CN115108928B - Nitrogen mustard-tetralone derivative, preparation method and application thereof - Google Patents

Nitrogen mustard-tetralone derivative, preparation method and application thereof Download PDF

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CN115108928B
CN115108928B CN202210827715.9A CN202210827715A CN115108928B CN 115108928 B CN115108928 B CN 115108928B CN 202210827715 A CN202210827715 A CN 202210827715A CN 115108928 B CN115108928 B CN 115108928B
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nitrogen mustard
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CN115108928A (en
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梁远维
梁茂隽
李翠玉
丘文桦
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Guangdong Ocean University
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Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a nitrogen mustard-tetralone derivative, and a preparation method and application thereof. The nitrogen mustard-tetralone derivative provided by the invention has excellent fluorescence performance, can emit green fluorescence, can be used as a fluorescent probe to track the release of a drug, and also has excellent in-vitro anti-tumor activity; the compound is prepared by taking 4- [ bis (beta-chloroethyl) amino ] benzaldehyde and substituted or unsubstituted 1-tetralone as raw materials through condensation reaction in a solvent under the catalysis of alkali, the preparation method is simple and feasible, the preparation can be performed in one step, the requirement on equipment is low, and the compound is suitable for large-scale production.

Description

Nitrogen mustard-tetralone derivative, preparation method and application thereof
Technical Field
The invention belongs to the technical field of biological medicine. More particularly, relates to a nitrogen mustard-tetralone derivative, a preparation method and application thereof.
Background
With the development of modern medicine, tumor treatment and imaging show an integrated trend. Many medicaments are urgently required to have the tracking functions of medicament delivery and treatment at the same time in design, and the release and curative effect of the medicaments can be monitored in real time. In recent years, research on fluorescent probes has been rapidly advanced. Fluorescence imaging technology has become an effective tool for drug delivery monitoring, contributing to improved therapeutic efficacy. The anti-tumor medicine with fluorescence has the functions of treatment and tracking, can monitor the release and curative effect of the medicine in real time, and is widely researched. Nitrogen mustard is a clinically common antitumor drug, and its structure includes an alkylated moiety (bis beta-chloroethylamine) and a carrier moiety. The alkylated moiety is a functional group with anticancer activity and the carrier moiety affects primarily the physicochemical and pharmacokinetic properties of the drug. Although nitrogen mustards come in a variety of forms, nitrogen mustards that have both potent fluorophores and anticancer activity structurally are rare. For example, chinese patent application discloses a hydrogen peroxide-responsive nitrogen mustard antitumor prodrug and a preparation method thereof, which takes diethanolamine derivatives as lead compounds, designs and synthesizes a series of nitrogen mustard antitumor prodrugs, and the nitrogen mustard antitumor prodrug has good effect of inhibiting tumor cell proliferation, but does not have fluorescence capability. Therefore, it is desirable to provide a fluorescent dye which has both good fluorescent properties and antitumor activity.
Disclosure of Invention
The invention aims to overcome the defect and the defect that the existing antitumor drugs cannot have fluorescence performance and antitumor activity at the same time, and provides the nitrogen mustard-tetralone derivative which has better fluorescence performance and antitumor activity at the same time.
The object of the present invention is to provide a process for the preparation of said nitrogen mustard-tetralone derivatives.
It is another object of the present invention to provide the use of the nitrogen mustard-tetralone derivative or a pharmaceutically acceptable salt thereof for preparing a fluorescent probe.
The invention also aims to provide the application of the nitrogen mustard-tetralone derivative or the pharmaceutically acceptable salt thereof in preparing antitumor drugs.
Another object of the present invention is to provide an antitumor drug.
The above object of the present invention is achieved by the following technical solutions:
A nitrogen mustard-tetralone derivative has a structure shown in a formula (I):
Wherein R is C 1～8 alkyl, C 1～8 alkoxy, halogen, hydroxy or hydrogen which are monosubstituted at the 6-position or the 7-position.
Preferably, the R is C 1～4 alkyl, C 1～4 alkoxy, halogen, hydroxy or hydrogen monosubstituted in the 6-or 7-position.
More preferably, the R is methyl, methoxy, halogen, hydroxy or hydrogen monosubstituted in the 6-or 7-position.
The invention further provides a preparation method of the nitrogen mustard-tetralone derivative, which comprises the following steps:
dissolving 4- [ bis (beta-chloroethyl) amino ] benzaldehyde and a compound shown in a formula (II) in an organic solvent, and carrying out condensation reaction and post-treatment under the catalysis of alkali to obtain the compound;
wherein R is as defined above.
