Platinum (IV)-peroxy prodrug molecule and application thereof

Abstract

The invention discloses a platinum (IV)-internal peroxy prodrug molecule and application thereof, and belongs to the technical field of biological medicine. The series of molecules are characterized by being Pt (IV) complexes modified by internal peroxide and mitochondrial targeting groups. The synthesis method sequentially comprises the following steps: carrying out oxidation and hydroxyl modification on a platinum drug, introducing a mitochondrial targeting group and a singlet oxygen carrier through an esterification reaction, and carrying out a photosensitive reaction to prepare the endoperoxide. The series of molecules are reduced into Pt (II) drugs in a tumor microenvironment, singlet oxygen is released at the same time, a mitochondrial targeting group can accurately deliver the treatment molecules, and cancers are efficiently treated. A representative molecule Oxa-EM is selected for instance analysis, the molecule generates a Pt (II) complex with anticancer activity while releasing singlet oxygen, and the singlet oxygen-Pt combined anticancer purpose is achieved. Probes DPBF and SOSG are selected to prove that the molecule releases singlet oxygen, and high performance liquid chromatography is utilized to successfully prove that the Pt (II) complex is released in a reducing environment. Further cell and animal level experiments verify that the molecule has excellent anti-tumor efficacy and safety. The invention discloses design, synthesis and biological test of platinum (IV)-peroxy prodrug molecules, and the platinum (IV)-peroxy prodrug molecules have a wide anticancer application prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine and relates to a class of platinum (IV)-endoperoxy prodrug molecules and applications. Background Art

[0002] Oxaliplatin is a third-generation platinum anticancer drug, a platinum compound of diaminocyclohexane, in which the amino group of cisplatin is replaced by a 1,2-diaminocyclohexane group. Similar to other platinum drugs, it targets DNA, with Pt atoms forming cross-links with DNA to antagonize its replication and transcription. It is widely used in chemotherapy for gastrointestinal cancer patients worldwide. However, most cancer treatment drugs are cytotoxic, not only killing tumor tissue but also damaging normal cells and tissues. To improve the quality of patient care, a series of Pt(IV) complexes with advantages such as low toxicity, oral administration, and targeted effects have been developed. Pt(IV) complexes are axially connected to Pt(II) complexes with ligands of varying or identical efficacy, resulting in novel Pt complexes that not only possess superior water solubility, lipid solubility, and targeting, but also possess the specific function of the ligand. Pt(IV) complexes offer advantages over Pt(II) complexes, including greater kinetic inertness and associated reduced side effects, activation of the axial ligand via reductive elimination, and the ability to functionalize the axial ligand of the Pt(IV) complex. Furthermore, Pt(IV) complexes have been labeled as prodrugs because reductive elimination promotes the generation of cytotoxic Pt(II) complexes in the hypoxic tumor environment.

[0003] Pt chemotherapy also faces serious drug resistance challenges in the clinical treatment of colorectal cancer. Therefore, it is crucial to find effective methods to overcome this drug resistance and improve treatment efficacy. Summary of the Invention

[0004] To solve the problems existing in the prior art, the present invention provides a class of Pt(IV)-endoperoxide complex prodrug molecules. Based on the anti-cancer properties of endoperoxides and Pt(IV), the molecule releases toxic singlet oxygen through a reverse cyclization reaction of the peroxide structure. At the same time, it utilizes reducing substances overexpressed in the tumor microenvironment to promote the generation of Pt(II) complexes with anti-cancer activity, thereby achieving synergistic treatment with singlet oxygen and chemotherapy drugs.

