CN-121974892-A - Activatable multi-mode diagnosis and treatment integrated near infrared photosensitizer and synthesis and application thereof

Abstract

The invention discloses an activatable multi-mode diagnosis and treatment integrated near infrared photosensitizer and synthesis and application thereof, and belongs to the technical field of biomedicine. The structural formula of the photosensitizer is shown as follows: The photosensitizer is a glutathione activated disulfide synergistic diagnosis and treatment integrated near infrared photosensitizer.

Inventors

• WANG JINGYUN
• LIU XIAOSHENG
• ZENG SHUANG
• LI HAIDONG

Assignees

• 大连理工大学

Dates

Publication Date

20260505

Application Date

20251230

Claims (9)

1. 1. An activatable multi-mode diagnosis and treatment integrated near infrared photosensitizer is characterized in that the structural formula of the photosensitizer is shown as follows:
2. 2. the method for preparing the activatable multi-mode diagnosis and treatment integrated near infrared photosensitizer as set forth in claim 1, comprising the steps of: (1) The synthesis of the compound Cy-1 comprises the steps of refluxing 2, 3-trimethyl indole and iodoethane in a reaction solvent at 75-85 ℃ for 12-24 hours under the condition of nitrogen to obtain the compound Cy-1; (2) The synthesis of the compound Cy-2, namely, refluxing phosphorus oxychloride and cyclohexanone in a reaction solvent at 30-50 ℃ for 1-5 hours to obtain the compound Cy-2; (3) The synthesis of the compound Cy comprises the steps of carrying out reflux stirring on the compound Cy-1, the compound Cy-2 and sodium acetate in a reaction solvent at 135-140 ℃ for 3-5 hours to obtain the compound Cy; (4) The synthesis of a compound Cy-Br, namely, heating 5-bromobenzene-1, 3-diol and the compound Cy for 8-12 hours at 30-60 ℃ in the presence of NaH and under the nitrogen atmosphere to obtain the compound Cy-Br; (5) The synthesis of a compound Cy-DNBS, namely, in the presence of triethylamine, reacting the compound Cy-Br with 2, 4-dinitrobenzene sulfonyl chloride for 2-4 hours at 20-30 ℃ in the presence of nitrogen atmosphere to obtain the compound Cy-DNBS; The reaction formula is as follows:
3. 3. The preparation method of claim 2, wherein in the step (1), the molar ratio of 2, 3-trimethylindole to iodoethane is 1:3-1:7, and the reaction solvent is anhydrous acetonitrile.
4. 4. The preparation method of claim 2, wherein in the step (2), the ratio of phosphorus oxychloride to cyclohexanone is 4-5:1, the reaction solvent is a mixed solvent of dimethylformamide and dichloromethane, and the volume ratio of dimethylformamide to dichloromethane in the mixed solvent is 1-3:1.
5. 5. The preparation method of claim 2, wherein in the step (3), the molar ratio of the compound Cy-1 to the compound Cy-2 to sodium acetate is 2-3:1:2, and the reaction solvent is acetic anhydride.
6. 6. The preparation method according to claim 2, wherein in the step (4), the molar ratio of 5-bromobenzene-1, 3-diol to the compound Cy is 0.5-1.5:1, the molar ratio of the compound Cy to NaH is 1:0.8-1.2, and the reaction solvent is N, N-dimethylformamide.
7. 7. The preparation method of claim 2, wherein in the step (5), the molar ratio of the compound Cy-Br to the 2, 4-dinitrobenzenesulfonyl chloride is 1:2-3, the molar ratio of the compound Cy-Br to the triethylamine is 1:2-3, and the reaction solvent is methylene dichloride.
8. 8. The process according to claim 2, wherein in step (1), after completion of the reaction, the solvent is removed in vacuo, the red solid product is obtained by precipitation and purification with diethyl ether, and the obtained intermediate is dried in vacuo and used in the next step without further purification; In the step (2), after the reaction is finished, cooling, pouring the reaction product into ice, standing for 8-12 hours at the temperature of 4 ℃, carrying out suction filtration after rotary evaporation of dichloro to collect yellow solid, washing precipitate with ice water, and carrying out vacuum drying to obtain an intermediate for the next step without further purification; In the step (3), after the reaction is finished, pouring the reaction solution into diethyl ether, removing acetic anhydride by filtration, filtering to obtain a black green solid, washing with diethyl ether, and drying in vacuum to obtain an intermediate for the next step without further purification; In the step (4), after the reaction is finished, the reaction mixture is cooled to room temperature, the reaction mixture is quenched by ice, the organic solvent is removed under reduced pressure after the extraction of methylene dichloride, and the crude product is purified by silica gel column chromatography to obtain a blue-green solid; in the step (5), after the reaction is finished, the organic solvent is removed under reduced pressure after dichloromethane extraction, and the purple-black solid is obtained after silica gel column chromatography purification.
9. 9. The use of an activatable, multimodal diagnostic integrated near infrared photosensitizer in the manufacture of a photodynamic therapy drug according to claim 1.

