An aminothiourea lysosome-targeting iridium complex, and a preparation method and application thereof

Abstract

This invention discloses an aminothiourea iridium complex. It also discloses a method for preparing and applying a lysosomal-targeted iridium complex based on an aminothiourea ligand. The complex is constructed from a coumarin-thiourea ligand and an iridium dimer under alkaline conditions via in-situ isomerization and co-coordination. Under sodium bicarbonate regulation, the ligand undergoes intramolecular cyclization rearrangement to form a five-membered heterocyclic intermediate containing S and N atoms, which further rearranges with the iridium center to ultimately generate N. ^ S-type bidentate chelated semi-sandwich iridium complexes. The complexes described in this invention exhibit good chemical stability and significant antitumor activity, with inhibitory effects on tumor cells approaching or exceeding those of cisplatin. Furthermore, these complexes demonstrate lysosomal targeting properties, showing promising application prospects in anticancer drug development.

Description

Technical Field

[0001] This invention relates to metal complexes, specifically an aminothiourea lysosome-targeted iridium complex, its preparation method, and its application, belonging to the field of chemical pharmaceuticals. Background Technology

[0002] With the continuous rise in cancer incidence, the development of novel anticancer drugs has become a key challenge in the international medical and health field. Traditional platinum-based antitumor drugs, exemplified by cisplatin, have achieved breakthrough therapeutic effects in clinical tumor treatment, but they suffer from significant toxic side effects, easily induce drug resistance in tumor cells, and lack selectivity for targeting normal tissue cells. Therefore, the development of novel metal-based anticancer drugs with both high antitumor activity and low toxicity has become a research focus in the interdisciplinary field of biomedicine and coordination chemistry. In recent years, organometallic complexes have shown great application potential in the field of antitumor drug development due to their easily modifiable structures and unique biological mechanisms of action. Among them, iridium(III) complexes with a half-sandwich configuration have become a research hotspot in the field of metal anticancer drugs due to their high anticancer activity and novel targets. Peter J. Salter's research group previously reported two classes of semi-sandwich iridium organometallic anticancer complexes (see structural formulas A and B in the figure below, Acc. Chem. Res. 2014, 47, 1174-1185). In these complexes, the cyclopentadienyl ligand occupies three coordination sites at the iridium center, C... ^ N or N ^ The N-type bidentate chelating ligand occupies two coordination sites, while the chloride ion occupies the remaining coordination site, ultimately forming a stable octahedral spatial configuration. This type of iridium complex has become a common configuration in this field due to its good structural stability, and its anticancer mechanism differs fundamentally from traditional platinum-based drugs, achieving antitumor effects through multiple targets and pathways. However, most existing iridium complexes utilize C... ^ N or N ^ N-type ligand systems have limited structural regulatory space, making it difficult to achieve precise control over biological activity and subcellular localization. Therefore, developing novel ligand systems and constructing iridium complexes with novel coordination modes is of great significance for expanding their structural diversity and enhancing their antitumor properties.

[0003] Summary of the Invention This invention uses coumarin-thiourea ligand as N ^ The S-bidone chelate ligand is introduced into the synthesis system of semi-sandwich iridium complexes. This ligand contains both modifiable coumarin and thiourea units, providing a diverse structural basis for the regulation of the chemical stability and biological activity of the complexes.

[0004] Based on the above design, the present invention aims to construct a novel N-type ... ^ The S-chelated semi-sandwich type iridium complex IV (see formula below) was synthesized. However, during the synthesis of the above-mentioned target complex, this invention unexpectedly discovered that, in the presence of sodium bicarbonate, the coumarin-thiourea ligand not only undergoes coordination reaction with the iridium center, but also undergoes in-situ isomerization and intramolecular cyclization rearrangement reactions, thereby generating a novel coordination structure I (see formula below). Its antitumor activity was then investigated. Experimental results showed that this complex not only possesses good antitumor activity but also exhibits significant lysosomal targeting characteristics.