[0005] The technical solution of the present invention: a compound of formula (1):

[0006] Among them, L1 is selected from 、 ; L2 is selected from hydroxyl, 、 、 ; R1, R4, R5, and R6 are each independently selected from hydroxyl, trimethylsilyl, amino, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, alkoxyl having 1 to 5 carbon atoms, alkylamino having 1 to 6 carbon atoms, alkoxyalkyl having 2 to 6 carbon atoms, alkyl having 1 to 10 carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl having 2 to 6 carbon atoms, aryl having 6 to 14 carbon atoms, cycloalkyl having 3 to 10 carbon atoms, or ; R2, R3, and R7 are each independently selected from hydrogen, hydroxy, trimethylsilyl, amino, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkylamino having 1 to 6 carbon atoms, alkoxyalkyl having 2 to 6 carbon atoms, alkyl having 1 to 10 carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl having 2 to 6 carbon atoms, aryl having 6 to 14 carbon atoms, cycloalkyl having 3 to 10 carbon atoms, or ; Wherein, x is an integer from 1 to 2000.

[0007] Furthermore, R1, R4, R5, and R6 are each independently selected from an alkoxy group having 1 to 2 carbon atoms, an alkoxyalkyl group having 2 to 6 carbon atoms, an alkyl group having 1 to 10 carbon atoms, and a trifluoromethyl group; R2, R3, and R7 are each independently selected from hydrogen, an alkoxy group having 1 to 2 carbon atoms, an alkoxyalkyl group having 2 to 6 carbon atoms, an alkyl group having 1 to 10 carbon atoms, and a trifluoromethyl group.

[0008] Furthermore, R1, R4, R5, and R6 are each independently an alkyl group having 1 to 6 carbon atoms, and R2, R3, and R7 are hydrogen.

[0009] Furthermore, R1, R4, R5, and R6 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, or n-hexyl, and R2, R3, and R7 are hydrogen.

[0010] Use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a singlet oxygen-releasing material.

[0011] Use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating cancer.

[0012] Furthermore, the cancer is lung cancer, breast cancer, liver cancer, pancreatic cancer, colorectal cancer, ovarian cancer, prostate cancer, testicular cancer, nasopharyngeal cancer, esophageal cancer, malignant lymphoma, head and neck squamous cell carcinoma, thyroid cancer and osteosarcoma.

[0013] A pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof.

[0014] The present invention has the following beneficial effects: Carboxylic acid derivatives of 1,4-dimethylnaphthalene and triphenylphosphine serve as axial ligands to link dihydroxyoxaliplatin and Pt(IV), resulting in a Pt(IV)-endoperoxide complex. A singlet oxygen carrier drug is attached to one or both sides of the Pt(IV) complex molecule via an esterification reaction. This molecule, through in vitro photoreaction, is then transformed into a drug capable of storing and releasing singlet states. Reducing substances in the tumor microenvironment promote activation of the anticancer Pt(II) complex, enabling the drug molecule to effectively reach the tumor site. The synergistic effect of singlet oxygen and the Pt(II) complex enhances tumor cell cytotoxicity and reduces drug resistance.

[0015] This molecule releases toxic singlet oxygen through a reverse cyclization reaction of the endoperoxide structure. Simultaneously, reducing substances in the tumor microenvironment promote the release of the anti-cancer active Pt(II) complex, enabling combined therapy with singlet oxygen and chemotherapy drugs. The singlet oxygen carrier molecule, acting as an axial ligand for the Pt(IV) complex, can simultaneously deliver singlet oxygen and the active Pt(II) complex, enhancing the killing effect on tumor cells, reducing drug side effects, and minimizing damage to normal cells. Furthermore, this orthogonal anti-cancer mechanism also helps reduce drug resistance in tumor cells.

[0016] Oxa-EM testing confirmed that the anticancer molecule provided by the present invention releases singlet oxygen while simultaneously forming a Pt(II) complex with anticancer activity, enabling singlet oxygen-Pt combined anticancer therapy. DPBF capture and SOSG testing confirmed that the anticancer molecule can normally release singlet oxygen, while high-performance liquid chromatography successfully demonstrated the in situ generation of the Pt(II) complex; this conclusion was also verified at the cellular and animal levels. The present invention successfully establishes a singlet oxygen-Pt chemotherapeutic drug combined anticancer system with broad application prospects. After endoperoxide formation, singlet oxygen is thermally released with a half-life of 4.2 hours at 37°C. It is then reduced to a carboxylic acid derivative that is a pharmacologically inactive singlet oxygen carrier. The reducing agent promotes the activation of the Pt(II) complex with anticancer activity. Compared to its precursor and Pt chemotherapeutic drugs, endoperoxides exhibit significantly enhanced toxicity to cancer cells, a potent tumor cell-killing effect also demonstrated in mice treated for liver cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 This is the change in UV absorption after incubation of DPBF and Oxa-E.

