Carbazole quinoline heterocomplex as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to a carbazole quinoline heterocomplex fluorescent probe, a preparation method and application, the carbazole quinoline heterocomplex fluorescent probe has a structure shown in a general formula I. The carbazole quinoline heterocomplex can be activated under acidic pH, generates near-infrared fluorescence by utilizing an ICT principle, can be applied to an acidic microenvironment of tumor tissues, and can be used for detecting the tumor tissues. The carbazole quinoline heterocomplex can selectively and rapidly generate pH-sensitive near-infrared fluorescence at a tumor site, a solution of the carbazole quinoline heterocomplex is sprayed or locally injected on a tumor focus site and surrounding tissues, and rapid and selective fluorescence imaging and tracing are carried out on the tumor focus tissue by using a fluorescence endoscope or a living imaging instrument; the fluorescent imaging selectivity of the tumor tissue is higher, and the background fluorescence interference is lower.

Description

technical field

[0001] The invention relates to the field of biomedicine, relates to a class of carbazoquinoline hybrid compounds, a preparation method and application, and in particular relates to a class of pH-sensitive, near-infrared imaging carbazoquinoline hybrid compound fluorescent probes and a preparation method and application thereof . Background technique

[0002] In 2021, cancer statistics show that cancer remains a major public health problem worldwide, causing enormous pain and burden to families and society. If the early onset of cancer can be detected in time, the vast majority of patients can be cured without the risk of recurrence. Therefore, early diagnosis of tumors has attracted much attention in recent years.

[0003] The early onset of tumors is difficult to detect due to their changes at the microscopic molecular scale. Due to the absence of external manifestations, the patient also ignored the presence of the tumor. In preclinical trials and clin...

Examples

Embodiment 1

[0036] Example 1: (E)-9-ethyl-3-(2-(quinolin-4-yl)vinyl)-9H-carbazole (I 1 ) preparation

[0037] 9-ethyl-9H-carbazole-3-carbaldehyde (500mg, 1.0mmol) and 4-methylquinoline (320mg, 1.0mmol) were added to a single-necked flask, dissolved in absolute ethanol (10ml), followed by adding 1 -2 drops of piperidine, refluxed at 85 °C for 12 h, after monitoring the reaction by TLC, suction filtration, recrystallization and purification to obtain compound I 1 , the yield is 85%.

[0038] (I 1 ) spectral data are: 1 H NMR (400MHz, DMSO-d 6 )δ9.39(d,J=6.3Hz,1H,ArH),9.15(d,J=8.5Hz,1H,ArH),8.78(s,1H,ArH),8.55–8.46(m,3H,ArH) ,8.42(m,2H,ArH),8.34(d,J=15.6Hz,1H,CH),8.26(m,1H,ArH),8.17(d,J=8.7Hz,1H,ArH),8.05(m , 2H, ArH), 7.84(s, 1H, ArH), 7.45(m, 1H, CH), 4.53(q, 2H, CH) 2 ),1.33(t,J=6.0Hz,3H,CH 3 ).

Embodiment 2

[0039] Example 2: (E)-9-ethyl-6-(2-(quinolin-4-yl)vinyl)-9H-carbazol-3-amine (I 2 ) preparation

[0040] Referring to Example 1 (I 1 ), the 9-ethyl-9H-carbazole-3-carbaldehyde in the method is replaced by 9-ethyl-6-nitro-9H-carbazole-3-carbaldehyde, and finally compound 4 is obtained; 4 (500mg, 1.0mmol), iron powder (273mg, 4.0mmol), ammonium chloride (523mg, 8.0mmol) were added to a single-neck bottle, dissolved in absolute ethanol (20ml), refluxed at 80°C for 5h, and the reaction was completed by TLC monitoring Then, suction filtration, the filtrate was spin-dried, and purified by column chromatography to obtain compound I2 , the yield was 72%.

[0041] (I 2 ) spectral data are: 1 H NMR (400MHz, DMSO-d 6 )δ9.35(d, J=6.8Hz, 1H, ArH), 9.12(m, 1H, ArH), 8.82(s, 1H, ArH), 8.58–8.44(m, 4H, ArH), 8.33(d, J=15.6Hz, 1H, CH), 8.24(m, 1H, ArH), 8.16(m, 1H, ArH), 8.02(m, 2H, ArH), 7.85(s, 1H, ArH), 7.41(m, 1H,CH),4.52(m,2H,CH 2 ),1.31(t,J=6.0Hz,3H,CH 3 ).

