Endoplasmic reticulum positioning imaging/light-induced ferroptosis bifunctional probe

Abstract

The invention discloses an endoplasmic reticulum positioning imaging / light-induced ferroptosis bifunctional probe. The preparation method comprises the following steps: adding a certain amount of ligand containing a quinazolinone-pyridine structure into a non-polar solvent, adding a corresponding boride, adjusting a reaction solution to be alkaline by using triethylamine, carrying out a reflux reaction, cooling, standing, layering, extracting, and performing column chromatography separation by using an organic phase to finally obtain a pure product, wherein the organic phaseuses a mixture obtained after concentration. According to the invention, the probe structure mainly takes a quinazolinone-BF2 structure as a core structure, takes triphenylamine, carbazole or derivatives thereof as modification groups, has an organelle imaging function, and can induce tumor cell ferroptosis under a visible light induction condition; and the endoplasmic reticulum positioning imaging / light-induced ferroptosis bifunctional probe disclosed by the invention is the first case of endoplasmic reticulum positioning imaging / light-induced ferroptosis bifunctional probe, and has the biggest characteristic that the probe can be used for monitoring living cells in real time and realizing fixed-point induction of tumor cell ferroptosis through light induction and imaging, so that the aim of guiding treatment by imaging is fulfilled.

Description

technical field

[0001] The invention relates to the fields of fluorescent probes, biological imaging, photodynamic therapy and the like, in particular to a dual-functional probe of endoplasmic reticulum localization imaging / light-induced ferroptosis. Background technique

[0002] Ferroptosis, a process of cell death resulting from the abnormal accumulation of iron-dependent intracellular lipid peroxidation, is morphologically, biochemically, and genetically distinct from other forms of cell death. Ferroptosis has been found to inhibit tumor growth and increase the sensitivity of various tumors to chemotherapy and immunotherapy. Inducing ferroptosis in cancer cells is becoming a new strategy for treating tumors, especially for malignant tumors with high drug resistance and strong metastases .

[0003] Whether the accumulation of lipid peroxidation products in specific organelles plays a key role in the induction of ferroptosis, and how the damage and morphological changes of...

Examples

Embodiment 1

[0051]

[0052] In a 100mL reactor, add (E)-2-(4-(4-(diphenylamino)styryl)pyridin-2-yl)quinazolin-4(3H)-one 4.92g (10mmol) , add 50mL of toluene as a solvent, stir and mix evenly, add 1.38mL (10mmol) of triethylamine and boron trifluoride ether complex, heat and reflux, react for 30h, after the reaction, pour the reaction solution into water, wait After the layers were separated, extracted with dichloromethane, and the organic phase was concentrated using a rotary evaporator to remove the solvent. Separation by column chromatography to obtain the target product. The yield was 45%. The following are the NMR and mass spectrometry data of the product:

[0053] 1 H NMR (400 MHz, DMSO-d 6 ) δ =8.94 (d, J = 5.9 Hz, 1H), 8.68 (s, 1H),8.30 – 8.16 (m, 2H), 8.11 (d, J = 16.3 Hz, 1H), 7.94 – 7.78 (m, 2H ), 7.66(dd, J = 19.8, 7.8 Hz, 3H), 7.48 (d, J = 16.3 Hz, 1H), 7.39 (t, J = 7.7 Hz,4H), 7.15 (dd, J = 17.6, 7.5 Hz , 6H), 6.96 (d, J = 8.5 Hz, 2H) ppm.

[0054] 13 C NMR (101 MH...

Embodiment 2

[0074]

[0075] In a 100mL reactor, add (E)-6-(dimethylamino)-2-(4-(4-(diphenylamino)styryl)pyridin-2-yl)quinazoline-4( 5.35g (10mmol) of 3H)-ketone, add 50mL of toluene as a solvent, stir and mix evenly, add 1.38mL (10mmol) of triethylamine and boron trifluoride ether complex, heat and reflux, react for 30h, and the reaction is over Finally, the reaction solution was poured into water, and after layers were separated, it was extracted with dichloromethane, and the organic phase was concentrated by a rotary evaporator to remove the solvent. Separation by column chromatography to obtain the target product. The yield was 45%. The following are the NMR and mass spectrometry data of the product:

[0076] 1 H NMR (400 MHz, Chloroform-d) δ= 9.00 (d, J = 8.5 Hz, 1H), 8.56 (d, J = 1.8 Hz, 1H), 7.86 (s, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.46 (d, J = 8.1 Hz,1H), 7.45 – 7.39 (m, 2H), 7.39 – 7.34 (m, 1H), 7.32 – 7.25 (m, 4H), 7.29 –7.19 (m, 1H), 7.17 – 7.08 (m, 7H), 7.04 (tt, J = 7.7...

