099。
example 14
An ICT fluorophore for a nitrogen mustard having the molecular structure of compound 3g of the formula:
the preparation method of the compound 3g comprises the following steps:
4- [ bis (beta-chloroethyl) amino]Benzaldehyde (1 mol), 5-methyl-2-acetylfuran (1 mol) and NaOH (1.5 mol) were added to ethanol (160 mL) and reacted at room temperature for 24 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give 3g of the compound. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Example 15
An ICT fluorophore for a nitrogen mustard having the molecular structure shown below in compound 3 h:
the preparation method of the compound 3h comprises the following steps:
4- [ bis (beta-chloroethyl) amino]Benzaldehyde (1 m)ol), 3-chloro-2-acetylfuran (1 mol), CH 3 ONa (1.5 mol) was added to methanol (160 mL) and reacted at 60 ℃ for 5 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give a compound for 3 hours. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Characterization data: 1 H NMR(600MHz,DMSO-d 6 )δ:8.18(d,J＝4.12Hz, 1H,thiophene-H),7.74(d,J＝8.88Hz,2H,ArH),7.67(d,J＝15.30Hz, 1H,CH),7.59(d,J＝15.30Hz,1H,CH),7.35(d,J＝4.12Hz,1H, thiophene-H),6.84(d,J＝8.88Hz,2H,ArH),3.85～3.76(overlapped,8H, CH 2 ). 13 C NMR(150MHz,DMSO-d 6 )δ:181.04,149.42,145.84,144.85, 137.49,133.08,131.70,129.45,123.33,116.04,112.39,52.22,41.55. HR-MS(ESI)m/z:Calcd for C 17 H 17 Cl 3 NOS[M+H] + 388.0096,found 388.0095。
example 16
An ICT fluorophore for a nitrogen mustard having the molecular structure shown below in compound 3 h:
the preparation method of the compound 3h comprises the following steps:
reacting 4- [ bis (. Beta. -chloroethyl) amino group]Benzaldehyde (1 mol), 3-chloro-2-acetylfuran (1 mol) and NaOH (1.5 mol) were added to ethanol (160 mL) and reacted at room temperature for 24 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give the compound for 3 hours. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Example 17
An ICT fluorophore for a nitrogen mustard having the molecular structure shown in compound 3i of the formula:
the preparation method of the compound 3i comprises the following steps:
4- [ bis (beta-chloroethyl) amino]Benzaldehyde (1 mol), 4-chloro-2-acetylfuran (1 mol), CH 3 ONa (1.5 mol) was added to methanol (160 mL) and reacted at 60 ℃ for 5 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 3i. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Characterization data: 1 H NMR(600MHz,DMSO-d 6 )δ:7.78(d,J＝4.96Hz, 1H,thiophene-H),7.61(d,J＝8.88Hz,2H,ArH),7.57(d,J＝15.25Hz, 1H,CH),7.18(d,J＝15.25Hz,1H,CH),7.08(d,J＝4.96Hz,1H, thiophene-H),6.79(d,J＝8.88Hz,2H,ArH),7.55～7.52(overlapped,2H, thiophene-H,CH),3.79～3.72(overlapped,8H,CH 2 ),2.52(s,3H,CH 3 ). 13 C NMR(150MHz,DMSO-d 6 )δ:182.94,149.26,144.39,144.18, 137.43,133.49,131.28,123.33,119.77,112.55,100.00,52.32,41.56, 29.51.HR-MS(ESI)m/z:Calcd for C 18 H 20 Cl 2 NOS[M+H] + 368.0643, found 368.0648。
example 18
An ICT fluorophore for a nitrogen mustard having the molecular structure shown in compound 3i of the formula:
the preparation method of the compound 3i comprises the following steps:
4- [ bis (beta-chloroethyl) amino]Benzaldehyde (1 mol), 4-chloro-2-acetylfuran (1 mol) and NaOH (1.5 mol) were added to ethanol (160 mL) and reacted at room temperature for 24 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 3i. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Example 19
An ICT fluorophore for a nitrogen mustard having the molecular structure shown below for compound 3 j:
the preparation method of the compound 3j comprises the following steps:
reacting 4- [ bis (. Beta. -chloroethyl) amino group]Benzaldehyde (1 mol), 5-chloro-2-acetylfuran (1 mol), CH 3 ONa (1.5 mol) was added to methanol (160 mL) and reacted at 60 ℃ for 5 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 3j. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Characterization data: 1 H NMR(600MHz,DMSO-d 6 )δ:8.03(d,J＝1.11Hz, 1H,thiophene-H),7.68(d,J＝8.88Hz,2H,ArH),7.60(d,J＝15.19Hz, 1H,CH),7.55～7.52(overlapped,2H,thiophene-H,CH),6.79(d,J＝8.88 Hz,2H,ArH),3.80～3.72(overlapped,8H,CH 2 ),2.25(s,3H,CH 3 ). 13 C NMR(150MHz,DMSO-d 6 )δ:181.81,149.25,146.18,144.07,139.31, 135.03,131.50,130.62,123.58,117.44,112.46.00,52.31,41.62,15.90. HR-MS(ESI)m/z:Calcd for C 18 H 20 Cl 2 NOS[M+H] + 368.0643,found 368.0646。
