A near-infrared two-region emitting iridium (III) complex photosensitizer, a preparation method and application thereof

Abstract

This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to a near-infrared II luminescent iridium(III) complex photosensitizer, its preparation method, and its application. The near-infrared II luminescent iridium(III) complex photosensitizer disclosed in this invention generates singlet oxygen (…) under 550 nm illumination. 1 O2), hydroxyl radicals (•OH), superoxide anions (O2) •‑ We evaluated the antitumor activity of near-infrared luminescent iridium complexes using mouse breast cancer cells (4T1). Under unilluminated conditions, the near-infrared II luminescent iridium(III) complex photosensitizers showed no significant cytotoxicity to 4T1 cells, while under illumination, they exhibited good phototoxicity to 4T1 cells, with an IC50 value of [missing value]. 50 The concentration is 15.92 μM. We have invented a near-infrared II luminescent iridium(III) complex photosensitizer, which has excellent photoimmunodynamic therapeutic effects and will have important application prospects in the treatment of hypoxic tumors.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to a near-infrared II luminescent iridium(III) complex photosensitizer, its preparation method, and its application. Background Technology

[0002] Photodynamic therapy (PDT) is a disease treatment method based on photochemical reactions. Its core mechanism involves using a specific wavelength light source to excite photosensitizers accumulated at the lesion site in the presence of oxygen. Through energy transfer or electron transport, reactive oxygen species are generated, inducing apoptosis, necrosis, or immunogenic death of target cells. PDT boasts significant advantages such as high spatial selectivity, minimally invasive operation, low systemic toxicity, and low likelihood of inducing drug resistance. It achieves highly effective local treatment while maximally protecting surrounding normal tissues. With the continuous development of photosensitizer research, light source technology, and treatment protocols, the application of PDT has gradually expanded from traditional solid tumor treatment to areas such as antibacterial infections, skin diseases, vascular lesions, and some intracavitary diseases, demonstrating significant potential for multidisciplinary integration and clinical translation.

[0003] In recent years, the development of near-infrared II (NIR-II, 1000–1700 nm) luminescent photosensitizers has provided a new direction for improving the efficacy and precision of photodynamic therapy. Compared with traditional visible light or near-infrared I (NIR-I) photosensitizers, the NIR-II system has significant advantages in optical penetration, therapeutic integration, and treatment safety: In terms of optical performance, biological tissues absorb and scatter NIR-II light weakly, and tissue autofluorescence in this band is extremely low, enabling not only centimeter-level deep tissue penetration but also supporting high signal-to-noise ratio and high-resolution fluorescence imaging. Furthermore, NIR-II light poses a lower risk of photodamage to normal tissues, allowing for the use of higher safe light doses to enhance therapeutic effects. Simultaneously, these photosensitizers typically possess excellent photostability and anti-bleaching ability, helping to maintain therapeutic activity under continuous irradiation and ensuring stable and controllable efficacy.

[0004] Therefore, designing and synthesizing a novel near-infrared II luminescent iridium(III) complex photosensitizer is of great significance for solving the current challenges of deep tissue diagnosis and treatment in PDT technology. Summary of the Invention

[0005] The purpose of this invention is to address existing problems by providing a near-infrared II luminescent iridium(III) complex photosensitizer, its preparation method, and its application.

[0006] This invention is achieved through the following technical solution: A near-infrared II luminescent iridium(III) complex photosensitizer, the chemical structural formula of which is shown below: ; Wherein, D is selected from any one of the following groups: triphenylamino, tetraphenylvinyl, fluorenyl, carbazolyl, dihydroindolyl, phenoxazinyl, phenthiazinyl, pyrrolyl, piperidinyl, piperazinyl, gurtolyl, tetrahydroquinolinyl, phenanthrololinyl, quinolinyl, isoquinolinyl, pyridiniumimidazolyl, pyridothiazolyl, pyridooxazinyl, phenazinyl, phthalazinyl, quinazolinyl, quinoxalinyl.

[0007] Specifically, the present invention provides the following compounds: ; ; ; ; More preferably, D is triphenylamine.

