Preparation of iridium complex photosensitizer of type i and its application in pharmaceutical field

Abstract

The present application relates to the technical field of pharmaceutical chemistry, in particular to preparation and application of type I iridium complex photosensitizer in the field of pharmacy, and the chemical structural formula of the type I iridium complex photosensitizer is one of the following. The type I iridium complex photosensitizer prepared by the present application has the following advantages: no obvious cytotoxicity to adenocarcinoma human alveolar basal epithelial cells (A549) under the condition of no light, and a large number of type I active oxygen superoxide anions O2 ·‑ are generated under the condition of light, good phototoxicity to A549 cells is shown, the IC50 is only 6.1 μM and 3.4 μM, the type I iridium complex photosensitizer emits wavelength in the near-infrared II region, has deeper tissue penetration ability, shows excellent photodynamic therapy effect, and has important application prospect in the field of photodynamic therapy drugs for anti-hypoxic tumors and deep tissue tumors.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, and more particularly to the preparation of type I iridium complex photosensitizers and their application in the pharmaceutical field. Background Technology

[0002] Globally, cancer remains one of the leading causes of death in the 21st century. Currently, chemotherapy is one of the main clinical treatments for cancer. Since cisplatin was discovered to have anticancer activity in 1967, basic research and clinical application of platinum-based anticancer drugs have developed rapidly. Statistics show that over 50% of all cancer chemotherapy regimens in my country are based on platinum or contain platinum-based drugs. However, platinum-based drugs suffer from significant toxicity, poor tumor selectivity, and the tendency for tumor tissues to develop tolerance. Therefore, designing and synthesizing novel metal complex photosensitizers and expanding their novel tumor treatment strategies are of great significance in both basic research and clinical application. Among various metal complexes, iridium complexes possess excellent photostability, cell permeability, large Stokes shift, and unique antitumor mechanisms, such as disrupting organelle activity, inducing cytoplasmic vacuum, and inhibiting enzyme activity, attracting widespread attention from researchers.

[0003] Photodynamic therapy (PDT) is a novel light-mediated tumor treatment modality that primarily relies on photoactivated photosensitizers to exert its therapeutic effect. It boasts advantages such as non-invasiveness, high spatiotemporal selectivity, strong controllability, and low toxicity, showing great promise for clinical treatment of various diseases. Most photosensitizers are oxygen-dependent type II photosensitizers, and the hypoxic nature of the tumor microenvironment limits their PDT efficacy. However, type I photosensitizers can generate free radical reactive oxygen species through electron transfer, exhibiting high phototoxicity and low oxygen dependence, effectively addressing the challenge of PDT for hypoxic tumors. However, currently developed metal complex photosensitizers have relatively short absorption and emission wavelengths, mostly within the visible light range (400-700 nm), resulting in limited tissue penetration depth. The high photon energy also causes significant damage to the organism, and severe light scattering hinders the diagnosis and treatment of tumors in deep tissues. In contrast, near-infrared (NIR, >700 nm) emission wavelengths can effectively reduce background interference from biological tissues, achieving deeper tissue penetration and facilitating anti-tumor PDT in deeper tissues. Therefore, there is a need to develop a type I metal complex photosensitizer with near-infrared luminescence for photodynamic therapy of tumors.

[0004] Therefore, existing technologies still need to be improved and developed. Summary of the Invention

[0005] In view of the shortcomings of the prior art, the present invention provides the preparation of type I iridium complex photosensitizers and their application in the pharmaceutical field, aiming to solve the problem that existing visible light photosensitizers are not suitable for photodynamic therapy of tumors in deep tissues and hypoxic environments.

[0006] Specifically, the technical solution of the present invention is as follows:

[0007] This invention provides a type I iridium complex photosensitizer, wherein the type I iridium complex photosensitizer is one of the following chemical structural formulas:

[0008]

[0009] This invention also provides a method for preparing the type I iridium complex photosensitizer, comprising the following steps:

[0010] S1. Under inert gas protection, methanol and toluene are mixed to obtain a first organic solvent. 2,7-Dibromodipyridine[3,2-a:2',3'-c]phenazine or 10,13-dibromodipyridine[3,2-a:2',3'-c]phenazine, (4-(bis(4-methoxyphenyl)aminophenyl)boronic acid, [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride and potassium carbonate are added to the first organic solvent to carry out a first heating reaction. After the reaction, the product is purified to obtain an intermediate solid.