[0018] Figure 2 This is the UV absorption change diagram after incubation of DPBF and Oxa-EM.

[0019] Figure 3is a graph showing the change in fluorescence intensity after incubation of SOSG and Oxa-E.

[0020] Figure 4 is a graph showing the change in fluorescence intensity after incubation of SOSG with Oxa-EM.

[0021] Figure 5 This is a graph showing the changes in liquid phase peak intensity after incubation of ascorbic acid and Oxa-N.

[0022] Figure 6 This is a graph showing the changes in liquid phase peak intensity after incubation of ascorbic acid and Oxa-NM.

[0023] Figure 7 Toxicity of different concentrations of Oxa, Oxa-N, Oxa-NM, Oxa-E, and Oxa-EM to A549, A549 / DDP, MCF-7, 4T1, HepG2, and LO2 cells.

[0024] Figure 8 This is a diagram showing the co-localization of ROS released by Oxa, Oxa-N, Oxa-NM, Oxa-E, and Oxa-EM in cells and mitochondria.

[0025] Figure 9 This is the survival curve of liver cancer mice during the treatment stages of Oxa, Oxa-N, Oxa-NM, Oxa-E, and Oxa-EM.

[0026] Figure 10 This is the weight change curve of liver cancer mice during the treatment stages of Oxa, Oxa-N, Oxa-NM, Oxa-E, and Oxa-EM. DETAILED DESCRIPTION

[0027] The technical solution of the present invention is described in detail below through specific implementation methods. It should be understood that the following specific implementation methods are only exemplary, and any changes or modifications that do not depart from the technical solution design of the present invention should be within the scope of protection of the rights of the present invention.

[0028] A type of Pt(IV)-endoperoxide complex prodrug molecule has the following structure:

[0029] Among them, L1 is selected from 、 . L2 is selected from hydroxyl, 、 、 .

[0030] R2, R3, and R7 are each independently selected from hydrogen, hydroxy, trimethylsilyl, amino, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkylamino having 1 to 6 carbon atoms, alkoxyalkyl having 2 to 6 carbon atoms, alkyl having 1 to 10 carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl having 2 to 6 carbon atoms, aryl having 6 to 14 carbon atoms, cycloalkyl having 3 to 10 carbon atoms, or ; R1, R4, R5, and R6 are each independently selected from hydroxyl, trimethylsilyl, amino, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, alkoxyl having 1 to 5 carbon atoms, alkylamino having 1 to 6 carbon atoms, alkoxyalkyl having 2 to 6 carbon atoms, alkyl having 1 to 10 carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl having 2 to 6 carbon atoms, aryl having 6 to 14 carbon atoms, cycloalkyl having 3 to 10 carbon atoms, or ; Wherein, x is an integer from 1 to 2000.

[0031] In some specific Pt(IV)-endoperoxide complex prodrug molecules, R2, R3, and R7 are each independently selected from hydrogen, an alkoxy group with 1-2 carbon atoms, an alkoxyalkyl group with 2-6 carbon atoms, an alkyl group with 1-10 carbon atoms, and a trifluoromethyl group; R1, R4, R5, and R6 are each independently selected from an alkoxy group with 1-2 carbon atoms, an alkoxyalkyl group with 2-6 carbon atoms, an alkyl group with 1-10 carbon atoms, and a trifluoromethyl group.

[0032] In some specific Pt(IV)-endoperoxide complex prodrug molecules, R2, R3, and R7 are each independently selected from hydrogen, an alkoxy group with 1-2 carbon atoms, an alkyl group with 1-6 carbon atoms, and a trifluoromethyl group; R1, R4, R5, and R6 are each independently selected from an alkoxy group with 1-2 carbon atoms, an alkyl group with 1-6 carbon atoms, and a trifluoromethyl group.