Preferably, the mass ratio of the 4- [ bis (β -chloroethyl) amino ] benzaldehyde to the compound of formula (ii) is 1: (1-2).
Preferably, the temperature of the condensation reaction is 25 ℃ to 80 ℃.
Preferably, the condensation reaction time is 12 to 48 hours.
Preferably, the base is one or more of NaOH, KOH, na 2CO3、K2CO3, sodium ethoxide or potassium ethoxide.
Preferably, the mass ratio of the base to the 4- [ bis (β -chloroethyl) amino ] benzaldehyde is 1: (10-15).
Preferably, the organic solvent is one or more of methanol, ethanol or dioxane.
Preferably, the step of post-processing comprises: the solvent is removed by filtration, and the filter residue is separated by silica gel column chromatography (mobile phase: CH 2Cl2/CH3 OH (35-45:1, v/v)).
The invention further protects the application of the nitrogen mustard-tetralone derivative or the pharmaceutically acceptable salt thereof in preparing fluorescent probes.
The invention further protects the application of the nitrogen mustard-tetralone derivative or the pharmaceutically acceptable salt thereof in preparing antitumor drugs.
The invention further provides an antitumor drug comprising the nitrogen mustard-tetralone derivative or pharmaceutically acceptable salt thereof.
The invention has the following beneficial effects:
The nitrogen mustard-tetralone derivative provided by the invention has excellent fluorescence performance, can emit green fluorescence, can be used as a fluorescent probe to track the release of a drug, and also has excellent in-vitro anti-tumor activity; the compound is prepared by taking 4- [ bis (beta-chloroethyl) amino ] benzaldehyde and substituted or unsubstituted 1-tetralone as raw materials through condensation reaction in a solvent under the catalysis of alkali, the preparation method is simple and feasible, the preparation can be performed in one step, the requirement on equipment is low, and the compound is suitable for large-scale production.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a compound 3a obtained by the preparation of example 1 of the present invention.
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the compound 3a obtained in example 1 of the present invention.
FIG. 3 is a high resolution mass spectrum of compound 3a prepared in example 1 of the present invention.
FIG. 4 is a graph showing the ultraviolet absorption spectrum and fluorescence spectrum of the compounds 3a to 3k prepared in examples 1 to 11 of the present invention.
FIG. 5 is a chart showing subcellular localization of compound 3b prepared in example 2 according to the present invention under a confocal laser microscope.
FIG. 6 is a graph showing cytotoxicity results of the compounds 3a to 3k prepared in examples 1 to 11 of the present invention against tumor cells Hela.
FIG. 7 is a graph showing cytotoxicity results of the compounds 3a to 3k prepared in examples 1 to 11 of the present invention against tumor cells Siha.
FIG. 8 is a graph showing the effect of compound 3b prepared in example 2 of the present invention on the Hela cell cycle.
FIG. 9 is a graph showing the apoptosis induction of Hela cells by the compound 3b prepared in example 2 of the present invention, wherein FIG. a is a graph showing the ratio of early apoptosis and late apoptosis detected by Annexin V-FITC and PI double-dyeing method, and FIG. b is a data statistical graph showing early apoptosis and late apoptosis detected by Annexin V-FITC and PI double-dyeing method.
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Reagents and materials used in the following examples are commercially available unless otherwise specified.
The flow chart of the preparation method in the embodiment of the invention is as follows:
Example 1 preparation of Compound 3a
Compound 2 (3 mmol) and 7-methyl-1-tetralone (3 mmol) were added to ethanol (50 mL) and stirred well, naOH (40 mmol) was added and stirred and reacted at room temperature for 48 hours, the solvent was removed by filtration, and the filter residue was chromatographed on silica gel to give the product, mobile phase: CH 2Cl2/CH3 OH (40:1, v/v).
Characterization data ：1H NMR(400MHz,DMSO-d6),δ,ppm:7.67(s,1H,CH),7.58(s,1H,ArH),7.39(d,2H,J＝8.86Hz,ArH),7.30(dd,1H,J＝1.52,7.74Hz,ArH),7.18(d,1H,J＝7.78Hz,ArH),6.77(d,2H,J＝8.91Hz,ArH),3.76～3.68(overlapped,8H,CH2),3.01(t,2H,J＝6.27Hz,CH2)2.80(t,2H,J＝6.27Hz,CH2)( fig. 1).