[0011] S2. Under inert gas protection, methanol and dichloromethane are mixed to obtain a second organic solvent. The intermediate solid and (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) are added to the second organic solvent, and a second heating reaction is carried out. After the reaction, the type I iridium complex photosensitizer is obtained by purification.

[0012] When 2,7-dibromodipyridine[3,2-a:2',3'-c]phenazine is added to S1, the chemical structure of which is shown as DPPZ-1 in the synthetic route (1), and the chemical structure of the intermediate product is shown as L1, the chemical structure of the type I iridium complex photosensitizer is Ir1. The synthetic route (1) is as follows:

[0013] (1)

[0014] When 10,13-dibromodipyridine[3,2-a:2',3'-c]phenazine is added to S1, the chemical structure of which is shown as DPPZ-2 in synthetic route (2), and the chemical structure of the intermediate product is shown as L2, the chemical structure of the type I iridium complex photosensitizer is Ir2. The synthetic route (2) is as follows:

[0015] (2)

[0016] Optionally, in step S1, the molar ratio of 2,7-dibromodipyridine[3,2-a:2',3'-c]phenazine, (4-(bis(4-methoxyphenyl)aminophenyl)boronic acid, [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride, and potassium carbonate is 1:2.3:0.1:3; and the molar ratio of 10,13-dibromodipyridine[3,2-a:2',3'-c]phenazine, (4-(bis(4-methoxyphenyl)aminophenyl)boronic acid, [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride, and potassium carbonate is 1:2.3:0.1:3.

[0017] Optionally, in step S1, the volume ratio of methanol to toluene in the first organic solvent is 1:1.

[0018] Optionally, in step S1, the temperature of the first heating reaction is 85°C, and the duration of the first heating reaction is 12 hours.

[0019] Optionally, in step S2, the molar ratio of the intermediate product to (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) is 2:1.

[0020] Optionally, in step S2, the volume ratio of methanol to dichloromethane in the second organic solvent is 2:1.

[0021] Optionally, in step S2, the temperature of the second heating reaction is 50°C, and the time of the first heating reaction is 24 hours.

[0022] The present invention further provides an application of the aforementioned type I iridium complex photosensitizer, wherein the type I iridium complex photosensitizer is used to prepare a drug for photodynamic therapy.

[0023] Optionally, the drug is an anti-adenocarcinoma human alveolar basal epithelial cell A549 drug using the type I iridium complex photosensitizer as the main active ingredient.

[0024] Beneficial effects:

[0025] This invention provides the preparation of type I iridium complex photosensitizers and their application in the pharmaceutical field. Compared with traditional photosensitizers, the type I iridium complex photosensitizers prepared by the method of this invention do not exhibit significant cytotoxicity against adenocarcinoma human alveolar basal epithelial cells (A549) under light-free conditions, while generating a large amount of superoxide anions (O2) under light-free conditions. ·-It exhibits good phototoxicity to A549 cells, with IC50 values ​​of only 6.1 μM and 3.4 μM. The type I iridium complex photosensitizer emits wavelengths in the near-infrared II region, allowing for deeper tissue penetration and demonstrating excellent photodynamic therapy effects. It has significant application prospects in the field of photodynamic therapy for hypoxic tumors and deep tissue tumors. Attached Figure Description

[0026] Figure 1 The synthetic route diagram for the type I iridium complex photosensitizer provided by this invention is shown.

[0027] Figure 2 The 1H NMR spectrum of the type I iridium complex photosensitizer Ir1 in deuterated chloroform provided in an embodiment of the present invention.

[0028] Figure 3 The 1H NMR spectrum of the type I iridium complex photosensitizer Ir2 provided by this invention in deuterated chloroform.

[0029] Figure 4 The UV-Vis absorption and fluorescence spectra of the type I iridium complex photosensitizer provided by this invention are shown.