example 20
An ICT fluorophore for a nitrogen mustard having the molecular structure shown below for compound 3 j:
the preparation method of the compound 3j comprises the following steps:
4- [ bis (beta-chloroethyl) amino]Benzaldehyde (1 mol), 5-chloro-2-acetylfuran (1 mol) and NaOH (1.5 mol) were added to ethanol (160 mL) and reacted at room temperature for 24 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 3j. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Example 21
An ICT fluorophore for a nitrogen mustard having the molecular structure shown below for compound 3 k:
the preparation method of the compound 3k comprises the following steps:
reacting 4- [ bis (. Beta. -chloroethyl) amino group]Benzaldehyde (1 mol), 5-methyl-2-acetylfuran (1 mol), CH 3 ONa (1.5 mol) was added to methanol (160 mL) and reacted at 60 ℃ for 5 hours. Then, the solvent was removed by distillation under the reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 3k. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Characterization data: 1 H NMR(600MHz,DMSO-d 6 )δ:8.06(d,J＝3.85Hz, 1H,thiophene-H),7.71(d,J＝8.88Hz,2H,ArH),7.62(d,J＝15.20Hz, 1H,CH),7.55(d,J＝15.20Hz,1H,CH),7.00(d,J＝3.86Hz,1H, thiophene-H),6.83(d,J＝8.88Hz,2H,ArH),3.82～3.77(overlapped,8H, CH 2 ),2.53(s,3H,CH 3 ). 13 C NMR(150MHz,DMSO-d 6 )δ:181.38, 149.77,149.08,144.50,143.61,133.64,131.39,127.95,123.51,117.17, 112.36,52.24,41.55,16.20.HR-MS(ESI)m/z:Calcd for C 18 H 20 Cl 2 NOS [M+H] + 368.0643,found 368.0640。
example 22
An ICT fluorophore for a nitrogen mustard having the molecular structure shown below for compound 3 k:
the preparation method of the compound 3k comprises the following steps:
4- [ bis (beta-chloroethyl) amino]Benzaldehyde (1 mol), 5-methyl-2-acetylfuran (1 mol) and NaOH (1.5 mol) were added to ethanol (160 mL) and reacted at room temperature for 24 hours. Then removing solvent by reduced pressure distillation, and performing silica gel column chromatography on the residue to obtain compoundSubstance 3k. Mobile phase: CH (CH) 2 Cl 2 ：CH 3 OH＝50:1(V/V)。
Technical effects
1. Test for fluorescence Properties
The compounds prepared in examples 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 and 21 were dissolved in ethanol, transferred to a double pass cuvette, and the absorption spectrum thereof was scanned by an ultraviolet spectrophotometer, and the corresponding maximum absorption wavelength thereof was recorded, to obtain the ultraviolet absorption spectrum of the compound. Meanwhile, the compounds prepared in examples 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 and 21 were dissolved in ethanol and transferred to a four-way cuvette, and the fluorescence emission spectra of the compounds were scanned by a fluorescence spectrophotometer. The excitation wavelength was designed to be the maximum absorption wavelength corresponding to each compound and the slit width was designed to be 10nm, and the results are shown in FIG. 1.
Maximum absorption wavelength (λ) of FIG. 1 max ) Maximum emission wavelength (λ) em ) And Stokes shift (Stokes shift) data were counted to obtain table 1. As is clear from Table 1, the compounds (3 a to 3 k) prepared in examples 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 and 21 had λ values max The range was 392nm to 421nm, the smallest of which was compound 3c prepared in example 3 and 392nm, and the largest was compounds 3h and 3i prepared in examples 15 and 17, both 412nm. Lambda of these fluorophores em Ranging from 516nm to 557 nm, the smallest of which is compound 3c prepared in example 5, 516nm, the largest of which has exceeded 560, examples 15, 17 and 19, respectively, corresponding to the lambda of the compound em 566nm, 565634 nm and 567nm, respectively. The range of stocks shift was also large, with a minimum of 113nm (example 3) and a maximum of 150nm (example 19). These results show that the compounds prepared in examples 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 and 21 of the present invention have long emission wavelengths and large stokes shift characteristics.