13C NMR(100MHz,DMSO-d6)δ,ppm:186.95,147.55,140.58,136.83,136.48,134.30,133.56,132.68,131.90,128.71,127.79,124.14,112.17,52.31,41.51,27.95,27.35,21.11( Fig. 2).
HR-MS (ESI) calcd for C 22H24Cl2NO[M+H]+ 388.1235,found 388.1238 (FIG. 3).
Example 2 preparation of Compound 3b
Compound 2 (3 mmol) and 7-fluoro-1-tetralone (3 mmol) were added to ethanol (50 mL) and stirred well, naOH (40 mmol) was added and stirred and reacted at room temperature for 48 hours, the solvent was removed by filtration, and the filter residue was chromatographed on silica gel to give the product, mobile phase: CH 2Cl2/CH3 OH (40:1, v/v).
Characterization data ：1H NMR(400MHz,DMSO-d6),δ,ppm:7.68(s,1H,CH),7.61(dd,1H,J＝2.23,9.15Hz,ArH),7.48(d,2H,J＝8.88Hz,ArH),7.44～7.41(overlapped,2H,ArH),6.85(d,2H,J＝8.88Hz,ArH),3.84～3.75(overlapped,8H,CH2),3.11(t,2H,J＝6.22Hz,CH2),2.91(t,2H,J＝6.22Hz,CH2).
13C NMR(100MHz,DMSO-d6)δ,ppm:185.97,160.37,147.78,139.64,137.82,135.39,132.87,131.11,130.91,123.94,120.49,113.33,112.20,52.29,41.50,27.49,27.15.
HR-MS(ESI)calcd for C21H21Cl2FNO[M+H]+392.0984,found 392.0988.
EXAMPLE 3 preparation of Compound 3c
Compound 2 (3 mmol) and 7-chloro-1-tetralone (3 mmol) are added into ethanol (50 mL) and stirred uniformly, naOH (40 mmol) is added and stirred, then the mixture is reacted at room temperature for 48 hours, the solvent is removed by filtration, and the filter residue is subjected to silica gel column chromatography to obtain a product, and a mobile phase is CH 2Cl2/CH3 OH (40:1, v/v).
Characterization data ：1H NMR(400MHz,DMSO-d6),δ,ppm:7.85(d,1H,J＝2.35Hz,ArH),7.69(s,1H,CH),7.61(dd,1H,J＝2.35,8.13Hz,ArH),7.48(d,2H,J＝8.89Hz,ArH),7.43(d,1H,8.13Hz,ArH),6.85(d,2H,J＝8.89Hz,ArH),3.83～3.75(overlapped,8H,CH2),3.11(t,2H,J＝6.41Hz,CH2),2.92(t,2H,J＝6.41Hz,CH2).
13C NMR(100MHz,DMSO-d6)δ,ppm:185.75,147.82,142.27,137.94,135.25,133.08,132.91,132.13,131.06,130.85,126.86,123.90,112.20,52.28,41.50,27.61,26.94.
HR-MS(ESI)calcd for C21H21Cl3NO[M+H]+408.0689,found 408.0691.
EXAMPLE 4 preparation of Compound 3d
Compound 2 (3 mmol) and 7-bromo-1-tetralone (3 mmol) were added to ethanol (50 mL) and stirred well, naOH (40 mmol) was added and stirred and reacted at room temperature for 48 hours, the solvent was removed by filtration, and the filter residue was chromatographed on silica gel to give the product, mobile phase: CH 2Cl2/CH3 OH (40:1, v/v).
Characterization data ：1H NMR(400MHz,DMSO-d6),δ,ppm:7.99(d,1H,J＝2.23Hz,ArH),7.73(dd,1H,J＝2.23,8.15Hz,ArH),7.68(s,1H,CH),7.48(d,2H,J＝8.93Hz,ArH),7.36(d,1H,J＝8.15Hz,ArH),6.85(d,2H,J＝8.93Hz,ArH),3.84～3.75(overlapped,8H,CH2),3.11(t,2H,J＝6.36Hz,CH2),2.89(t,2H,J＝6.36Hz,CH2).
13C NMR(100MHz,DMSO-d6)δ,ppm:185.64,147.82,142.64,137.94,135.91,135.53,132.91,131.31,130.83,129.87,123.90,120.35,112.20,52.29,41.50,27.66,26.89.