[0030] Figure 5 The type I iridium complex photosensitizer provided by this invention uses ABDA as a photosensitive agent under 550 nm illumination. 1 UV-Vis absorption spectrum of O2 probe.

[0031] Figure 6 The fluorescence spectrum of the type I iridium complex photosensitizer provided by this invention using DHR123 as an O2·- probe under 633 nm illumination.

[0032] Figure 7 The type I iridium complex photosensitizer provided by this invention is effective under illumination (633 nm, 45.9 mW cm⁻¹). -2 Effects of 2h and dark environments on the activity of adenocarcinoma human alveolar basal epithelial cells (A549). Detailed Implementation

[0033] This invention provides the preparation of type I iridium complex photosensitizers and their application in the pharmaceutical field. To make the objectives, technical solutions, and effects of this invention clearer and more explicit, the invention is further described in detail below. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the scope of protection of the invention.

[0034] This invention provides a type I iridium complex photosensitizer, wherein the type I iridium complex photosensitizer is one of the following chemical structural formulas:

[0035]

[0036] In a typical PDT process, the photosensitizer (PS) is first photoexcited to a singlet state (S1) and generates an S1 exciton; the S1 exciton transitions to a three-state excited state (T1) through an intersystem crossing (ISC) process; finally, the T1 exciton interacts with the surrounding oxygen-containing substrate to generate reactive oxygen species (ROS) that kill cancer cells.

[0037] The aforementioned iridium complex exhibits a significant redshift in absorption and emits wavelengths in the near-infrared II region. The molecular structure of this iridium complex contains an electron-rich anisole group, conforming to a DAD-type structure, which generates energy ΔE during the intersystem crossing process from S1 to T1. ST Decrease, resulting in lower ΔE ST This value allows for better generation of reactive oxygen species, producing oxygen-independent type I reactive oxygen species, superoxide anion radicals (O2), through an electron transfer process. ·- The iridium metal center in iridium complexes has excellent cell entry capabilities, exhibits no cytotoxicity in the dark, and generates a large amount of type I reactive oxygen species under red light irradiation, thus enabling it to effectively kill cancer cells without relying on an oxygen-dependent environment.

[0038] This invention also provides a method for preparing the type I iridium complex photosensitizer, as detailed below:

[0039] a) When the chemical structural formula of the type I iridium complex photosensitizer is Ir1, its synthetic route is as follows:

[0040] (1)

[0041] The preparation method of type I iridium complex photosensitizer Ir1 includes the following specific steps:

[0042] S1. Under an inert gas atmosphere, 2,7-dibromodipyridine[3,2-a:2',3'-c]phenazine (chemical structure shown as DPPZ-1 in synthetic route (1)), (4-(bis(4-methoxyphenyl)aminophenyl)boronic acid, [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride and potassium carbonate are added to a mixed organic solvent of methanol and toluene. After heating and reacting, an orange-red solution is obtained. The orange-red solution is separated and purified by column chromatography to obtain an orange-red solid, which is the intermediate product (chemical structure shown as L1 in synthetic route (1)).

[0043] S2. Under an inert gas atmosphere, the orange-red solid of the above intermediate and (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) were added to a mixed organic solvent of methanol and dichloromethane. After heating, a red solution was obtained. The red solution was purified by column chromatography to obtain the type I iridium complex photosensitizer Ir1.

[0044] Nitrogen can be used as an inert gas, but it is not limited to nitrogen.

[0045] In some embodiments, in step S1, the volume ratio of methanol to toluene is 1:1.

[0046] In some embodiments, in step S1, the molar ratio of 2,7-dibromodipyridine[3,2-a:2',3'-c]phenazine, [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride, and potassium carbonate is 1:2.3:0.1:3.

[0047] In some embodiments, the heating reaction in step S1 is carried out at a temperature of 85°C for 12 hours.

[0048] In some embodiments, in step S2, the molar ratio of intermediate product L1 to (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) is 2:1.

[0049] In some embodiments, in step S2, the volume ratio of methanol to dichloromethane is 2:1.

[0050] In some embodiments, in step S2, the heating reaction is carried out at a temperature of 50°C for 24 hours.