[0033] Some specific Pt(IV)-endoperoxide complex prodrug molecules are characterized in that R2, R3, and R7 are each independently selected from hydrogen and an alkyl group with 1-6 carbon atoms; R1, R4, R5, and R6 are each independently an alkyl group with 1-6 carbon atoms.

[0034] In some specific Pt(IV)-endoperoxide complex prodrug molecules, R1, R4, R5, and R6 are each independently an alkyl group having 1 to 6 carbon atoms, and R2, R3, and R7 are hydrogen.

[0035] In some specific Pt(IV)-endoperoxide complex prodrug molecules, R1, R4, R5, and R6 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, or n-hexyl, and R2, R3, and R7 are hydrogen.

[0036] The application of the Pt(IV)-endoperoxide complex prodrug molecule in the preparation of singlet oxygen releasing materials.

[0037] The Pt(IV)-endoperoxide complex prodrug molecule is used in the preparation of a drug for delivering singlet oxygen to cells, tissues or organs.

[0038] A specific Pt-endoperoxide complex prodrug molecule has the following structure:

[0039] The preparation steps and reaction formula of the Pt-endoperoxide complex prodrug molecule of the present invention are as follows:

[0040] Under the protection of inert gas, compound 4 and compound A or B are heated in an organic solvent to react and esterify to obtain compound C.

[0041] Compound C and compound A-1, B-1 or E are mixed in an organic solvent, O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and triethylamine are added to the solution and heated to react to obtain compound D.

[0042] Compound D was dissolved in an organic solvent and cooled to 0°C in an ice bath. A catalytic amount of methylene blue was added, and the mixture was stirred under an oxygen atmosphere. During the reaction, the reaction solution was irradiated with 625 nm red light to obtain the target compound F.

[0043] Wherein, the definitions of R1-R7 and X are the same as those in the above-mentioned Pt(IV)-endoperoxide complex prodrug molecular structure.

[0044] The preparation process of compounds A and B is as follows:

[0045] Compound A-1 or B-1 is dissolved in an organic solvent, N-hydroxysuccinimide is added to dissolve the compound, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is added to the solution. The mixture is stirred at room temperature overnight to obtain compound A or B.

[0046] The specific embodiments of the present invention are described in detail below in conjunction with the technical solutions: Example 1

[0047] Preparation of Oxa-N, Oxa-E, Oxa-NM, and Oxa-EM:

[0048] Step a: Compound 1 (600.0 mg, 1.97 mmol) and N-hydroxysuccinimide (NHS) (249.2 mg, 2.17 mmol, 1.1 equivalents) were mixed with anhydrous DCM (20.0 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (453.2 mg, 2.36 mmol, 1.2 equivalents) was added to the solution. The mixture was stirred at room temperature overnight. After the reaction, the mixture was washed with saturated NH4Cl solution (3 x 20 mL). The organic layer was dried over anhydrous Na2SO4, the solution was filtered through a silica gel pad, and the solvent was removed under vacuum. The crude product was purified using silica gel column chromatography (Hex:EA=2:1, v / v) to obtain compound 2 (671.7 mg, yield 85%).

[0049] Step b: Compound 3 (500.0 mg, 1.26 mmol) and 30% H2O2 (10.0 mL) were added to H2O (5.0 mL) and stirred at 60°C for 5 hours. After the reaction, the solution was cooled to room temperature, the product was collected by centrifugation, and lyophilized to afford compound 4 (475.7 mg, 88% yield).

[0050] Step c: Compound 4 (300.0 mg, 0.70 mmol) and compound 2 (337.0 mg, 0.84 mmol, 1.2 equivalents) were mixed in anhydrous DMSO (5.0 mL). The mixture was stirred at 60°C under a nitrogen atmosphere for 24 hours. After the reaction, the mixture was washed with anhydrous Et2O until it became viscous. The mixture was dissolved in MeOH (1.0 mL), and Et2O (10.0 mL) was added to precipitate a white solid. The white solid was collected and washed with Et2O (3 x 10 mL) to obtain Oxa-N (315.4 mg, 63% yield).