[0005] Compared to the expected target structure, the complex obtained in this invention exhibits significant changes in both coordination mode and molecular structure, representing a novel coordination configuration. Its possible rearrangement reaction mechanism is shown in the following diagram: In the presence of bicarbonate, the coumarin-thiourea ligand first undergoes deprotonation, initiating an electronic rearrangement of the ligand skeleton. During this process, the C=S bonds of the thiourea unit break and recombine, accompanied by electron transfer, allowing the sulfur atom to form a coordinate bond with the iridium center, thus generating intermediate B. Subsequently, the ortho-nitrogen atom in intermediate B undergoes a nucleophilic attack on the carbonyl carbon, inducing an intramolecular cyclization reaction to form a five-membered heterocyclic structure containing N and S atoms. This process is accompanied by proton transfer and the formation of hydroxyl groups. Further, the intermediate undergoes continuous proton migration and electron rearrangement, causing interconversion between the hydroxyl and carbonyl groups, gradually leading to a stable configuration. Finally, via enol-keto tautomerism, a stable five-membered heterocyclic structure containing N and S atoms is formed, with N... ^ The S-shaped bidental arrangement coordinates with the iridium center to obtain the target iridium complex I. The above process involves multiple steps of proton transfer and electron rearrangement, but this invention is not limited to the specific reaction mechanism.

[0006] This invention discloses an aminothiourea iridium complex with the molecular structural formula (I): ; In the formula, R1 is hydrogen, methyl, isopropyl, phenyl, or benzyl.

[0007] The aminothiourea iridium complex of the present invention, wherein in formula (I), R1 is hydrogen, and the specific structural formula is shown in formula 1; in formula (I), R1 is methyl, and the specific structural formula is shown in formula 2; in formula (I), R1 is isopropyl, and the specific structural formula is shown in formula 3; in formula (I), R1 is phenyl, and the specific structural formula is shown in formula 4; in formula (I), R1 is benzyl, and the specific structural formula is shown in formula 5. The method for preparing the iridium complex containing coumarin-thiourea ligands by rearrangement according to the present invention includes the following steps: under nitrogen protection, with the addition of the dimer shown in formula (III), methanol and sodium bicarbonate, the coumarin-thiourea ligand shown in formula (II) undergoes isomerization and coordinates with metallic iridium to form the N-containing five-membered heterocycle of formula (I) containing S and N. ^ The S-bidentate chelated iridium complex; sodium bicarbonate is added to catalyze structural isomerization to form the complex; the specific synthetic route is as follows: .

[0008] When the complex is 1, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer, 27.7 mg of ligand (formula (II) R1 = hydrogen), 8.4 mg of sodium bicarbonate and 20 mL of anhydrous methanol were added to a 100 mL Schlenk flask. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporation. The remaining solid was dissolved in dichloromethane and the sodium bicarbonate was removed by sintering. The filtrate was evaporated by rotary evaporation to a minimum amount. Excess hexane was added, which produced a precipitate. The precipitate was filtered by sintering and washed with hexane. The filter cake was dissolved in 10 mL of CH2Cl2 in a reagent bottle. 20 mL of hexane was slowly added along the bottle wall to separate the layers. The yellow solid 1 was obtained by recrystallization by diffusion method. When the complex is 2, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer, 29.1 mg of ligand (formula (II) R1 = methyl), 8.4 mg of sodium bicarbonate and 20 mL of anhydrous methanol were added to a 100 mL Schlenk flask. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporation. The remaining solid was dissolved in dichloromethane and the sodium bicarbonate was removed by sintering. The filtrate was evaporated by rotary evaporation to remove the minimum amount. Excess hexane was added, which produced a precipitate. The precipitate was filtered by sintering and washed with hexane. The filter cake was dissolved in 10 mL of CH2Cl2 in a reagent bottle. 20 mL of hexane was slowly added along the bottle wall to separate the layers. The yellow solid 2 was obtained by recrystallization by diffusion method. When the complex is 3, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer, 31.9 mg of ligand (formula (II) R1 = isopropyl), 8.4 mg of sodium bicarbonate and 20 mL of anhydrous methanol were added to a 100 mL Schlenk flask. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporation. The remaining solid was dissolved in dichloromethane and the sodium bicarbonate was removed by sintering. The filtrate was evaporated by rotary evaporation to remove the minimum amount of solvent. Excess hexane was added, and a precipitate was formed. The precipitate was filtered by sintering and washed with hexane. The filter cake was dissolved in 10 mL of CH2Cl2 in a reagent bottle. 20 mL of hexane was slowly added along the bottle wall to separate the layers. The yellow solid 3 was obtained by recrystallization by diffusion method. When the complex is 4, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer, 35.3 mg of ligand (formula (II) R1 = phenyl), 8.4 mg of sodium bicarbonate and 20 mL of anhydrous methanol were added to a 100 mL Schlenk flask. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporation. The remaining solid was dissolved in dichloromethane and the sodium bicarbonate was removed by sintering. The filtrate was evaporated by rotary evaporation to remove the minimum amount of solvent. Excess hexane was added, and a precipitate was formed. The precipitate was filtered by sintering and washed with hexane. The filter cake was dissolved in 10 mL of CH2Cl2 in a reagent bottle. 20 mL of hexane was slowly added along the bottle wall to separate the layers. The yellow solid 4 was obtained by recrystallization by diffusion method. When the complex is 5, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer, 36.7 mg of ligand (formula (II) R1 = benzyl), 8.4 mg of sodium bicarbonate and 20 mL of anhydrous methanol were added to a 100 mL Schlenk flask. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator. The remaining solid was dissolved in dichloromethane and the sodium bicarbonate was removed by sintering filter. The filtrate was evaporated by rotary evaporator to remove the minimum amount. Excess hexane was added, which produced a precipitate. The precipitate was filtered by sintering filter and washed with hexane. The filter cake was dissolved in 10 mL of CH2Cl2 in a reagent bottle. 20 mL of hexane was slowly added along the bottle wall to separate the layers. The yellow solid 5 was obtained by recrystallization by diffusion method.