[0051] b) When the chemical structural formula of the type I iridium complex photosensitizer is Ir2, its synthetic route is as follows:

[0052] (2)

[0053] The preparation method of type I iridium complex photosensitizer Ir2 includes the following specific steps:

[0054] S1. Under an inert gas atmosphere, 10,13-dibromobispyrido[3,2-a:2',3'-c]phenazine (chemical structure shown as DPPZ-2 in synthetic route (2)), (4-(bis(4-methoxyphenyl)aminophenyl)boronic acid, [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride and potassium carbonate are added to a mixed organic solvent of methanol and toluene. After heating and reacting, a purple solution is obtained. The solution is then separated and purified by column chromatography with an orange-red solution to obtain a purple solid, which is the intermediate product (chemical structure shown as L2 in synthetic route (2)).

[0055] S2. Under an inert gas atmosphere, the purple solid of the above intermediate product and (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) were added to a mixed organic solvent of methanol and dichloromethane. After heating, a blue-purple solution was obtained. The red solution was separated and purified by column chromatography to obtain the type I iridium complex photosensitizer Ir2.

[0056] Nitrogen can be used as an inert gas, but it is not limited to nitrogen.

[0057] In some embodiments, in step S1, the volume ratio of methanol to toluene is 1:1.

[0058] In some embodiments, in step S1, the molar ratio of 10,13-dibromobispyrido[3,2-a:2',3'-c]phenazine, (4-(bis(4-methoxyphenyl)aminophenyl)boronic acid, [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride, and potassium carbonate is 1:2.3:0.1:3.

[0059] In some embodiments, the heating reaction in step S1 is carried out at a temperature of 85°C for 12 hours.

[0060] In some embodiments, in step S2, the molar ratio of intermediate product L2 to (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) is 2:1.

[0061] In some embodiments, in step S2, the volume ratio of methanol to dichloromethane is 2:1.

[0062] In some embodiments, in step S2, the heating reaction is carried out at a temperature of 50°C for 24 hours.

[0063] This invention also provides an application of the aforementioned type I iridium complex photosensitizer, which is used to prepare a drug for photodynamic therapy.

[0064] In some embodiments, the drug is an anti-adenocarcinoma human alveolar basal epithelial cell A549 drug using the type I iridium complex photosensitizer as the main active ingredient.

[0065] The present invention will be further described below with reference to specific embodiments.

[0066] The equipment used in this embodiment is all conventional experimental equipment, and the materials and reagents used are all commercially available unless otherwise specified.

[0067] Example 1

[0068] Under nitrogen protection, 2,7-dibromodipyridine[3,2-a:2',3'-c]phenazine (200 mg, 0.45 mmol), (4-(bis(4-methoxyphenyl)aminophenyl)boronic acid (365 mg, 1.05 mmol), [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (33.3 mg, 0.046 mmol), and potassium carbonate (188.4 mg, 1.36 mmol) were added to a mixed organic solvent of methanol and toluene (10 mL, volume ratio 1:1). The mixture was stirred and heated overnight to obtain an orange-red solution. The solution was then purified by column chromatography to obtain an orange-red solid (its chemical structure is shown below). Figure 1 (As shown in L1 of the synthesis route).

[0069] Orange-red solid L1 (49.7 mg, 0.056 mmol) and (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) (30 mg, 0.028 mmol) were added to a mixed organic solvent of methanol and dichloromethane (9 mL, volume ratio 1:2). The mixture was stirred and heated for 24 h to obtain a red solution. The solution was purified by column chromatography to obtain the type I iridium complex photosensitizer Ir1.

[0070] The molecular formula of the type I iridium complex photosensitizer Ir1 is: C 80 H 60 IrN8O4Cl; the 1H NMR spectrum of this product is as follows: Figure 2 Shown: 1H NMR(500MHz,Chloroform-d)δppm:9.85(s,2H),8.53–8.39(m,4H),8.06(d,J=9.9Hz,2H),7.98(d,J=8.1Hz,2H),7.85(t,J=7.7Hz,2H),7.76(d,J= 8.0Hz,2H),7.64(d,J=5.6Hz,2H),7.40(s,4H),7.11(t,J=7.5Hz,12H),7 .06–6.96(m,6H),6.93–6.86(m,8H),6.46(d,J=7.5Hz,2H),3.84(s,12H).