[0051] Step d: A catalytic amount of methylene blue (MB) was added to a MeOH solution of Oxa-N (50.0 mg, 0.07 mmol). The solution was irradiated with red light (625 nm) at 0°C under an oxygen atmosphere until the starting material was completely consumed. The solution was placed on a short silica gel to remove the methylene blue, and the eluate was concentrated under vacuum to afford Oxa-E (42.5 mg, 82% yield). Step e: Oxa-N (100.0 mg, 0.14 mmol) and (3-carboxypropyl) (triphenyl) phosphonium bromide (TPP) (73.0 mg, 0.17 mmol, 1.2 equiv) were mixed in anhydrous DMF (5.0 mL), and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (67.4 mg, 0.21 mmol, 1.5 equiv) and triethylamine (Et3N) (21.3 mg, 0.21 mmol, 1.5 equiv) were added to the solution. The mixture was stirred at 45°C for 12 hours. After the reaction, the mixture was washed with Et2O until it became viscous. The mixture was dissolved in MeOH (1.0 mL), and Et2O (10.0 mL) was added to precipitate a light yellow solid. The light yellow solid was collected and washed with ultrapure water (3 x 2.0 mL), acetone (3 x 2.0 mL) and Et2O (3 x 10.0 mL) to obtain Oxa-NM (80.6 mg, yield 51 %).

[0052] Step f: To a solution of Oxa-NM (50.0 mg, 0.04 mmol) in MeOH was added a catalytic amount of methylene blue (MB). The solution was irradiated with red light (625 nm) at 0°C under an oxygen atmosphere until the starting material was completely consumed. The solution was placed on a short silica gel column to remove the methylene blue, and the eluate was concentrated under vacuum to afford Oxa-EM (45.8 mg, 89% yield). Example 2

[0053] Experiments on the release of singlet oxygen from endoperoxides Oxa-E and Oxa-EM.

[0054] Singlet oxygen sensor green (SOSG) and 1,3-diphenylisobenzofuran (DPBF) were used as probes to detect singlet oxygen released from the endoperoxides Oxa-E and Oxa-EM in aqueous and organic solutions, respectively. Oxa-E (50µM final concentration) and Oxa-EM (50µM final concentration) were incubated with SOSG (10µM final concentration) in PBS buffer (pH 7.4, 1% DMF) at 37°C. Fluorescence was measured using fluorescence spectroscopy under excitation at 504nm. Figure 3 and Figure 4 The fluorescence intensity changes of SOSG after incubation with Oxa-E and Oxa-EM are shown respectively. The increase in intensity at 530 nm indicates the generation of singlet oxygen in the aqueous solution.

[0055] Meanwhile, Oxa-E (250µM) and Oxa-EM (250µM) were mixed with DPBF (50µM, final concentration) in DMF at 37°C in the dark and subjected to UV-Vis analysis at the indicated times. Figure 1 and Figure 2 The UV absorption changes after incubation of DPBF with Oxa-E and Oxa-EM were respectively observed. The decrease in absorbance at 417 nm was monitored, indicating that singlet oxygen was released from the endoperoxides. Example 3

[0056] Reduction Study of Pt(IV) Complex The release of Oxa-N and Oxa-NM in the presence of excess reducing agents was monitored by high-performance liquid chromatography. Oxa-N and Oxa-NM were dissolved in 100 mM phosphate buffer (pH 7.0) and reacted with ascorbic acid (10 equivalents) at 37°C. The reaction was recorded by HPLC every 2 hours. The mobile phase consisted of water (0.1% TFA) and acetonitrile. A linear gradient of 100–90% water (0.1% TFA) to acetonitrile was run for 5 minutes, followed by a constant concentration of 50% water (0.1% TFA) for 5 minutes, followed by a linear gradient of 50% to 0% water (0.1% TFA) to acetonitrile for 10 minutes, and then a constant concentration of 100% acetonitrile was maintained over a 30-minute period. Figure 5 and Figure 6 The following plots show the changes in HPLC peak intensity after incubation with ascorbic acid, Oxa-N, and Oxa-NM. The HPLC signal indicates the release of Pt, while corresponding HPLC signals for the ligands on both sides are also detected. The molecule can cleanly reduce and release the axial ligand, and the HPLC peak of Oxa-NM decreases more slowly than that of Oxa-N, suggesting that Oxa-NM may be more stable in the bloodstream.