HR-MS(ESI)calcd for C21H21BrCl2NO[M+H]+452.0184,found 452.0182.
EXAMPLE 5 preparation of Compound 3e
Compound 2 (3 mmol) and 7-methoxy-1-tetralone (3 mmol) are added into ethanol (50 mL) and stirred uniformly, naOH (40 mmol) is added and stirred, then the mixture is reacted at room temperature for 48 hours, the solvent is removed by filtration, and the filter residue is subjected to silica gel column chromatography to obtain a product, and a mobile phase is CH 2Cl2/CH3 OH (40:1, v/v).
Characterization data ：1H NMR(400MHz,DMSO-d6),δ,ppm:7.66(s,1H,CH),7.46(d,1H,ArH),7.46(d,2H,J＝8.83Hz,ArH),7.42(d,1H,J＝2.80Hz,ArH),7.29(d,1H,J＝8.30Hz,ArH),7.14(dd,1H,J＝2.80,8.30Hz,ArH),6.84(d,2H,J＝8.83Hz,ArH),3.82～3.76(overlapped,11H,CH3,CH2),3.08(t,2H,J＝6.21Hz,CH2),2.85(t,2H,J＝6.21Hz,CH2).
13C NMR(100MHz,DMSO-d6)δ,ppm:186.71,158.60,147.58,137.11,135.88,134.60,132.73,131.65,130.11,124.07,120.77,112.14,110.66,55.74,52.28,41.49,27.46.
HR-MS(ESI)calcd for C22H24Cl2NO2[M+H]+404.1184,found 404.1185.
EXAMPLE 6 preparation of Compound 3f
Compound 2 (3 mmol) and 7-hydroxy-1-tetralone (3 mmol) are added into ethanol (50 mL) and stirred uniformly, naOH (40 mmol) is added and stirred, then the mixture is reacted at room temperature for 48 hours, the solvent is removed by filtration, and the filter residue is subjected to silica gel column chromatography to obtain a product, and a mobile phase is CH 2Cl2/CH3 OH (40:1, v/v).
Characterization data ：1H NMR(400MHz,DMSO-d6),δ,ppm:9.60(s,1H,OH),7.62(s,1H,CH),7.45(d,2H,J＝8.70Hz,ArH),7.31(d,1H,J＝2.52Hz,ArH),7.17(d,1H,J＝8.12Hz,ArH),6.96(dd,1H,J＝2.52Hz,8.12Hz,ArH),6.84(d,2H,J＝8.70Hz,ArH),3.83～3.75(overlapped,8H,ArH),3.06(t,2H,J＝6.12Hz,ArH),2.80(t,2H,J＝6.12Hz,ArH).
13C NMR(100MHz,DMSO-d6)δ,ppm:186.97,156.68,147.59,136.88,134.66,134.20,132.72,131.98,129.99,124.23,121.39,113.12,112.22,52.36,41.57,27.63,27.56.
HR-MS(ESI)calcd for C21H22Cl2NO2[M+H]+390.1028,found 390.1026.
EXAMPLE 7 preparation of Compound 3g
Compound 2 (3 mmol) and 1-tetralone (3 mmol) were added to ethanol (50 mL) and stirred well, naOH (40 mmol) was added and stirred and reacted at room temperature for 48 hours, the solvent was removed by filtration, and the filter residue was chromatographed on silica gel to give the product, mobile phase: CH 2Cl2/CH3 OH (40:1, v/v).
Characterization data ：1H NMR(400MHz,DMSO-d6),δ,ppm:7.95(dd,1H,J＝1.15,7.69Hz,ArH),7.68(s,1H,CH),7.57(ddd,J＝1.15,7.46,8.89Hz,ArH),7.49(d,2H,J＝8.86Hz,ArH),7.43～7.37(overlapped,2H,ArH),6.87(d,2H,J＝8.86Hz,ArH),3.85～3.77(overlapped,8H,CH2),3.13(t,J＝6.75Hz,CH2),2.94(t,J＝6.75Hz,CH2).
13C NMR(100MHz,DMSO-d6)δ,ppm:186.88,147.58,143.46,137.03,133.73,133.56,132.74,131.69,128.78,127.67,127.35,124.04,112.14,52.28,41.50,28.30,27.26.
HR-MS(ESI)calcd for C21H21Cl2NO[M+H]+374.1078,found 374.1075.