[0071] Example 2

[0072] Under nitrogen protection, 10,13-dibromobispyrido[3,2-a:2',3'-c]phenazine (200 mg, 0.45 mmol), (4-(bis(4-methoxyphenyl)aminophenyl)boronic acid (365 mg, 1.05 mmol), [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (33.3 mg, 0.046 mmol), and potassium carbonate (188.5 mg, 1.36 mmol) were added to a mixed organic solvent of methanol and toluene (10 mL, volume ratio 1:1). The mixture was stirred and heated overnight to obtain a purple solution. The solution was purified by column chromatography to obtain a purple solid L2 (its chemical structure is shown below). Figure 1 (as shown in L2 of the synthesis route);

[0073] Purple solid L2 (102 mg, 0.11 mmol) and (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) (62 mg, 0.06 mmol) were added to a mixed organic solvent of methanol and dichloromethane (10 mL, volume ratio 1:2). The mixture was stirred and heated for 24 h to obtain a blue-purple solution. The solution was purified by column chromatography to obtain the type I iridium complex photosensitizer Ir2.

[0074] The molecular formula of the type I iridium complex photosensitizer Ir2 is: C 80 H 60 IrN8O4Cl, the 1H NMR spectrum of this product is as follows: Figure 3 Shown: 1H NMR(600MHz,Chloroform-d)δppm:9.56(d,J=9.4Hz,1H),8.36(d,J=6.4Hz,1H),8 .11(s,2H),7.99(d,J=8.1Hz,1H),7.95(d,J=8.2Hz,2H),7.83–7.69(m,8H),7.59( d,J=5.7Hz,2H),7.21(d,J=8.9Hz,6H),7.14(d,J=8.7Hz,4H),7.12–7.03(m,4H), 6.99(d,J=0.9Hz,2H), 6.90(d,J=9.0Hz,6H), 6.41(d,J=7.4Hz,2H), 3.82(s,12H).

[0075] Characterization and testing

[0076] (1) UV-Vis absorption and emission spectra of type I iridium complex photosensitizers

[0077] The UV absorption and fluorescence spectra of type I iridium complex photosensitizers Ir1 (30 μM) and Ir2 (100 μM) in aqueous solution were measured using a UV-Vis spectrophotometer, as follows: Figure 4As shown, the absorption wavelength of the type I iridium complex photosensitizer Ir1 is around 500 nm, and the absorption wavelength of the type I iridium complex photosensitizer Ir2 is around 600 nm. The fluorescence spectra of Ir1 and Ir2 were measured using the maximum absorption wavelengths of 488 nm and 600 nm, respectively, as excitation wavelengths. Figure 4 As shown, the iridium complex photosensitizers emit fluorescence in the near-infrared region. Ir1, an iridium complex photosensitizer, receives fluorescence in the 630-1100 nm range when excited at 600 nm; Ir2, an iridium complex photosensitizer, receives fluorescence in the 800-1400 nm range when excited at 700 nm. Metal complexes with near-infrared luminescence properties can effectively address some limitations in the treatment of deep tumors, such as tissue penetration depth and imaging of deep tumors.

[0078] (2) Type I iridium complex photosensitizers are photoactivated to produce singlet oxygen ( 1 O2) test

[0079] Using 9,10-anthratridiyl-bis(methylene)dimalonic acid (ABDA) as a singlet oxygen indicator, the UV absorption of ABDA decreases after it captures singlet oxygen. This was used to determine the ability of the type I iridium complex photosensitizers Ir1 and Ir2 prepared in the examples to release singlet oxygen.

[0080] A mixed solution of 10 μM iridium complex photosensitizer Ir1 and 8 μM ABDA was placed at 550 nm (15.5 mW cm⁻¹). -2 Under illumination, the ultraviolet absorption of ABDA was measured every 5 minutes using an ultraviolet-visible spectrophotometer.