[0009] Beneficial effects This invention provides an N based on coumarin-thiourea ligands ^ S-bidate iridium complexes, their preparation methods, and their antitumor applications. A key feature of this invention is that during the synthesis of the complex, the ligands undergo in-situ isomerization and cyclization rearrangement under the action of sodium bicarbonate, forming a five-membered heterocyclic structure containing S and N atoms, and forming a stable N atom with the iridium center. ^ S-chelation coordination mode.

[0010] Compared with the prior art, the present invention has the following advantages: (1) A method for constructing novel coordination structures based on in-situ ligand rearrangement is proposed; (2) A novel class of N was obtained ^ S-chelated semi-sandwich type iridium complex; (3) The complex has good lysosomal targeting ability and significant antitumor activity. Attached Figure Description

[0011] Figure 1 The 1H NMR spectrum of complex 1 of this invention; Figure 2 Mass spectrometry of complex 1 of the present invention; Figure 3 The single-crystal structure of complex 1 prepared in this invention (hydrogen atoms have been omitted in the figure for clarity). Figure 4 The 1H NMR spectrum of complex 2 of this invention; Figure 5 Mass spectrometry of complex 2 of the present invention; Figure 6 The single-crystal structure of complex 2 prepared in this invention (hydrogen atoms have been omitted in the figure for clarity); Figure 7 The 1H NMR spectrum of complex 3 of this invention; Figure 8 Mass spectrometry of complex 3 of the present invention; Figure 9 The 1H NMR spectrum of complex 4 of this invention; Figure 10 Mass spectrometry of complex 4 of the present invention; Figure 11 The single-crystal structure of complex 4 prepared in this invention (hydrogen atoms have been omitted in the figure for clarity). Figure 12 The 1H NMR spectrum of complex 5 of this invention; Figure 13 This is the mass spectrometry of coordination compound 5 of the present invention.

[0012] Figure 14 The single-crystal structure of complex 5 prepared in this invention (hydrogen atoms have been omitted in the figure for clarity); Figure 15 This is a subcellular colocalization diagram of complex 3 of the present invention. Detailed Implementation

[0013] The present invention is further illustrated by the following examples of representative compounds, but these descriptions do not limit the invention.

[0014] The starting compounds used in the synthesis of these compounds are commercial products or can be prepared from known synthetic methods. All methods for preparing organic compounds are available in the literature, and these methods are fundamental and obvious to synthetic chemists. Therefore, the following descriptions of synthetic methods can be considered detailed and specific.