[0008] A method for preparing the near-infrared II luminescent iridium(III) complex photosensitizer includes the following steps: S1. Under N2 protection, 6-bromobenzo[d]thiazole, (4-(diphenylamino)phenyl)boronic acid, tetra(triphenylphosphine)palladium and potassium carbonate were added to a mixed solvent of tetrahydrofuran and water. The mixture was stirred and heated to obtain a yellow solution. The solution was then purified by column chromatography to obtain a yellow solid compound 1. S2. Under N2 protection, the yellow solid compound 1 obtained in S1, iodopentafluorobenzene and potassium tert-butoxide were added to toluene solvent, stirred and heated to obtain a reddish-brown solution, which was then purified by column chromatography to obtain a white solid compound 2. S3. Under N2 protection, compound 2 obtained in S2, palladium acetate, tetrabutylammonium bromide and diisopropylethylamine were added to toluene solvent, stirred and heated to obtain a yellow solution, which was then purified by column chromatography to obtain a yellow solid compound TBTz. S4. Under N2 protection, TBTz and [(ppy)2IrCl]2 obtained in S3 were added to a mixed organic solvent of chloroform and methanol. After stirring and heating, a purple solution was obtained. The purple solid complex TBTz-Ir was obtained by column chromatography separation and purification.

[0009] More preferably, in step S1, the molar ratio of 6-bromobenzo[d]thiazole, (4-(diphenylamino)phenyl)boronic acid, tetra(triphenylphosphine)palladium and potassium carbonate is 7:8.3:0.1:36.17, the volume ratio of tetrahydrofuran and water is 4:1, and the heating is carried out under N2 atmosphere at 70 °C for 12 h.

[0010] More preferably, in step S2, the molar ratio of the yellow solid compound 1, iodopentafluorobenzene, and potassium tert-butoxide is 2:3:3, and the reaction is carried out under N2 atmosphere at 25 °C for 12 h.

[0011] More preferably, in step S3, the molar ratio of compound 2, palladium acetate, tetrabutylammonium bromide and diisopropylethylamine is 0.79:0.079:0.39:5.75, and the reaction is carried out under N2 atmosphere at 70 °C for 12 h.

[0012] More preferably, in step S4, the molar ratio of TBTz to [(ppy)2IrCl]2 is 2:1, the volume ratio of chloroform to methanol is 2:1, and the heating is carried out under N2 atmosphere at 50 °C for 12 h.

[0013] More preferably, the specific synthetic route is as follows: ; Application of the near-infrared II luminescent iridium(III) complex photosensitizer in the preparation of anti-hypoxic tumor drugs.

[0014] An anti-hypoxic tumor drug, wherein the drug uses the near-infrared II luminescent iridium(III) complex photosensitizer as the main active ingredient.

[0015] Application of the near-infrared II luminescent iridium(III) complex photosensitizer in photodynamic therapy.

[0016] Preferably, the iridium complex is a drug for treating mouse breast cancer.

[0017] The present invention has the following advantages over the prior art: The near-infrared II luminescent iridium(III) complex photosensitizer disclosed in this invention generates singlet oxygen (…) under 550 nm illumination. 1 O2), hydroxyl radicals (•OH) and superoxide anions (O2) •- We evaluated the antitumor activity of near-infrared luminescent iridium complexes using mouse breast cancer cells (4T1). Under unilluminated conditions, the near-infrared II luminescent iridium(III) complex photosensitizers showed no significant cytotoxicity to 4T1 cells, while under illumination, they exhibited good phototoxicity to 4T1 cells, with an IC50 value of [missing value]. 50The concentration is 15.92 μM. We have invented a near-infrared II luminescent iridium(III) complex photosensitizer, which has excellent photoimmunodynamic therapeutic effects and will have important application prospects in the treatment of hypoxic tumors. Attached Figure Description

[0018] Figure 1 Synthetic route diagram of near-infrared II luminescent iridium(III) complex photosensitizer provided by the present invention; Figure 2 The 1H NMR spectrum of the near-infrared II luminescent iridium(III) complex photosensitizer ligand TBTz in deuterated chloroform provided by this invention; Figure 3 The 1H NMR spectrum of the near-infrared II luminescent iridium(III) complex photosensitizer TBTz-Ir in deuterated chloroform provided by this invention; Figure 4 The mass spectrum of the near-infrared II luminescent iridium(III) complex photosensitizer TBTz-Ir provided by this invention; Figure 5 The UV-Vis absorption spectrum of the near-infrared II luminescent iridium(III) complex photosensitizer in DMSO provided by this invention; Figure 6 The fluorescence emission spectrum of the near-infrared II luminescent iridium(III) complex photosensitizer in DMSO provided by the present invention; Figure 7 ABDA was used as a near-infrared II luminescent iridium(III) complex photosensitizer under 550 nm illumination. 1 UV-Vis absorption spectrum of the O2 probe; Figure 8 The UV-Vis absorption spectrum of the near-infrared II luminescent iridium(III) complex photosensitizer under 550 nm illumination using ABTS as a •OH probe; Figure 9 DHR123 was used as an O2 photosensitive agent for near-infrared II luminescent iridium(III) complexes under 550 nm illumination. •- Fluorescence emission spectrum of the probe; Figure 10 A near-infrared II luminescent iridium(III) complex photosensitizer under illumination (550 nm, 13.2 mW cm⁻¹). -2 Cytotoxicity of 4T1 cells under 0.5h and dark conditions. Detailed Implementation