[0081] A mixed solution of 10 μM iridium complex photosensitizer Ir2 and 8 μM ABDA was placed at 550 nm (15.5 mW cm⁻¹). -2 Under illumination, the ultraviolet absorption of ABDA was measured every 5 minutes using an ultraviolet-visible spectrophotometer.

[0082] like Figure 5 As shown, under red light irradiation for 30 minutes, the ultraviolet absorption of ABDA hardly changed, indicating that the type I iridium complex photosensitizers Ir1 and Ir2 prepared in the embodiments of the present invention do not produce singlet oxygen.

[0083] (3) Type I iridium complex photosensitizers are photoactivated to generate superoxide anions (O2). ·- )test

[0084] Using DHR123 as a superoxide anion indicator, when DHR123 captures O2... ·- Subsequently, the fluorescence of DHR123 is enhanced, thereby determining the release of superoxide anions O2 from the type I iridium complex photosensitizers Ir1 and Ir2 prepared in the examples.·- The ability.

[0085] A mixed solution of 10 μM type I iridium complex photosensitizer Ir1 and 10 μM DHR123 was placed at 633 nm (45.9 mW cm⁻¹). -2 Under illumination, the fluorescence of DHR123 was measured every 30 seconds using a fluorescence spectrometer.

[0086] A mixed solution of 10 μM type I iridium complex photosensitizer Ir2 and 10 μM DHR123 was placed at 633 nm (45.9 mW cm⁻¹). -2 Under illumination, the fluorescence of DHR123 was measured every 30 seconds using a fluorescence spectrometer.

[0087] like Figure 6 As shown, the fluorescence of DHR123 increased significantly after 210 s of illumination, indicating that the type I iridium complex photosensitizers Ir1 and Ir2 prepared in the embodiments of the present invention can generate a large amount of type I active oxygen superoxide anions O2. ·- The ability.

[0088] (4) Cytotoxicity of type I iridium complex photosensitizers on adenocarcinoma human alveolar basal epithelial cells (A549)

[0089] A549 cells were seeded in 96-well plates (5000 cells per well). After the cells recovered their morphology, they were incubated for 8 hours with different concentrations of type I iridium complex photosensitizers Ir1 and Ir2 (0 μM, 1.56 μM, 3.13 μM, 6.25 μM, 12.5 μM, 25 μM, 50 μM, 100 μM). The cells were then treated for 2 hours in the dark and under light (633 nm, 45.9 mW cm⁻²) respectively, followed by replacement with fresh DMEM culture medium. The cells were then placed statically in a cell culture incubator. After 40 hours, 25 μL of LTT solution (5 mg / mL) was added to each well. -1 After incubating for another 4 hours, the supernatant was removed, and 150 μL LDMSO 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.

[0090] Figure 7 The results showed that, in the absence of light, the type I iridium complex photosensitizers Ir1 and Ir2 had no significant toxic or inhibitory effects on A549 cells. However, under light conditions, the type I iridium complex photosensitizers Ir1 and Ir2 exhibited phototoxicity significantly different from the dark group, showing significant inhibitory effects on A549 cells, with IC50 values ​​reaching 6.1 μM and 3.4 μM, respectively. This indicates that the type I iridium complex photosensitizers Ir1 and Ir2 possess significant antitumor activity under photoexcitation conditions.

[0091] As can be seen, the type I iridium complex photosensitizers Ir1 and Ir2 in this invention can generate O2 under 633nm red light radiation. ·- It exhibits excellent anti-tumor activity under red light irradiation, with IC50 values ​​reaching 6.1 μM and 3.4 μM, respectively. However, it is essentially non-toxic to cancer cells in dark environments and holds promise for photodynamic therapy of hypoxic tumors.

[0092] In summary, this invention provides the preparation of type I iridium complex photosensitizers and their application in the pharmaceutical field. The type I iridium complex photosensitizers obtained by the above preparation method do not exhibit significant cytotoxicity against adenocarcinoma human alveolar basal epithelial cells (A549) under light-free conditions, but generate a large amount of superoxide anions (O2) under light-free conditions. ·- It exhibits good phototoxicity to A549 cells, with IC50 values ​​of only 6.1 μM and 3.4 μM. The type I iridium complex photosensitizer emits wavelengths in the near-infrared II region, enabling it to penetrate deeper into tissues and demonstrating excellent photodynamic therapy effects. It has significant application prospects in the field of photodynamic therapy for hypoxic tumors and deep tissue tumors.