Example 8 preparation of Compound 3h
Compound 2 (3 mmol) and 6-fluoro-1-tetralone (3 mmol) were added to ethanol (50 mL) and stirred well, naOH (40 mmol) was added and stirred and reacted at room temperature for 48 hours, the solvent was removed by filtration, and the filter residue was chromatographed on silica gel to give the product, mobile phase: CH 2Cl2/CH3 OH (40:1, v/v).
Characterization data ：1H NMR(400MHz,DMSO-d6),δ,ppm:8.00(dd,1H,J＝6.16,8.50Hz,ArH),7.66(s,1H,CH),7.46(d,2H,J＝8.89Hz,ArH),7.25～7.18(overlapped,2H,ArH),6.85(d,2H,J＝8.89Hz,ArH),3.83-3.75(overlapped,8H,CH2),3.11(t,2H,J＝6.62Hz,CH2),2.94(t,J＝6.62Hz,CH2).
13C NMR(100MHz,DMSO-d6)δ,ppm:185.64,166.43,163.93,147.66,146.91,137.26,132.75,131.23,130.66,124.01,115.23,112.19,52.31,41.51,28.27,27.07.
HR-MS(ESI)calcd for C21H21Cl2FNO[M+H]+392.0984,found 392.0984.
EXAMPLE 9 preparation of Compound 3i
Compound 2 (3 mmol) and 6-chloro-1-tetralone (3 mmol) are added into ethanol (50 mL) and stirred uniformly, naOH (40 mmol) is added and stirred, then reacted at room temperature for 48 hours, the solvent is removed by filtration, the filter residue is chromatographed on silica gel column to obtain the product, mobile phase: CH 2Cl2/CH3 OH (40:1, v/v).
Characterization data ：1H NMR(400MHz,DMSO-d6),δ,ppm:7.92(d,1H,J＝8.39Hz,ArH),7.67(s,1H,CH),7.49-7.43(overlapped,4H,ArH),6.8 5(d,2H,J＝8.91Hz,ArH),3.83～3.75(overlapped,8H,CH2),3.11(t,2H,J＝6.63Hz,CH2),2.93(t,2H,J＝6.63Hz,CH2).
13C NMR(100MHz,DMSO-d6)δ,ppm:185.95,147.74,145.59,138.23,137.53,132.83,132.53,131.12,129.76,128.45,127.54,123.96,112.20,52.30,41.50,27.95,26.98.
HR-MS(ESI)calcd for C21H21Cl3NO[M+H]+408.0689,found 408.0688.
EXAMPLE 10 preparation of Compound 3j
Compound 2 (3 mmol) and 6-bromo-1-tetralone (3 mmol) were added to ethanol (50 mL) and stirred well, naOH (40 mmol) was added and stirred and reacted at room temperature for 48 hours, the solvent was removed by filtration, and the filter residue was chromatographed on silica gel to give the product, mobile phase: CH 2Cl2/CH3 OH (40:1, v/v).
Characterization data ：1H NMR(400MHz,DMSO-d6),δ,ppm:7.83(d,1H,J＝8.36Hz,ArH),7.67～7.64(overlapped,2H,ArH,CH),7.59(dd,1H,J＝1.92,8.36Hz,ArH),7.47(d,2H,J＝8.89Hz,ArH),6.85(d,2H,J＝8.89Hz,ArH),3.83～3.75(overlapped,8H,CH2),3.10(t,2H,J＝6.61Hz,CH2),2.93(t,2H,J＝6.61Hz,CH2).
13C NMR(100MHz,DMSO-d6)δ,ppm:186.13,147.74,145.70,137.55,132.84,131.40,131.10,130.47,129.82,127.53,126.50,123.95,112.19,52.29,41.50,27.87,26.98.
HR-MS(ESI)calcd for C21H21BrCl2NO[M+H]+452.0184,found 452.0187.
EXAMPLE 11 preparation of Compound 3k
Compound 2 (3 mmol) and 6-methoxy-1-tetralone (3 mmol) are added into ethanol (50 mL) and stirred uniformly, naOH (40 mmol) is added and stirred, then the mixture is reacted at room temperature for 48 hours, the solvent is removed by filtration, and the filter residue is subjected to silica gel column chromatography to obtain a product, and a mobile phase is CH 2Cl2/CH3 OH (40:1, v/v).