[0015] Example 1 When the complex is 1, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer, 27.7 mg of ligand (formula (II) R1 = hydrogen), 8.4 mg of sodium bicarbonate, and 20 mL of anhydrous methanol were added to a 100 mL Schlenk flask. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporation. The remaining solid was dissolved in dichloromethane and the sodium bicarbonate was removed by sintering. The filtrate was evaporated by rotary evaporation to remove the minimum amount of solvent. Excess hexane was added, and a precipitate was formed. The precipitate was filtered by sintering and washed with hexane. The filter cake was dissolved in 10 mL of CH2Cl2 in a reagent bottle. 20 mL of hexane was slowly added along the bottle wall to separate the layers. The solution was recrystallized by diffusion to obtain 38.6 mg of yellow solid 1, with a yield of 60.3%. Nuclear magnetic resonance characterization 1 H NMR (400 MHz, DMSO- d 6) δ 10.54 (s, 1H, OH), 10.21 (s, 1H, NH), 7.57 (d, J = 6.1 Hz, 1H, aryl-H), 7.31 (t, J = 5.8 Hz, 1H, aryl-H), 6.85-6.77 (m, 2H, aryl-H), 2.60 (s, 3H, C-CH3), 1.69 (s, 15H, Cp) -C H 3). Mass spectrometry: C 22 H 25 The theoretical value of IrN3O3S is 604.6513, and the actual measured value is 604.6547, [M-Cl]. + . Elemental analysis: Theoretical value C 22 H 25 ClIrN3O3S: C, 41.34; H, 3.94; N, 6.57, Actual measured: C, 41.51; H, 3.95; N, 6.56. Example 2 When the complex is 2, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer, 29.1 mg of ligand (formula (II) R1 = methyl), 8.4 mg of sodium bicarbonate, and 20 mL of anhydrous methanol were added to a 100 mL Schlenk flask. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporation. The remaining solid was dissolved in dichloromethane and the sodium bicarbonate was removed by sintering. The filtrate was evaporated by rotary evaporation to remove the minimum amount of solvent. Excess hexane was added, and a precipitate was formed. The precipitate was filtered by sintering and washed with hexane. The filter cake was dissolved in 10 mL of CH2Cl2 in a reagent bottle. 20 mL of hexane was slowly added along the bottle wall to separate the layers. The solution was recrystallized by diffusion to obtain 39.6 mg of yellow solid 2, with a yield of 60.8%. Nuclear magnetic resonance characterization 1 H NMR (400 MHz, DMSO- d 6) δ 10.99 (s, 1H, OH), 7.56 (d, J = 7.1 Hz, 1H, aryl-H), 7.30 (t, J = 6.7 Hz, 1H, aryl-H), 6.87-6.76 (m, 2H, aryl-H), 3.21 (s, 3H, N-CH3), 2.60 (s, 3H, C-CH3), 1.69 (s, 15H, Cp) -C H 3). Mass spectrometry: C 23 H 27 The theoretical value of IrN3O3S is 618.6669, and the actual measured value is 618.6685, [M-Cl] + . Elemental analysis: Theoretical value C 23 H 27 ClIrN3O3S: C, 42.29; H, 4.17; N, 6.43, Actual measured: C, 42.41; H, 4.16; N, 6.44. Example 3 When the complex is 3, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer, 31.9 mg of ligand (formula (II) R1 = isopropyl), 8.4 mg of sodium bicarbonate, and 20 mL of anhydrous methanol were added to a 100 mL Schlenk flask. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporation. The remaining solid was dissolved in dichloromethane and the sodium bicarbonate was removed by sintering. The filtrate was evaporated by rotary evaporation to remove the minimum amount of solvent. Excess hexane was added, and a precipitate was formed. The precipitate was filtered by sintering and washed with hexane. The filter cake was dissolved in 10 mL of CH2Cl2 in a reagent bottle. 