Embodiment 3

[0086]

[0087] In a 100mL reactor, add (E)-2-(4-(4-(diphenylamino)styryl)pyridin-2-yl)benzo[g]quinazolin-4(3H)-one 5.43g (10mmol), add 50mL of toluene as a solvent, stir and mix evenly, add 1.38mL (10mmol) of triethylamine and boron trifluoride ether complex, heat and reflux, react for 30h, after the reaction is completed, the reaction solution Pour into water, wait for the layers to be separated, extract with dichloromethane, and use a rotary evaporator to concentrate the organic phase to remove the solvent. Separation by column chromatography to obtain the target product. The yield was 45%. The following are the NMR and mass spectrometry data of the product:

[0088] 1 H NMR (400 MHz, Chloroform-d) δ= 9.00 (d, J = 8.5 Hz, 1H), 8.57 (d, J = 1.9 Hz, 1H), 8.50 (dd, J = 2.0, 0.7 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H),7.94 (ddd, J = 7.8, 2.0, 1.2 Hz, 1H), 7.85 (s, J = 8.4 Hz, 1H), 7.61 – 7.47(m, 2H), 7.46 – 7.39 (m, 2H), 7.39 – 7.33 (m, 1H), 7.33 – 7.24 (m, 4H), 7.29 – 7.18 (...

technical field

[0001] The invention relates to the fields of fluorescent probes, biological imaging, photodynamic therapy and the like, in particular to a dual-functional probe of endoplasmic reticulum localization imaging / light-induced ferroptosis. Background technique

[0002] Ferroptosis, a process of cell death resulting from the abnormal accumulation of iron-dependent intracellular lipid peroxidation, is morphologically, biochemically, and genetically distinct from other forms of cell death. Ferroptosis has been found to inhibit tumor growth and increase the sensitivity of various tumors to chemotherapy and immunotherapy. Inducing ferroptosis in cancer cells is becoming a new strategy for treating tumors, especially for malignant tumors with high drug resistance and strong metastases .

[0003] Whether the accumulation of lipid peroxidation products in specific organelles plays a key role in the induction of ferroptosis, and how the damage and morphological changes of...

Examples

Embodiment 1

[0051]

[0052] In a 100mL reactor, add (E)-2-(4-(4-(diphenylamino)styryl)pyridin-2-yl)quinazolin-4(3H)-one 4.92g (10mmol) , add 50mL of toluene as a solvent, stir and mix evenly, add 1.38mL (10mmol) of triethylamine and boron trifluoride ether complex, heat and reflux, react for 30h, after the reaction, pour the reaction solution into water, wait After the layers were separated, extracted with dichloromethane, and the organic phase was concentrated using a rotary evaporator to remove the solvent. Separation by column chromatography to obtain the target product. The yield was 45%. The following are the NMR and mass spectrometry data of the product:

[0053] 1 H NMR (400 MHz, DMSO-d 6 ) δ =8.94 (d, J = 5.9 Hz, 1H), 8.68 (s, 1H),8.30 – 8.16 (m, 2H), 8.11 (d, J = 16.3 Hz, 1H), 7.94 – 7.78 (m, 2H ), 7.66(dd, J = 19.8, 7.8 Hz, 3H), 7.48 (d, J = 16.3 Hz, 1H), 7.39 (t, J = 7.7 Hz,4H), 7.15 (dd, J = 17.6, 7.5 Hz , 6H), 6.96 (d, J = 8.5 Hz, 2H) ppm.

[0054] 13 C NMR (101 MH...

Embodiment 2

[0074]

[0075] In a 100mL reactor, add (E)-6-(dimethylamino)-2-(4-(4-(diphenylamino)styryl)pyridin-2-yl)quinazoline-4( 5.35g (10mmol) of 3H)-ketone, add 50mL of toluene as a solvent, stir and mix evenly, add 1.38mL (10mmol) of triethylamine and boron trifluoride ether complex, heat and reflux, react for 30h, and the reaction is over Finally, the reaction solution was poured into water, and after layers were separated, it was extracted with dichloromethane, and the organic phase was concentrated by a rotary evaporator to remove the solvent. Separation by column chromatography to obtain the target product. The yield was 45%. The following are the NMR and mass spectrometry data of the product:

[0076] 1 H NMR (400 MHz, Chloroform-d) δ= 9.00 (d, J = 8.5 Hz, 1H), 8.56 (d, J = 1.8 Hz, 1H), 7.86 (s, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.46 (d, J = 8.1 Hz,1H), 7.45 – 7.39 (m, 2H), 7.39 – 7.34 (m, 1H), 7.32 – 7.25 (m, 4H), 7.29 –7.19 (m, 1H), 7.17 – 7.08 (m, 7H), 7.04 (tt, J = 7.7...

Embodiment 3

[0086]

[0087] In a 100mL reactor, add (E)-2-(4-(4-(diphenylamino)styryl)pyridin-2-yl)benzo[g]quinazolin-4(3H)-one 5.43g (10mmol), add 50mL of toluene as a solvent, stir and mix evenly, add 1.38mL (10mmol) of triethylamine and boron trifluoride ether complex, heat and reflux, react for 30h, after the reaction is completed, the reaction solution Pour into water, wait for the layers to be separated, extract with dichloromethane, and use a rotary evaporator to concentrate the organic phase to remove the solvent. Separation by column chromatography to obtain the target product. The yield was 45%. The following are the NMR and mass spectrometry data of the product:

[0088] 1 H NMR (400 MHz, Chloroform-d) δ= 9.00 (d, J = 8.5 Hz, 1H), 8.57 (d, J = 1.9 Hz, 1H), 8.50 (dd, J = 2.0, 0.7 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H),7.94 (ddd, J = 7.8, 2.0, 1.2 Hz, 1H), 7.85 (s, J = 8.4 Hz, 1H), 7.61 – 7.47(m, 2H), 7.46 – 7.39 (m, 2H), 7.39 – 7.33 (m, 1H), 7.33 – 7.24 (m, 4H), 7.29 – 7.18 (...

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