Characterization data ：1H NMR(400MHz,DMSO-d6),δ,ppm:7.90(d,1H,J＝8.66Hz,ArH),7.60(s,1H,CH),7.45(d,2H,J＝8.85,ArH),6.95(dd,1H,J＝2.33,8.66Hz,ArH),6.90(d,1H,J＝2.33Hz,ArH),6.84(d,2H,J＝8.85,ArH),3.85(s,3H,CH3),3.83～3.75(overlapped,8H,CH2),3.08(t,J＝6.76Hz,CH2),2.90(t,J＝6.76Hz,CH2).
13C NMR(100MHz,DMSO-d6)δ,ppm:185.80,163.52,147.47,146.10,136.26,132.61,130.24,127.22,124.28,114.08,112.21,111.44,56.04,52.37,41.58,28.77,27.36.
HR-MS(ESI)calcd for C22H24Cl2NO2[M+H]+404.1184,found 404.1181.
Experimental example 1 fluorescent Performance test
The compounds prepared in examples 1 to 11 were dissolved in ethanol and transferred to a two-way cuvette, and their absorption spectra were scanned by an ultraviolet spectrophotometer, the wavelength range was set to 250nm to 700nm, and their corresponding maximum absorption wavelengths were recorded, to obtain the ultraviolet absorption spectra of the compounds, and the results are shown in fig. 4.
The compounds prepared in examples 1 to 11 were dissolved in ethanol and transferred to a four-way cuvette, and the fluorescence emission spectrum of the compounds was scanned by a fluorescence spectrophotometer. The excitation wavelength was designed as the maximum absorption wavelength for each compound, and the slit width was designed to be 10nm, as a result of which see fig. 4.
The maximum absorption wavelength, maximum emission wavelength, and Stokes shift (Stokes shift) data of fig. 4 are counted in table 1. As can be seen from Table 1, the maximum absorption wavelength (λ max) of the compounds prepared in examples 1 to 11 ranges from 394nm to 409nm, the smallest of which is the compound 3k prepared in example 11, 394nm, and the largest of which is the compound 3d prepared in example 4, 409nm. The maximum emission wavelength (lambda em) ranges from 526nm to 550nm, with the smallest being 526nm for compound 3k prepared in example 11 and the largest being 550nm for compound 3c prepared in example 3. The Stokes shift (Stockes shift) ranges from 130 to 142nm. These results show that the compounds prepared in examples 1 to 11 of the present invention have emission wavelengths mainly in the green light range, and have large stokes shift and good fluorescence properties.
TABLE 1 maximum absorption wavelength and maximum emission wavelength (nm) of the compounds
Experimental example 2 intracellular Release of drug
HeLa cells were seeded in 2 cm glass dishes, and after cell attachment, incubated with compound 3b (20. Mu.M), lysosome red fluorescent probe (Lyso-TRACKER RED, 1. Mu.M) and DNA fluorescent dye (Hoechst 33342, 1. Mu.M) for 4h at 37℃and then the supernatant was gently blotted, washed once with PBS and 2mL of PBS was added. The fluorescence signal of the cells was observed by confocal laser scanning microscopy, merge is a fluorescence image of compound 3b, lyso-TRACKER RED, hoechst33342 superimposed together, and the results are shown in FIG. 5.
As can be seen from fig. 5, the fluorescent signal incubated with compound 3b was strong (green), most of the signal overlapped with the signal of the enzyme red fluorescent probe (red), indicating that the release of compound 3b was mainly localized to lysosomes. In addition, a small portion of the green fluorescent signal is clearly visible in the nucleus and overlaps with the cellular DNA fluorescent dye, so that a small amount of 3b is released into the nucleus. It can be inferred that 3b first enters the lysosome, and after the lysosome membrane breaks, 3b is released, 3b further into the nucleus.
Experimental example 3 in vitro antiproliferative Activity
About 4X 10 3 cells were seeded into 96-well dishes when tumor cells (Siha and Hela) were in the logarithmic growth phase, and after 24 hours of cell attachment, 100. Mu.M of drugs (1, 2, 4, 8, 16, 32 and 64. Mu.M) at different concentrations (3 a to 3k of compounds prepared in examples 1 to 11) diluted in 10% FBS-containing medium were added to each well. After cells were cultured for 72 hours with drug, the medium in 96 well plates was discarded, 5mg/mL MTT reagent (thiazole blue tetrazolium bromide, PBS as solvent) was added to each well, incubation was continued in an incubator for 4 hours, the supernatant was removed, 150. Mu.L DMSO was added, shaking was performed for 15 minutes, and the value of OD 570 (absorbance at 570 nm) per well was read with an ELISA reader to calculate the change in activity of cells after treatment with different concentrations of drug, and the experimental results were shown in FIGS. 6 to 7.