Embodiment 3

[0042] Example 3: Compound I obtained in Example 1 of the present invention 1 Ultraviolet absorption spectroscopy under different pH conditions

[0043] The fluorescent compound of the present invention is dissolved in an aqueous ethanol solution containing 50% to prepare a detection solution with pH=3-8 and a concentration of 20 μM. The UV-Vis spectrophotometer is used to test the UV absorption spectrum data, and the results show that the maximum UV absorption wavelength of the fluorescent compound of the present invention is in the range of 450-600 nm. wherein compound I 1 The UV absorption peak around 490 nm varies with compound I 1 On the contrary, its UV absorption peak around 530nm increases with the decrease of pH, and its peak value differs by 40 times ( figure 1 ).

technical field

[0001] The invention relates to the field of biomedicine, relates to a class of carbazoquinoline hybrid compounds, a preparation method and application, and in particular relates to a class of pH-sensitive, near-infrared imaging carbazoquinoline hybrid compound fluorescent probes and a preparation method and application thereof . Background technique

[0002] In 2021, cancer statistics show that cancer remains a major public health problem worldwide, causing enormous pain and burden to families and society. If the early onset of cancer can be detected in time, the vast majority of patients can be cured without the risk of recurrence. Therefore, early diagnosis of tumors has attracted much attention in recent years.

[0003] The early onset of tumors is difficult to detect due to their changes at the microscopic molecular scale. Due to the absence of external manifestations, the patient also ignored the presence of the tumor. In preclinical trials and clin...

Examples

Embodiment 1

[0036] Example 1: (E)-9-ethyl-3-(2-(quinolin-4-yl)vinyl)-9H-carbazole (I 1 ) preparation

[0037] 9-ethyl-9H-carbazole-3-carbaldehyde (500mg, 1.0mmol) and 4-methylquinoline (320mg, 1.0mmol) were added to a single-necked flask, dissolved in absolute ethanol (10ml), followed by adding 1 -2 drops of piperidine, refluxed at 85 °C for 12 h, after monitoring the reaction by TLC, suction filtration, recrystallization and purification to obtain compound I 1 , the yield is 85%.

[0038] (I 1 ) spectral data are: 1 H NMR (400MHz, DMSO-d 6 )δ9.39(d,J=6.3Hz,1H,ArH),9.15(d,J=8.5Hz,1H,ArH),8.78(s,1H,ArH),8.55–8.46(m,3H,ArH) ,8.42(m,2H,ArH),8.34(d,J=15.6Hz,1H,CH),8.26(m,1H,ArH),8.17(d,J=8.7Hz,1H,ArH),8.05(m , 2H, ArH), 7.84(s, 1H, ArH), 7.45(m, 1H, CH), 4.53(q, 2H, CH) 2 ),1.33(t,J=6.0Hz,3H,CH 3 ).

Embodiment 2

[0039] Example 2: (E)-9-ethyl-6-(2-(quinolin-4-yl)vinyl)-9H-carbazol-3-amine (I 2 ) preparation

[0040] Referring to Example 1 (I 1 ), the 9-ethyl-9H-carbazole-3-carbaldehyde in the method is replaced by 9-ethyl-6-nitro-9H-carbazole-3-carbaldehyde, and finally compound 4 is obtained; 4 (500mg, 1.0mmol), iron powder (273mg, 4.0mmol), ammonium chloride (523mg, 8.0mmol) were added to a single-neck bottle, dissolved in absolute ethanol (20ml), refluxed at 80°C for 5h, and the reaction was completed by TLC monitoring Then, suction filtration, the filtrate was spin-dried, and purified by column chromatography to obtain compound I2 , the yield was 72%.

[0041] (I 2 ) spectral data are: 1 H NMR (400MHz, DMSO-d 6 )δ9.35(d, J=6.8Hz, 1H, ArH), 9.12(m, 1H, ArH), 8.82(s, 1H, ArH), 8.58–8.44(m, 4H, ArH), 8.33(d, J=15.6Hz, 1H, CH), 8.24(m, 1H, ArH), 8.16(m, 1H, ArH), 8.02(m, 2H, ArH), 7.85(s, 1H, ArH), 7.41(m, 1H,CH),4.52(m,2H,CH 2 ),1.31(t,J=6.0Hz,3H,CH 3 ).

Embodiment 3

[0042] Example 3: Compound I obtained in Example 1 of the present invention 1 Ultraviolet absorption spectroscopy under different pH conditions

[0043] The fluorescent compound of the present invention is dissolved in an aqueous ethanol solution containing 50% to prepare a detection solution with pH=3-8 and a concentration of 20 μM. The UV-Vis spectrophotometer is used to test the UV absorption spectrum data, and the results show that the maximum UV absorption wavelength of the fluorescent compound of the present invention is in the range of 450-600 nm. wherein compound I 1 The UV absorption peak around 490 nm varies with compound I 1 On the contrary, its UV absorption peak around 530nm increases with the decrease of pH, and its peak value differs by 40 times ( figure 1 ).

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