[0057] Example 4: Cell viability detection The cytotoxicity profile of Oxa-E and Oxa-EM was assessed using the MTT assay. Cells (5,000 cells per well, A549, A549 / DDP, MCF-7, 4T1, HepG2, and LO2) were seeded into 96-well plates and incubated at 37°C for 24 hours. The cells were then treated with culture medium containing various concentrations of Oxa-E and Oxa-EM (0, 1.25, 2.5, 5, 10, 20, 40, and 80 μM), respectively. Oxa-oxaliplatin, Oxa-N, and Oxa-NM were used as controls. After 48 hours, the cells were treated with 0.5% MTT and incubated at 37°C for a further 4 hours. After removing the culture medium, 150 μL of DMSO was added to dissolve the formazan crystals, and the absorbance was measured at 570 nm using a microplate reader (SpectraMax i3x, MD). Figure 7 Toxicity of different concentrations of Oxa, Oxa-N, Oxa-NM, Oxa-E, and Oxa-EM to A549, A549 / DDP, MCF-7, 4T1, HepG2, and LO2 cells; the cell viability of cells treated with Oxa, Oxa-N, Oxa-NM, Oxa-E, and Oxa-EM was normalized to that of untreated cells, and the IC values were obtained using GraphPad Prism 8. 50 IC values of Oxa-EM for selected tumor cells 50 All of them are below micromolar. Its toxicity to A549 resistant cells is 26 times that of Pt, it has a resistance factor 3 times lower than that of Pt, and its selectivity is 3 times that of Pt. Compared with other drugs, it has extremely strong tumor killing ability and good safety.

[0058] Example 5: Co-localization analysis of ROS and mitochondria The green fluorescence of the ROS kit and the red fluorescence of the mitochondrial probe were used to verify the level and distribution of intracellular ROS. A549 / CDDP cells were seeded at 7,000 cells per confocal dish (3.5 cm) and incubated for 24 hours. Oxa, Oxa-N, Oxa-NM, Oxa-E, and Oxa-EM were prepared in cell-specific culture medium to a final concentration of 40 μM per dish. After 4 hours of incubation, the ROS green fluorescent probe (DCFH-DA) was diluted in serum-free culture medium to a final concentration of 10 μM, and the mitochondrial red probe was diluted to a final concentration of 200 nM. The cell culture medium was removed, and the diluted probe solution was added. The cells were incubated in a 37°C cell culture incubator for 20 minutes. The cells were washed three times with PBS to fully remove any DCFH-DA and mitochondrial red probe that had not entered the cells. The cells were maintained in a mild environment in 1 ml of serum-free culture medium per dish and imaged using a 100x confocal microscope. Figure 8Figure 3 is the co-localization diagram of ROS released by Oxa, Oxa-N, Oxa-NM, Oxa-E, and Oxa-EM in cells and their mitochondria. The Oxa-E and Oxa-EM groups had higher levels of intracellular ROS, indicating the effective release of singlet oxygen in cells. It was also noted that the green fluorescence of ROS in the Oxa-EM group was highly concentrated in the mitochondria. The higher colocalization coefficient also indicated that Oxa-EM was highly aggregated in the mitochondria, successfully verifying the ability of Oxa-EM to target mitochondria. Example 6