[0019] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be described in detail below with reference to specific embodiments and comparative examples. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other implementation methods obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0020] Unless otherwise specified, all equipment used in this embodiment is conventional experimental equipment, and all materials and reagents used are commercially available unless otherwise specified. Experimental methods without special instructions are also conventional experimental methods.

[0021] Example 1: Preparation of near-infrared luminescent iridium(III) complex photosensitizer (1) Under N2 protection, 6-bromobenzo[d]thiazole (7 mmol, 1.5 g), 4-(diphenylamino)phenyl)boronic acid (8.3 mmol, 2.4 g), tetra(triphenylphosphine)palladium (0.1 mmol, 123 mg) and potassium carbonate (36.17 mmol, 5 g) were added to a mixed solvent of tetrahydrofuran (20 mL) and water (5 mL), stirred and heated to obtain a yellow solution, which was purified by column chromatography to obtain a yellow solid compound 1; (2) Under N2 protection, compound 1 (1.36 mmol, 513 mg), iodopentafluorobenzene (2.04 mmol, 597 mg) and KOtBu (2.04 mmol, 228 mg) were added to toluene (10 mL), stirred and heated to obtain a reddish-brown solution, which was then purified by column chromatography to obtain a white solid compound 2.

[0022] (3) Under N2 protection, compound 2 (0.79 mmol, 400 mg), palladium acetate (0.079 mmol, 17.8 mg), tetrabutylammonium bromide (0.39 mmol, 127 mg) and diisopropylethylamine (5.75 mmol, 1 mL) were added to toluene (15 mL), stirred and heated to obtain a yellow solution, which was purified by column chromatography to obtain a yellow solid TBTz.

[0023] like Figure 2 As shown, the 1H NMR spectrum of the product is as follows: 1H NMR (CDCl3, 600 MHz, δ / ppm): 8.17 (dd, J= 8.5, 1.4 Hz, 2H), 8.14 (d, J = 2.0 Hz, 2H), 7.77 (dt, J = 8.6, 1.7 Hz, 2H), 7.59-7.54 (m, 4H), 7.32-7.27 (m, 8H), 7.19-7.14 (m, 12H), 7.07 (td, J = 7.4,1.5 Hz, 4H). (4) Under N2 protection, TBTz (0.079 mmol, 60 mg) and [(ppy)2IrCl]2 (0.040 mmol, 43 mg) obtained from S3 were added to a mixed organic solvent of chloroform (6 mL) and methanol. After stirring and heating, a purple solution was obtained. The purple solid complex TBTz-Ir was obtained by column chromatography separation and purification.

[0024] like Figure 3 As shown, the 1H NMR spectrum of the product is as follows: 1 H NMR (DMSO- d 6, 500 MHz, δ / ppm): 8.68 (d,J = 1.9 Hz, 2H), 8.26 (d, J = 8.2 Hz, 2H), 7.97 (dd, J = 7.9, 1.4 Hz, 2H), 7.92 (td, J = 7.9, 7.5, 1.5 Hz, 2H), 7.86 (m, 2H), 7.65 (m, 4H), 7.53 (dd, J= 9.1, 1.8 Hz, 2H), 7.35 (m, 8H), 7.11 (m, 16H), 6.99 (dd, J = 8.5, 6.4 Hz,6H), 6.71 (d, J = 8.9 Hz, 2H), 6.23 (m, 2H). Figure 4 The results show that MS: calcd. forC 72 H 50 ClIrN6S2[M-Cl] + : 1255.32, found: 1255.50. Example 2: UV-Vis absorption and emission spectra of near-infrared luminescent iridium complex photosensitizers The UV absorption and fluorescence spectra of TBTz-Ir in DMSO solution were measured using a UV-Vis spectrophotometer, as follows: Figure 5As shown, the maximum absorption wavelength of the iridium complex TBTz-Ir is around 550 nm. The fluorescence spectrum of TBTz-Ir was measured using an excitation wavelength of 515 nm, as shown below. Figure 6 As shown, the maximum emission wavelength of this iridium complex TBTz-Ir is approximately 880 nm.