20 mL of hexane was slowly added along the bottle wall to separate the layers. The solution was recrystallized by diffusion to obtain 34.8 mg of yellow solid 3, with a yield of 51.1%. Nuclear magnetic resonance characterization 1 H NMR (400 MHz, DMSO- d 6) δ 11.37 (s, 1H, OH), 10.29 (s, 1H, aryl-H), 7.58 (t, J = 5.4 Hz, 1H, aryl-H), 7.37 (t, J = 6.2 Hz 1H, aryl-H), 6.93-6.85 (m, 2H, aryl-H), 4.05 (d, J = 6.5 Hz, 1H, (C H (CH3)2), 2.66 (s, 3H, C-CH3), 1.75 (s, 15H, Cp -CH3), 1.62 (s, 6H, (CH(C H 3)2). Mass spectrometry: C 25 H 31 The theoretical value of IrN3O3S is 645.6904, and the actual measured value is 645.6908, [M-Cl] + . Elemental analysis: Theoretical value C 25 H 31 ClIrN3O3S: C, 44.08; H, 4.59; N, 6.17, Actual measured: C, 44.72; H, 4.60; N, 6.18. Example 4 When the complex is 4, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer, 35.3 mg of ligand (formula (II) R1 = phenyl), 8.4 mg of sodium bicarbonate, and 20 mL of anhydrous methanol were added to a 100 mL Schlenk flask. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporation. The remaining solid was dissolved in dichloromethane and the sodium bicarbonate was removed by sintering. The filtrate was evaporated by rotary evaporation to remove the minimum amount of solvent. Excess hexane was added, and a precipitate was formed. The precipitate was filtered by sintering and washed with hexane. The filter cake was dissolved in 10 mL of CH2Cl2 in a reagent bottle. 20 mL of hexane was slowly added along the bottle wall to separate the layers. The product was recrystallized by diffusion to obtain 38.5 mg of yellow solid 4, with a yield of 53.8%. Nuclear magnetic resonance characterization 1 H NMR (400 MHz, DMSO- d 6) δ 9.55 (s, 1H, OH), 9.38 (s, 1H, aryl-H), 8.00 (d, J = 7.6 Hz, 1H, aryl-H), 7.83 (d, J = 7.0 Hz, 1H, aryl-H), 7.73 (d, J = 6.1 Hz, 1H, aryl-H), 7.48-7.41 (m, 2H, aryl-H), 7.26 (t, J = 6.3Hz, 2H, aryl-H), 6.91 (t, J = 5.8 Hz, 1H, aryl-H), 2.62 (s, 3H, C-CH3), 1.50 (s, 15H, Cp) -CH3). Mass spectrometry: C 28 H 29 The theoretical value of IrN3O3S is 680.6826, and the actual measured value is 680.6863, [M-Cl] + . Elemental analysis: Theoretical value C 28 H 29 ClIrN3O3S: C, 47.02; H, 4.09; N, 5.87, Actual measured: C, 47.16; H, 4.08; N, 5.86. Example 5 When the complex is 5, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer, 36.7 mg of ligand (formula (II) R1 = benzyl), 8.4 mg of sodium bicarbonate, and 20 mL of anhydrous methanol were added to a 100 mL Schlenk flask. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporation. The remaining solid was dissolved in dichloromethane and the sodium bicarbonate was removed by sintering. The filtrate was evaporated by rotary evaporation to remove the minimum amount of solvent. Excess hexane was added, and a precipitate was formed. The precipitate was filtered by sintering and washed with hexane. The filter cake was dissolved in 10 mL of CH2Cl2 in a reagent bottle. 20 mL of hexane was slowly added along the bottle wall to separate the layers. The product was recrystallized by diffusion to obtain 37.8 mg of yellow solid 5, with a yield of 51.8%. Nuclear magnetic resonance characterization 1 H NMR (500 MHz, DMSO- d 6) δ 10.91 (s, 1H, OH), 7.55 (d, J =9.1 Hz, 1H, aryl-H), 7.40 (dd, J = 11.2, 7.3 Hz, 4H, aryl-H), 7.34-7.28 (m, 2H, aryl-H), 6.86-6.78 (m, 2H, aryl-H), 4.92-4.82 (m, 2H, aryl-C) H 2) , 2.61 (s,3H, C-CH3), 1.65 (s, 15H, Cp -C H 3). Mass spectrometry: C 29 H 31 The theoretical value of IrN3O3S is 694.6982, and the actual measured value is 694.6989, [M-Cl] + . Elemental analysis: Theoretical value C 29 H 31 IrN3O3S: C, 47.76; H, 4.28; N, 5.76, Actual measured: C, 47.89; H, 4.27; N, 5.75. Example 6 Assay on the inhibitory activity of ligand II (R1 = phenyl) and complexes 1-5 on tumor cell lines: (1) Preparation of the test compound: Dissolve the solid ligand and complex in DMSO to prepare a stock solution of a certain concentration. Dilute the stock solution further with cell culture medium until the working concentration is reached, and culture for 24 h.