[0059] Animal experiments H22 tumors cultured in mice were cut into 1 mm³ pieces. Mice were anesthetized with 70 mg / kg pentobarbital and sterile laparotomy was performed. The tumor pieces were then punctured into the liver. Seven days later, the mice were randomly divided into six groups: control, Oxa, Oxa-N, Oxa-NM, Oxa-E, and Oxa-EM. The control group received a tail vein injection of 100 μL of a solvent control (5% glucose solution containing 5% DMSO, v / v). The drug-treated groups received a tail vein injection of 100 μL of an equal volume of a solvent solution containing 3.0 mg / kg of Pt equivalents. Drug administration was continued every other day for 14 days. Survival was recorded daily, and mice were sacrificed after 21 days. Figure 9 This is the survival curve of liver cancer mice during the treatment stages of Oxa, Oxa-N, Oxa-NM, Oxa-E, and Oxa-EM. Figure 10 Figure 2 shows the weight changes of mice bearing liver cancer during treatment with Oxa, Oxa-N, Oxa-NM, Oxa-E, and Oxa-EM. The weight of mice in each group remained stable during treatment, indicating that the tail vein injection regimen did not cause significant systemic toxicity. Survival analysis showed that the survival rate of mice in the Oxa-EM group was significantly higher than that in the control group, further confirming the high biosafety of this treatment regimen. Liver pathology revealed that both the control and Oxa groups developed large tumor lesions, while significant differences in tumor burden were observed between the different Pt(IV) complex groups. The tumor volume in the Oxa-NM group was significantly smaller than that in the model and Oxa groups. Only a single small nodule was observed in the Oxa-E group, with further reduction in tumor volume. The tumor in the Oxa-EM group almost completely regressed. These results confirm that platinum-endoperoxide complexes can significantly enhance their antitumor effects. The platinum-endoperoxide complex Oxa-EM, modified with a mitochondrial targeting group, exhibits promising therapeutic potential for inhibiting tumor growth in an orthotopic liver cancer model.

[0060] The above embodiments are only used to illustrate the present invention. Any equivalent transformations and improvements based on the technical solution of the present invention should not be excluded from the protection scope of the present invention.

Claims

1. A compound of formula (1): ； in, L1 is selected from 、 ; L2 is selected from hydroxyl, 、 、 ; R1, R4, R5, and R6 are each independently selected from hydroxyl, trimethylsilyl, amino, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, alkoxyl having 1 to 5 carbon atoms, alkylamino having 1 to 6 carbon atoms, alkoxyalkyl having 2 to 6 carbon atoms, alkyl having 1 to 10 carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl having 2 to 6 carbon atoms, aryl having 6 to 14 carbon atoms, cycloalkyl having 3 to 10 carbon atoms, or ; R2, R3, and R7 are each independently selected from hydrogen, hydroxy, trimethylsilyl, amino, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkylamino having 1 to 6 carbon atoms, alkoxyalkyl having 2 to 6 carbon atoms, alkyl having 1 to 10 carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl having 2 to 6 carbon atoms, aryl having 6 to 14 carbon atoms, cycloalkyl having 3 to 10 carbon atoms, or ; Wherein, x is an integer from 1 to 2000.

2. The compound according to claim 1, characterized in that R1, R4, R5, and R6 are each independently selected from an alkoxy group having 1 to 2 carbon atoms, an alkoxyalkyl group having 2 to 6 carbon atoms, an alkyl group having 1 to 10 carbon atoms, and a trifluoromethyl group; R2, R3, and R7 are each independently selected from hydrogen, an alkoxy group having 1 to 2 carbon atoms, an alkoxyalkyl group having 2 to 6 carbon atoms, an alkyl group having 1 to 10 carbon atoms, and a trifluoromethyl group.

3. The compound according to claim 1, characterized in that R1, R4, R5, and R6 are each independently an alkyl group having 1 to 6 carbon atoms, and R2, R3, and R7 are hydrogen.

4. The compound according to claim 1, characterized in that R1, R4, R5, and R6 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, or n-hexyl, and R2, R3, and R7 are hydrogen.

5. Use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a singlet oxygen-releasing material.

6. Use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating cancer.

7. The use according to claim 6, characterized in that: The cancers are lung cancer, breast cancer, liver cancer, pancreatic cancer, colorectal cancer, ovarian cancer, prostate cancer, testicular cancer, nasopharyngeal cancer, esophageal cancer, malignant lymphoma, head and neck squamous cell carcinoma, thyroid cancer and osteosarcoma.

8. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

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