[0025] Example 3: Near-infrared luminescent iridium complex photosensitizer photoactivation generates singlet oxygen ( 1 O2) test Using 9,10-anthratridiyl-bis(methylene)dimalonic acid (ABDA) as a singlet oxygen indicator, the UV absorption of ABDA decreased after capturing singlet oxygen, thus determining the ability of TBTz-Ir from Example 1 to release singlet oxygen. A mixed solution of 3 µM TBTz-Ir and 100 µM ABDA was placed at 550 nm (13.2 mW cm⁻¹). -2 Under illumination by light, the ultraviolet absorption of ABDA was measured every 30 seconds using a UV-Vis spectrophotometer. Figure 7 As shown, after 180 min of red light irradiation, the ultraviolet absorption of ABDA gradually decreased, indicating that the TBTz-Ir of the present invention generates singlet oxygen.

[0026] Example 4: Test for photoactivation of near-infrared luminescent iridium complex photosensitizer to generate hydroxyl radicals (•OH) Using 2,2'-adiazonium(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) as a superoxide anion indicator, the absorption of ABTS was enhanced after it captured •OH, thus determining the ability of TBTz-Ir in Example 1 to release •OH. A mixed solution of 10 µM TBTz-Ir and 80 µM ABTS was placed at 550 nm (13.2 mW cm⁻¹). -2 Under illumination by light, the absorption of ABTS was measured every 1 minute using an absorption spectrometer. Figure 8 As shown, the absorption of ABTS increased significantly after 5 minutes of light irradiation, indicating that the TBTz-Ir of the present invention has the ability to generate hydroxyl radicals.

[0027] Example 5: Near-infrared luminescent iridium complex photosensitizer photoactivation generates superoxide anions (O2). •- )test Using DHR123 as a superoxide anion indicator, when DHR123 captures O2... •- Subsequently, the fluorescence of DHR123 was enhanced, thereby determining the O2 release from TBTz-Ir in Example 1. •- The ability to [observe / contain] a mixed solution of 5 µM TBTz-Ir and 20 µM DHR123 was tested at 550 nm (13.2 mW cm⁻¹).-2 Under illumination by light, the fluorescence of DHR123 was measured every 2 minutes using a fluorescence spectrometer. Figure 9 As shown, the fluorescence of DHR123 increased significantly after 14 min of illumination, indicating that the TBTz-Ir of the present invention has the ability to generate superoxide anions.

[0028] Experimental example: Cytotoxicity of near-infrared luminescent iridium complex photosensitizer on 4T1 cells 4T1 cells were seeded in 96-well plates (5000 cells per well). After the cells recovered their morphology, they were incubated with different concentrations of TBTz-Ir (0 µM, 1.25 µM, 2.5 µM, 5 µM) for 4 h, respectively, in the dark and under light (550 nm, 13.2 mW cm⁻¹). -2 After 0.5 h of treatment, the culture medium (DMEM) was replaced. The cells were then placed statically in a cell culture incubator. After 40 h, 25 μL of MTT solution (5 mg / mL) was added to each well. -1 After incubation for another 4 hours, the supernatant was removed, and 150 μL of DMSO was added to each well. The cells were shaken for 15 minutes. Finally, the changes in optical density (OD) at 490 nm were monitored using a Bio-rad microplate reader to reflect the cell viability. Figure 10 The results showed that TBTz-Ir had no significant toxic or inhibitory effect on 4T1 cells under darkness. However, under light conditions, TBTz-Ir exhibited phototoxicity significantly different from the dark group, showing a significant inhibitory effect on 4T1 cells, and the IC50 value was significantly higher. 50 The concentration reached 15.92 µM, indicating that TBTz-Ir exhibits significant antitumor activity under photoexcitation conditions.