TABLE 1. Lambda of Compounds max ,λ em And Stokes shift
| Compound (I) | | |
3c | 3d | 3e | 3f | | 3h | 3i | 3j | 3k | ||||
| λ max | 412 | 411 | 392 | 409 | 403 | 410 | 409 | 421 | 421 | 417 | 399 | ||||
| λ em | 542 | 524 | 516 | 552 | 546 | 553 | 549 | 566 | 563 | 567 | 529 | ||||
| Stokes shift | 130 | 113 | 124 | 143 | 143 | 143 | 140 | 145 | 142 | 150 | 130 |
2. In vitro antiproliferative activity
When the lung cancer cells (NCI-H460, A549) were in logarithmic growth phase, about 2X 10 cells were seeded in 96-well culture plates 3 Adding 100 μ M of drug (0, 1, 2, 4, 8, 16, 32, 64 μ M) diluted with 10% FBS-containing culture medium into each well after cell attachment, incubating at 37 deg.C for 72 hr, discarding culture medium, adding 100 μ L of CCK8 reagent into each well, and culturingIncubate in the incubator for 2 hours. Read each well OD with microplate reader 450 Values to calculate the change in activity of cells after treatment with different concentrations of drug.
The cytotoxicity test results of the compounds 3a to 3k prepared in examples 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 and 21 are shown in fig. 2, wherein part a is the results of NCI-H460 cells and part B is the results of a549 cells. As can be seen from FIG. 2, the anti-proliferative capacity of the compound against both lung cancer cells NCI-H460 and A549 is increased with the increase of the concentration of the compound, and the compound shows good anti-proliferative activity. For NCI-H460 cells, the cytotoxic activity of compounds 3 a-3 g was relatively low, and their IC 50 The value is 23.1 to 29.8. Mu.M. When methyl groups with electron donating effect are introduced, the cytotoxic activity is not significantly altered. When R is chlorine, the cytotoxic activity of the compound is remarkably increased no matter the chlorine is positioned at 3, 4 and 5 positions, and when the concentration of the compound is more than 4 mu M, the activity of the compounds 3h, 3i and 3j is higher than that of other compounds, and the IC is higher 50 The values were only 16.6, 14.2, 15.0. Mu.M, respectively. Similarly, compounds 3 a-3 g were also relatively weak against A549 cells and IC 50 The value is 26.3 to 33.5. Mu.M. However, the introduction of chlorine atoms significantly increases the activity, more than twice as much as 3d, IC, of the active compound 50 The values were 13.1, 17.1 and 14.6. Mu.M, respectively. The results show that the synthesized compound has good anticancer activity, and the compound 3h obtained in example 15 has the best activity on A549 cells.
3. Cell morphology
Cells were seeded in 2cm dishes (2X 10) 5 Individual cells/dish), two concentrations of the compound obtained in example 15 were added for 3h (10 μ M, 20 μ M) incubation for 48 hours, then the medium was removed, washed once with PBS, and the cell morphology was observed under an inverted microscope. As can be seen from fig. 3, after the cells were incubated for 3h with the compound, a549 cells showed swelling and necrosis, and the adhesion of the cells decreased and the protrusions retracted or disappeared. This result demonstrates programmed cell death.
4. Subcellular imaging localization
A549 cells were seeded in a 2cm glass culture dish, and after cell attachment, the cells were incubated with compound 3h (20. Mu.M), lysosome red fluorescent probe (Lyso-tracker Red, 1. Mu.M) and DNA fluorescent dye ( Hoechst 33342, 1. Mu.M) at 37 ℃ for 4h, after which the supernatant was gently aspirated, washed once with PBS, and 2mL of PBS was added. The fluorescence signal of the cells observed by a confocal laser scanning microscope, merge is the fluorescence image of the compound 3b, lyso-Tracker Red, hoechst 33342 integrated and superposed together, and the result is shown in FIG. 4. As can be seen in fig. 4, the fluorescent signal of incubation with compound 3h was strong (green), and most of the signal overlapped with that of the enzyme red fluorescent probe (red), indicating that the release of compound 3h was mainly localized to lysosomes. In addition, a small portion of the green fluorescent signal was clearly visible in the nucleus and overlapped with the cellular DNA fluorescent dye, so that the compound obtained in example 15 was released into the nucleus in a small amount for 3h.
5. Clone formation assay
Cells in logarithmic growth phase were seeded in six-well plates after passage. After the cells adhered, 10. Mu.M and 20. Mu.M of the compound were added for 3h and incubated for 48 h. The medium was discarded, excess medium was washed with PBS, cells were digested with trypsin, each group of cells was seeded at 800 cells/well in a 6-well plate, and the medium was added and incubated for 10-14 days. The culture medium was discarded, washed 2 times with PBS to remove excess culture medium, fixed with methanol at room temperature for 30 minutes, washed with PBS to remove excess methanol, stained with crystal violet stain (1 mM) for 10 minutes, washed with PBS to remove excess stain, and photographed, as shown in FIG. 5, as seen in FIG. 5, when the concentration was 10. Mu.M, the number of cell clones treated for 3 hours was 121, which was significantly reduced compared to 161 without drug combination. When the attempt was 20. Mu.M, the cell clone number was further reduced to 75. It is demonstrated that the compound 3h obtained in example 15 has a strong anti-proliferative effect on a549 cells.