Description

Activatable multi-mode diagnosis and treatment integrated near infrared photosensitizer and synthesis and application thereof Technical Field The invention belongs to the technical field of biomedicine, and particularly relates to a glutathione activated sulfur dioxide synergistic multi-mode diagnosis and treatment integrated near infrared photosensitizer capable of specifically identifying and killing tumor cells and a synthesis preparation method thereof, and application of the photosensitizer to multi-mode identification and photodynamic therapy of tumors. Background Photodynamic therapy (PDT) is one of the most promising methods for treating cancer, with significant advantages over traditional therapies. A key component of PDT is a photosensitizer, which can generate Reactive Oxygen Species (ROS) under light. Highly reactive ROS rapidly damage intracellular biomolecules, including proteins, lipids, or nucleic acids, through oxidation, resulting in cancer cell death. However, most photosensitizers are in an "always on" state, and therefore, once the photosensitizers are exposed to light, ROS are also generated in healthy cells, resulting in nonspecific photodamage to normal tissue cells. Therefore, the design of the photosensitizer with tumor specific opening reduces the side effects on healthy tissues, so that the photosensitizer can selectively generate ROS only at the tumor part, which is of great significance. Although photosensitizers can effectively cause cell death by ROS produced, tumor cells can cope with oxidative stress induced by PDT by up-regulating expression of Glutathione (GSH), thereby reducing the therapeutic effect of PDT. Sulfur dioxide (SO 2) gastherapy, including the consumption of excess GSH and the enhancement of oxidative stress by up-regulating ROS levels. Thus, combining PDT with SO 2 gas therapy may enhance anticancer effects. However, high concentrations of sulfur dioxide can also cause damage to normal biological tissues. Accurate on-demand release of SO 2 in space, time and dosage is critical to gas therapy. The hemicyanine is a near infrared dye with biological safety, and the hemicyanine dye is widely researched and applied due to the advantages of high molar extinction coefficient, near infrared fluorescence emission and the like. However, the reported hemicyanine photosensitizer has limited its application in tumor diagnosis and treatment due to its fluorescence and photosensitizing activity "always on" properties. In addition, reported tumor diagnostic probes often have only fluorescence recognition capability for tumors, and often are difficult to use due to poor penetration depth. The photoacoustic imaging is widely applied as a deep tissue imaging technology, so that the hemicyanine molecules have tumor activatable fluorescence, and the photoacoustic signal has important significance for realizing multi-mode diagnosis of cancers. Therefore, the conventional hemicyanine photosensitizer is urgently required to be optimized through rational design, and has activatable multi-mode diagnosis and treatment integration such as fluorescence/optoacoustic/photodynamic/gas release and the like while ensuring excellent photophysical properties, so that the hemicyanine photosensitizer has important significance for diagnosis and treatment of clinical tumors. Disclosure of Invention In order to solve the problems in the prior art, the invention provides an activatable multi-mode diagnosis and treatment integrated near infrared photosensitizer, synthesis and application thereof, wherein the photosensitizer is glutathione activated disulfide synergistic diagnosis and treatment integrated near infrared photosensitizer (Cy-DNBS). And further provides an absorption emission spectrum of the photosensitizer in solution. Meanwhile, imaging and treatment results of tumor cells and tumor-bearing mice are provided, and as the photosensitizer has the function of releasing sulfur dioxide after activation of high-level glutathione of the tumor, the tumor cells are killed by active oxygen generated by the photosensitizer after illumination, and the synergistic treatment of gas and the photosensitizer on the tumor can be realized by means of the sulfur dioxide released after GSH activation response, so that the anti-tumor effect of the photosensitizer is further enhanced. An activatable multi-mode diagnosis and treatment integrated near infrared photosensitizer (Cy-DNBS) takes a reported hemicyanine photosensitizer Cy-Br as a matrix, and is covalently connected with 2, 4-dinitrobenzenesulfonic acid (DNBS) as a glutathione response unit, so that the function of activating the photosensitizer by glutathione and simultaneously releasing sulfur dioxide is realized. The structural formula of the photosensitizer (Cy-DNBS) is shown as follows: the preparation method of the photosensitizer comprises the following steps: The reaction formula is as follows: (1) And (3) synthesizing the compound Cy-1, namel