[0016] (2) Cell growth inhibition assay (MTT method): 1) Take 5000 human cervical cancer cells (HeLa) and human non-small cell lung cancer cells (A549) respectively, prepare cell suspensions, and seed them in 96-well culture plates; 2) Pre-culture cells in drug-free medium, incubate at 5% CO2 and 310 K for 24 hours, add the prepared test compound, and incubate for 24 hours; 3) Add 15 μL of 5 mg / mL MTT solution to each well and continue culturing for 4 hours to form purple crystalline formazan; 4) Terminate the culture, carefully aspirate the culture medium from the wells, add 100 μL of DMSO to each well to fully dissolve the formazan precipitate, mix with a shaker, and then measure the optical density of each well at a wavelength of 570 nm using a microplate reader. 5) Each experiment was repeated three times, IC 50 = Mean ± SEM. The inhibition rates of complexes 1-5 and commercial cisplatin on the growth of cancer cells HeLa and A549 are shown in Table 1.

[0017] Table 1 As shown in Table 1, the complex exhibited good antitumor activity against both A549 and HeLa cells, with an IC50 value of [missing information]. 50 The value ranged from 5.28 to 23.07 μM, and the overall activity was close to or partially superior to that of the commercially available anticancer drug cisplatin.

[0018] Further comparison of the activity data of ligand II (R1 = phenyl) and its corresponding complex 4 shows that complex 4 has strong antitumor activity (IC50). 50 =11.36-17.13 μM) is significantly superior to ligand II (IC). 50 The concentration of iridium (μM = 101-106 μM) indicates that the introduction of the iridium center significantly enhanced its biological activity. These results demonstrate that the synergistic effect between the ligand and the metal center is a key factor in improving antitumor activity. Such metal complexes show great potential for development in antitumor applications.

[0019] Example 7 Laser confocal microscopy can conveniently detect the targeting of the complex after it enters A549 cells. LysoTracker Red DND-99 (LTRD) and Mito Tracker Deep Red (MTDR) were used as fluorescent probes for lysosomes and mitochondria, respectively. A549 cells were incubated with the target complex (9.1 μM) at 37 °C for 1 h, followed by staining with LTRD (100 nM) and MTDR (50 nM) for 30 min. The cells were then washed three times with phosphate-balanced saline (PBS) buffer and observed under a laser confocal microscope. The excitation wavelength of the target complex was 405 nm, and the collection wavelength was 430–490 nm; the excitation wavelength of LTRD was 630 ± 30 nm, and the collection wavelength was 493–630 nm; MTDR was excited at 644 nm, and the emission wavelength was 690 ± 30 nm. The tests were performed as follows: Figure 15 As shown.

[0020] The Pearson correlation coefficients of complex 3 with the cell nucleus and mitochondria were measured to be 0.01 and 0.13, respectively, while the Pearson correlation coefficient with lysosomes reached 0.83. Figure 15 The above results indicate that the complex is mainly targeted and enriched in lysosomes, and has good lysosomal targeting characteristics.

[0021] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. An aminothiourea iridium complex, characterized in that, The structural formula is shown in equation (Ⅰ): ； In the formula, R1 is hydrogen, methyl, isopropyl, phenyl, or benzyl.