[0093] It should be understood that the application of the present invention is not limited to the examples above. Those skilled in the art can make improvements or modifications based on the above description, and all such improvements and modifications should fall within the protection scope of the appended claims.

Claims

1. A type I iridium complex photosensitizer, characterized in that, The type I iridium complex photosensitizer is one of the following chemical structural formulas:

2. The method for preparing the type I iridium complex photosensitizer as described in claim 1, characterized in that, Including the following steps: S1. Under inert gas protection, methanol and toluene are mixed to obtain a first organic solvent. 2,7-Dibromodipyridine[3,2-a:2',3'-c]phenazine or 10,13-dibromodipyridine[3,2-a:2',3'-c]phenazine, (4-(bis(4-methoxyphenyl)aminophenyl)boronic acid, [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride and potassium carbonate are added to the first organic solvent to carry out a first heating reaction. After the reaction, the product is purified to obtain an intermediate solid. S2. Under inert gas protection, methanol and dichloromethane are mixed to obtain a second organic solvent. The intermediate solid and (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) are added to the second organic solvent, and a second heating reaction is carried out. After the reaction, the type I iridium complex photosensitizer is obtained by purification. When 2,7-dibromodipyridine[3,2-a:2',3'-c]phenazine is added to S1, the chemical structure of which is shown as DPPZ-1 in the synthetic route (1), and the chemical structure of the intermediate product is shown as L1, the chemical structure of the type I iridium complex photosensitizer is Ir1. The synthetic route (1) is as follows: Alternatively, when 10,13-dibromodipyridine[3,2-a:2',3'-c]phenazine is added to S1, the chemical structure of which is shown as DPPZ-2 in synthetic route (2), and the chemical structure of the intermediate product is shown as L2, the chemical structure of the type I iridium complex photosensitizer is Ir2. The synthetic route (2) is as follows:

3. The method for preparing the type I iridium complex photosensitizer according to claim 2, characterized in that, In step S1, the molar ratio of 2,7-dibromodipyridine[3,2-a:2',3'-c]phenazine, (4-(bis(4-methoxyphenyl)aminophenyl)boronic acid, [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride, and potassium carbonate is 1:2.3:0.1:3; or, the molar ratio of 10,13-dibromodipyridine[3,2-a:2',3'-c]phenazine, (4-(bis(4-methoxyphenyl)aminophenyl)boronic acid, [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride, and potassium carbonate is 1:2.3:0.1:

3.

4. The method for preparing the type I iridium complex photosensitizer according to claim 2, characterized in that, In step S1, the volume ratio of methanol to toluene in the first organic solvent is 1:

1.

5. The method for preparing the type I iridium complex photosensitizer according to claim 2, characterized in that, In step S1, the temperature of the first heating reaction is 85°C, and the duration of the first heating reaction is 12 hours.

6. The method for preparing the type I iridium complex photosensitizer according to claim 2, characterized in that, In step S2, the molar ratio of the intermediate product to (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) is 2:

1.

7. The method for preparing the type I iridium complex photosensitizer according to claim 2, characterized in that, In step S2, the volume ratio of methanol to dichloromethane in the second organic solvent is 2:

1.

8. The method for preparing the type I iridium complex photosensitizer according to claim 2, characterized in that, In step S2, the temperature of the second heating reaction is 50°C, and the time of the first heating reaction is 24 hours.

9. The application of a type I iridium complex photosensitizer as described in claim 1, characterized in that, The type I iridium complex photosensitizer is used to prepare drugs for tumor photodynamic therapy.

10. The application of the type I iridium complex photosensitizer according to claim 9, characterized in that, The drug is an anti-adenocarcinoma human alveolar basal epithelial cell A549 drug using the type I iridium complex photosensitizer as the main active ingredient.

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