As can be seen from fig. 6 to 7, as the concentration of the compound increases, the antiproliferative capacity of each of the compounds 3a to 3k against both of the Hela (fig. 6) and Siha (fig. 7) tumor cells is continuously enhanced, and each of the compounds exhibits a remarkable antiproliferative activity.
The semi-inhibitory concentration (IC 50) of the compounds on tumor cells was calculated as shown in Table 2. As shown in table 2: the IC 50 of the compounds 3 a-3 k against Hela cells ranged from 5.5. Mu.M to 14.1. Mu.M; IC 50 for Siha cells ranged from 8.1. Mu.M to 18.0. Mu.M. The compounds are shown to have relatively obvious antiproliferative activity. In contrast, the fluorine substituted products, whether 7-or 6-substituted, were more potent against Siha cells, e.g., 3b and 3h had IC 50 values of 7.9. Mu.M and 8.1. Mu.M, respectively, for Siha cells, and half-inhibitory concentrations of 5.5. Mu.M and 5.9. Mu.M, respectively, for HeLa cells, with significantly higher effects than Siha cells, and the compound as a whole had greater effects on HeLa cells than Siha. These results show that the compounds prepared in examples 1 to 11 of the present invention have excellent antiproliferative activity.
TABLE 2 half-inhibitory concentration (. Mu.M) of Compounds 3 a-3 k on tumor cells Siha and Hela
Experimental example 4 cell cycle experiment
Hela cells were seeded in 6-well plates (2X 10 5/well), incubated for 48h with different concentrations of compound 3b (8. Mu.M ) respectively, medium was removed and washed with PBS, cells were digested with trypsin, washed with PBS, then fixed with 70% ethanol overnight, washed with PBS, stained with binding working fluid and Propidium Iodide (PI), and stored at 37℃for 20min without compound 3b added as a control. Samples were analyzed by flow cytometry, at least 10,000 cells per sample were collected, and the results are shown in FIG. 8.
As can be seen from FIG. 8, the G1 phase of Hela cells decreased from 60.1% to 10.5% and 4.1% of the control group at 3b concentrations of 8. Mu.M and 16. Mu.M, respectively; the S phase was increased from 28.3% (control) to 41.8% (8. Mu.M) and then decreased to 24.1% (16. Mu.M). In addition, after Hela cells were treated with 8. Mu.M and 16. Mu.M of Compound 3b, respectively, the proportion of cells in the G2/M phase of the cell cycle increased from untreated 11.6% to 47.7% and 71.9%, respectively. These results indicate that compound 3b is clearly responsible for Hela cell cycle arrest and is a arrest in the G2/M phase.
Experimental example 5 apoptosis experiments
After incubating Hela cells for 48h with 8 μm and 16 μm of compound 3b, they were digested with trypsin, washed with cold PBS, stained with Annexin V-FITC and PI (propidium iodide) in buffer for 20min, and the samples were analyzed by flow cytometry without adding compound 3b as a control, as shown in fig. 9.
As can be seen from FIG. 9, the early and late apoptosis rates of the untreated Hela cells of the control group were only 4.27% and 5.83%, respectively, whereas the early apoptosis rates of the Hela cells treated with Compound 3b were increased to 10.28% (8. Mu.M) and 19.94% (16. Mu.M), respectively, and the late apoptosis rates were significantly increased to 13.97% (8. Mu.M) and 22.54% (16. Mu.M), respectively. For total apoptotic cells, the rise was from 10.10% (control) to 24.25% (8. Mu.M) and 42.48% (16. Mu.M). Taken together, compound 3b was effective in inducing apoptosis in Hela cells, indicating that compound 3b inhibited tumor growth by inducing early and late apoptosis in Hela cells.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (8)

1. A nitrogen mustard-tetralone derivative, characterized by the structure as shown in formulas 3a-3 k:
2. the process for the preparation of nitrogen mustard-tetralone derivatives according to claim 1, characterized in that it comprises the following steps:
dissolving 4- [ bis (beta-chloroethyl) amino ] benzaldehyde and a compound shown in a formula (II) in an organic solvent, and carrying out condensation reaction and post-treatment under the catalysis of alkali to obtain the compound;
The compound of formula (II) is 7-methyl-1-tetralone, 7-fluoro-1-tetralone, 7-chloro-1-tetralone, 7-bromo-1-tetralone, 7-methoxy-1-tetralone, 7-hydroxy-1-tetralone, 6-fluoro-1-tetralone, 6-chloro-1-tetralone, 6-bromo-1-tetralone or 6-methoxy-1-tetralone.