2. The aminothiourea iridium complex according to claim 1, characterized in that, In formula (I), R1 is hydrogen, and the specific structural formula is shown in formula 1; in formula (I), R1 is methyl, and the specific structural formula is shown in formula 2; in formula (I), R1 is isopropyl, and the specific structural formula is shown in formula 3; in formula (I), R1 is phenyl, and the specific structural formula is shown in formula 4; in formula (I), R1 is benzyl, and the specific structural formula is shown in formula 5. 。 3. A method for preparing the aminothiourea iridium complex according to claim 1 or 2, characterized in that, Includes the following steps: Under nitrogen protection, with the addition of the dimer shown in formula (III), methanol, and sodium bicarbonate, the coumarin-thiourea ligand shown in formula (II) undergoes isomerization and coordinates with metallic iridium to form the N-containing five-membered heterocycle of formula (I) containing S and N. ^ The S-bidentate chelated iridium complex; sodium bicarbonate is added to catalyze structural isomerization to form the complex; the specific synthetic route is as follows: 。 4. The preparation method according to claim 3, characterized in that, When the complex is 1, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer, 27.7 mg of formula (II) ligand, 8.4 mg of sodium bicarbonate and 20 mL of anhydrous methanol were added to a 100 mL Schlenk flask. In formula (II), R1 = hydrogen. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator. The remaining solid was dissolved in dichloromethane and the sodium bicarbonate was removed by sintering filter. The filtrate was evaporated by rotary evaporator to remove the minimum amount of solvent. Excess hexane was added, and a precipitate was formed. The precipitate was filtered by sintering filter and washed with hexane. The filter cake was dissolved in 10 mL of CH2Cl2 in a reagent bottle. 20 mL of hexane was slowly added along the bottle wall to separate the layers. The yellow solid 1 was obtained by recrystallization by diffusion method. When the complex is 2, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer, 29.1 mg of formula (II) ligand, 8.4 mg of sodium bicarbonate and 20 mL of anhydrous methanol were added to a 100 mL Schlenk flask. In formula (II), R1 = methyl. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator. The remaining solid was dissolved in dichloromethane and the sodium bicarbonate was removed by sintering filter. The filtrate was evaporated by rotary evaporator to remove the minimum amount of solvent. Excess hexane was added, and a precipitate was formed. The precipitate was filtered by sintering filter and washed with hexane. The filter cake was dissolved in 10 mL of CH2Cl2 in a reagent bottle. 20 mL of hexane was slowly added along the bottle wall to separate the layers. The yellow solid 2 was obtained by recrystallization by diffusion method. When the complex is 3, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer, 31.9 mg of formula (II) ligand, 8.4 mg of sodium bicarbonate and 20 mL of anhydrous methanol were added to a 100 mL Schlenk flask and reacted at room temperature for 24 h. In formula (II), R1 = isopropyl. After the reaction, the solvent was evaporated by rotary evaporator, and the remaining solid was dissolved in dichloromethane. Sodium bicarbonate was removed by sintering filter. The filtrate was evaporated by rotary evaporator to remove the minimum amount of solvent. Excess hexane was added, and a precipitate was formed. The precipitate was filtered by sintering filter and washed with hexane. The filter cake was dissolved in a reagent bottle with 10 mL of CH2Cl2. 20 mL of hexane was slowly added along the bottle wall to separate the layers. The yellow solid 3 was obtained by recrystallization by diffusion method. When the complex is 4, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer, 35.3 mg of formula (II) ligand, 8.4 mg of sodium bicarbonate and 20 mL of anhydrous methanol were added to a 100 mL Schlenk flask and reacted at room temperature for 24 h. In formula (II), R1 = phenyl. After the reaction was completed, the solvent was evaporated by rotary evaporator, and the remaining solid was dissolved in dichloromethane. Sodium bicarbonate was removed by sintering filter. The filtrate was evaporated by rotary evaporator to a minimum amount, and excess unsuitable solvent n-hexane was added. Precipitation occurred. The precipitate was filtered by sintering filter and washed with n-hexane. The filter cake was dissolved in a reagent bottle with 10 mL of CH2Cl2. 20 mL of n-hexane was slowly added along the bottle wall to separate the layers. The yellow solid 4 was obtained by recrystallization by diffusion method. When the complex is 5, it is prepared by the following method: Under nitrogen protection, 39.6 mg of iridium dimer, 36.7 mg of formula (II) ligand, 8.4 mg of sodium bicarbonate and 20 mL of anhydrous methanol were added to a 100 mL Schlenk flask. In formula (II), R1 = benzyl. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was evaporated by rotary evaporator. The remaining solid was dissolved in dichloromethane and the sodium bicarbonate was removed by sintering filter. The filtrate was evaporated by rotary evaporator to remove the minimum amount of solvent. Excess hexane was added, and a precipitate was formed. The precipitate was filtered by sintering filter and washed with hexane. The filter cake was dissolved in a reagent bottle with 10 mL of CH2Cl2. 20 mL of hexane was slowly added along the bottle wall to separate the layers. The yellow solid 5 was obtained by recrystallization by diffusion method.

5. The use of the aminothiourea iridium complex according to claim 1 or 2 in the preparation of antitumor drugs.

6. The application according to claim 5, characterized in that, The cancer is either lung cancer or cervical cancer.

7. The use of the aminothiourea iridium complex according to claim 1 or 2 in a targeted probe.

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