[0029] In summary, the near-infrared II luminescent iridium(III) complex photosensitizer TBTz-Ir synthesized in this invention can efficiently generate various reactive oxygen species (including...) under 550 nm illumination. 1 O2, •OH and O2 •- This compound exhibits excellent photodynamic activity. In vitro cell experiments showed that the complex had no significant toxicity to mouse breast cancer cells (4T1) under dark conditions, demonstrating good biocompatibility; while under light conditions, it showed a significant killing effect on 4T1 cells, with an IC50 value of [missing value]. 50 The value is 15.92 µM. This complex exhibits both good photostability and the ability to generate multiple reactive oxygen species, and it can even induce tumor cell death in a hypoxic microenvironment, showing great potential for application in photodynamic therapy for hypoxic tumors.

[0030] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A near-infrared II luminescent iridium(III) complex photosensitizer, characterized in that, The chemical structural formula of the near-infrared II luminescent iridium(III) complex photosensitizer is shown below: ； Wherein, D is selected from any one of the following groups: triphenylamino, tetraphenylvinyl, fluorenyl, carbazolyl, dihydroindolyl, phenoxazinyl, phenthiazinyl, pyrrolyl, piperidinyl, piperazinyl, gurtolyl, tetrahydroquinolinyl, phenanthrololinyl, quinolinyl, isoquinolinyl, pyridiniumimidazolyl, pyridothiazolyl, pyridooxazinyl, phenazinyl, phthalazinyl, quinazolinyl, quinoxalinyl.

2. The near-infrared II luminescent iridium(III) complex photosensitizer according to claim 1, characterized in that, The D is triphenylamine.

3. A method for preparing the near-infrared II luminescent iridium(III) complex photosensitizer according to claim 2, characterized in that, Includes the following steps: S1. Under N2 protection, 6-bromobenzo[d]thiazole, (4-(diphenylamino)phenyl)boronic acid, tetra(triphenylphosphine)palladium and potassium carbonate were added to a mixed solvent of tetrahydrofuran and water. The mixture was stirred and heated to obtain a yellow solution. The solution was then purified by column chromatography to obtain a yellow solid compound 1. S2. Under N2 protection, the yellow solid compound 1 obtained in S1, iodopentafluorobenzene and potassium tert-butoxide were added to toluene solvent and stirred to obtain a reddish-brown solution. After separation and purification by column chromatography, a white solid compound 2 was obtained. S3. Under N2 protection, compound 2 obtained in S2, palladium acetate, tetrabutylammonium bromide and diisopropylethylamine were added to toluene solvent, stirred and heated to obtain a yellow solution, which was then purified by column chromatography to obtain a yellow solid compound TBTz. S4. Under N2 protection, TBTz and [(ppy)2IrCl]2 obtained in S3 were added to a mixed organic solvent of chloroform and methanol. After stirring and heating, a purple solution was obtained. The purple solid complex TBTz-Ir was obtained by column chromatography separation and purification.

4. The preparation method according to claim 3, characterized in that, In step S1, the molar ratio of 6-bromobenzo[d]thiazole, (4-(diphenylamino)phenyl)boronic acid, tetra(triphenylphosphine)palladium and potassium carbonate is 7:8.3:0.1:36.17, the volume ratio of tetrahydrofuran and water is 4:1, and the reaction is carried out under N2 atmosphere at 70 °C for 12 h.

5. The preparation method according to claim 3, characterized in that, The molar ratio of the yellow solid compound 1, iodopentafluorobenzene and potassium tert-butoxide in step S2 is 2:3:

3. The reaction is carried out under N2 atmosphere and at 25 °C with stirring for 12 h.

6. The preparation method according to claim 3, characterized in that, In step S3, the molar ratio of compound 2, palladium acetate, tetrabutylammonium bromide, and diisopropylethylamine is 0.79:0.079:0.39:5.75, and the reaction is carried out under N2 atmosphere at 70 °C for 12 h.

7. The preparation method according to claim 3, characterized in that, In step S4, the molar ratio of TBTz to [(ppy)2IrCl]2 is 2:1, the volume ratio of chloroform to methanol is 2:1, and the heating is carried out under N2 atmosphere at 50 °C for 12 h.

8. The preparation method according to claim 3, characterized in that, The specific synthesis route is shown below: 。 9. The use of the near-infrared II luminescent iridium(III) complex photosensitizer according to claim 1 in the preparation of anti-hypoxic tumor drugs.

10. An anti-hypoxic tumor drug, characterized in that, The drug uses the near-infrared II luminescent iridium(III) complex photosensitizer as described in claim 1 as its main active ingredient.

Images