6. Transwell cell migration
When the tumor cells are in logarithmic growth phase, the growth rate is about 5X 10 5 The density of individual cells/dish was seeded into 6-well plates, after adherence and 70-80% confluency, the medium containing 10% FBS was changed, 0. Mu.M, 10. Mu.M, 20. Mu.M of compound was added for 3h, after 48 hours of incubation, the medium was aspirated, washed 1 time with PBS, digested with 0.25% trypsin and washed 1 time with PBS, and the cells were resuspended with serum-free medium. Reading of cells using a cell counting plateCell suspension concentration 5 ten thousand cells were seeded into the upper chamber of a Transwell chamber with an 8 μm pore size and the volume was made up to 300. Mu.L with serum-free medium. 1mL of the medium containing 10% FBS was added to the lower chamber of the Transwell chamber and cultured in a 24-well plate. After 24 hours the Transwell chamber was removed, fixed with methanol for 15min, washed 1 time with PBS, stained with crystal violet for 10min, washed 1 time with PBS, cells that did not pass through the chamber were wiped with a cotton swab, and the number of migrated cells was photographed and counted under an inverted microscope.
As shown in FIG. 6, it can be seen from FIG. 6 that as the concentration of compound 3h obtained in example 15 increased (from 10 to 20. Mu.M), the number of cells transferred to the lower surface of the upper chamber of the Transwell plate decreased significantly, and that at a concentration of 10. Mu.M, the number of cells transferred was only 99, which was less than half of that of the drug-free group (195). When the drug concentration was increased to 20. Mu.M, the number of transferred cells was further reduced to 70, and the migration of most cells was inhibited. Only a few cells migrated to the lower surface of the upper chamber of the Transwell plate. This indicates that the compound 3h obtained in example 15 can exert an antitumor effect by reducing the migratory ability of tumor cells.
The above-described embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solutions of the present invention can be made by those skilled in the art without departing from the spirit of the present invention, and the technical solutions of the present invention are within the scope of the present invention defined by the claims.
Claims (9)
1. An ICT fluorophore comprising nitrogen mustard having the molecular structure of formula (I):
wherein, X is O or S;
r is H and CH 3 And Cl.
2. The ICT fluorescence of claim 1 for nitrogen-containing mustardGroup, characterized in that when said X is O and acyl is linked to carbon number 2, said R is H and/or CH 3 And substituted with carbon numbers 3, 4 and 5;
when the X is O and the acyl group is connected with the carbon number 3, the R is CH 3 And substituted with carbon numbers 2 and 5;
when the X is S and the acyl group is connected with the carbon No. 2, the R is CH 3 Or Cl, and substituted with carbon No. 3, 4 or 5;
when the X is S and acyl is attached to carbon number 3, the R is H and is substituted on carbon number 2, 4 or 5.
3. The method of preparing a nitrogen-containing mustard ICT fluorophore according to claim 1 or 2, comprising the steps of:
4- [ bis (beta-chloroethyl) amino ] benzaldehyde, acetyl-containing furan derivatives or acetyl-containing thiophene derivatives are uniformly mixed in a solvent, and then condensation reaction is carried out under the base catalysis condition, so as to prepare the compound shown in the formula (I).
4. The method of claim 3, wherein the molar ratio of the 4- [ bis (β -chloroethyl) amino ] benzaldehyde, acetylfuran-containing derivative, or acetylthiophene-containing derivative to base is 1:1: (1.0-2.0).
5. The method for preparing the ICT fluorophore for the nitrogen mustard according to claim 3, wherein the condensation reaction is carried out at a temperature of 0-110 ℃ for a period of 5-24 hours.
6. The method of claim 3, wherein the solvent comprises one or more of methanol, ethanol, acetonitrile, and toluene;
the base includes NaOH, KOH, na 2 CO 3 、K 2 CO 3 、CH 3 ONa、CH 3 OK、CH 3 CH 2 ONa and CH 3 CH 2 One or more OK;
the acetyl-containing furan derivative comprises one of the following substances:
the acetyl-containing thiophene derivative comprises one of the following substances:
7. use of a nitrogen-containing mustard ICT fluorophore according to claim 1 or 2 in cellular fluorescence imaging.
8. Use of a nitrogen-containing mustard ICT fluorophore according to claim 1 or 2 in the preparation of an anti-tumor medicament.
9. An antitumor drug characterized in that an active ingredient of the antitumor drug comprises the ICT fluorophore of the nitrogen-containing mustard of claim 1 or 2 or a pharmaceutically acceptable salt thereof.
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