3. The method of claim 2, wherein the organic solvent is one or more of methanol, ethanol, or dioxane.
4. The process according to claim 2, wherein the temperature of the condensation reaction is 25 ℃ to 80 ℃.
5. The method of claim 2, wherein the base is one or more of NaOH, KOH, na 2CO3、K2CO3, sodium ethoxide, or potassium ethoxide.
6. Use of a nitrogen mustard-tetralone derivative according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a fluorescent probe.
7. The use of a nitrogen mustard-tetralone derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of an antitumor drug.
8. An antitumor agent comprising the nitrogen mustard-tetralone derivative according to claim 1 or a pharmaceutically acceptable salt thereof.
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CN114230457B (en) * 2022-01-04 2023-06-09 中山大学 2-benzylidene tetralone derivatives, and preparation method and application thereof
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007133588A2 (en) * 2006-05-10 2007-11-22 Arizona Biomedical Research Commission Modified chalcone compounds as antimitotic agents
KR20140147619A (en) * 2013-06-20 2014-12-30 이화여자대학교 산학협력단 Novel chalcone derivatives and the use thereof
CN114591189A (en) * 2022-04-06 2022-06-07 广东海洋大学 Anthracene and nitrogen mustard substituted alpha, beta unsaturated ketone compound and preparation and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007133588A2 (en) * 2006-05-10 2007-11-22 Arizona Biomedical Research Commission Modified chalcone compounds as antimitotic agents
KR20140147619A (en) * 2013-06-20 2014-12-30 이화여자대학교 산학협력단 Novel chalcone derivatives and the use thereof
CN114591189A (en) * 2022-04-06 2022-06-07 广东海洋大学 Anthracene and nitrogen mustard substituted alpha, beta unsaturated ketone compound and preparation and application thereof

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
Benzylideneindenes with oxygen attached to the indene ring;Bahner, Carl T.，等;Journal of Medicinal Chemistry;19690731;第12卷(第04期);第721-722页 *
Design and in vitro biological evaluation of substituted chalcones synthesized from nitrogen mustards as potent microtubule targeted anticancer agents;Sabina; X. Janet，等;New Journal of Chemistry;第41卷(第10期);第 4097页式 1，第 4103页表 4 *
Nitrogen Mustard Based 2-Benzylidene-1-tetralone as ICT-Based Fluorescent Probe for Drug Release Monitoring and Cervical Cancer Therapy;Yuanwei Liang，等;Russian Journal of General Chemistry;第92卷(第11期);第2544–2552页 *
Spectroscopic Study on the Interaction of 4-dimethylaminochalcones with Phospholipids;V. Tomečková，等;Journal of Applied Spectroscopy;第81卷(第04期);第812页第2段、第813页图1、第818页"Conclusions" *
Synthesis and Antitumor Activity of Novel Nitrogen Mustard-Linked Chalcones;Xianwen Fang ，等;Arch Pharm (Weinheim);第346卷(第04期);第292页右栏第2段至第293页左栏第5行、第293页Scheme 1、第294页Scheme 2、第295页表1 *
Yashveer Gautam，等.2-(3′,4′-Dimethoxybenzylidene)tetralone induces anti-breast cancer activity through microtubule stabilization and activation of reactive oxygen species.RSC Adv..2016,第06卷(第40期),第33370页Scheme 1-2、第33371页表1、第33375-33376页"Chemical syntheses"第1段. *
含氮芥和蒽环的新型α,β-不饱和酮的合成、表征与抗肿瘤活性.含氮芥和蒽环的新型α,β-不饱和酮的合成、表征与抗肿瘤活性.合成化学.2022,第31卷(第02期),第154-160页. *
含氮芥基查尔酮类衍生物的合成、晶体结构及抗肿瘤活性;方线文;周丽珍;成昭;杨美盼;杨秉勤;;有机化学;20130315(第03期);第523-529页 *
黄伟婷，等.含氮芥和蒽环的新型α,β-不饱和酮的合成、表征与抗肿瘤活性.合成化学.2022,第154-160页. *

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