A fully conjugated bithiophene ligand and its preparation method, as well as a fully conjugated bithiophene metal complex and its preparation method and application

Abstract

The present invention relates to the technical field of research and development of photosensitizers for photodynamic therapy of tumors and photothermal agents for photothermal therapy, and provides a conjugated bithiophene ligand and a preparation method thereof, as well as a conjugated bithiophene metal complex and a preparation method and application thereof. The present invention is based on the conjugated bithiophene ligand dtdppz, and designs and invents its conjugated bithiophene ruthenium complex, conjugated bithiophene osmium complex and conjugated bithiophene iridium complex respectively. The conjugated bithiophene metal complex has extremely high stability and excellent two-photon absorption characteristics, has excellent biotoxicity and photothermal conversion ability under the action of infrared excitation light, and effectively inhibits the growth of melanoma in mice. The conjugated bithiophene metal complex provided by the present invention is a potential new infrared photodynamic photosensitizer and photothermal agent, and has broad application prospects in photodynamic therapy and photothermal therapy of tumors.

Description

Technical Field

[0001] The present invention relates to the technical field of research and development of photosensitizers for tumor photodynamic therapy and photothermal agents for photothermal therapy, and in particular to a conjugated bithiophene ligand and a preparation method thereof, as well as a conjugated bithiophene metal complex and a preparation method and application thereof. Background Art

[0002] Photodynamic therapy (PDT) is a new type of tumor treatment that emerged more than 40 years ago. It works by irradiating the lesion with a specific wavelength, activating the photosensitizer that selectively accumulates in the lesion tissue, and then triggering a photochemical reaction to destroy the lesion. In the new generation of PDT, the photosensitizer transfers energy to the surrounding oxygen, generating highly reactive singlet oxygen. 1 O2. Singlet oxygen 1 O2 can react with nearby biomacromolecules to produce cytotoxicity, thereby killing tumor cells. Compared with traditional cancer therapies, PDT has the advantage of being able to deliver precise and effective treatments with minimal side effects, thus attracting widespread attention and research.

[0003] Photothermal therapy (PTT) is an emerging non-invasive approach for treating localized tumors. This method uses photothermal conversion agents (PTAs) to convert near-infrared (NIR) light into heat for tumor cell ablation. This approach offers advantages such as minimal invasiveness to normal tissues, reduced side effects, and strong anti-tumor activity. To achieve optimal PTT therapeutic effects and effectively inhibit tumor growth after NIR irradiation, this approach can be regulated by reducing tissue scattering and absorption and enhancing the photothermal conversion efficiency of the light absorber.

[0004] Currently, transition metal platinum compounds, such as cisplatin, carboplatin, and oxaliplatin, remain the preferred drugs for clinical cancer treatment. However, these drugs suffer from side effects and drug resistance, which limits their potential application as anti-tumor agents. Therefore, there is an urgent need to design novel, low-toxic, and highly effective anti-tumor drugs. Within the research field of transition metal compounds, transition metal compounds such as ruthenium and osmium have attracted significant attention as potential anti-cancer agents. Furthermore, thiophene has been used to design and synthesize transition metal compounds with specific photophysical properties. Studies have shown that the efficacy of these compounds in in vitro photodynamic therapy is enhanced with the addition of thiophene to the compound structure.

[0005] Therefore, this patent invents a conjugated bithiophene metal complex based on the conjugated bithiophene ligand dtdppz. This complex not only exhibits extremely high stability and excellent two-photon absorption properties, but also produces excellent singlet oxygen, biotoxicity, and photothermal conversion capabilities under the action of infrared excitation light, effectively improving the efficiency of killing cancer cells. It is a potential new two-photon infrared photodynamic photosensitizer and photothermal agent. Summary of the Invention

[0006] In light of this, the present invention provides a conjugated bithiophene ligand and a method for preparing the same, as well as a conjugated bithiophene metal complex and its preparation method and application. The present invention provides a novel conjugated bithiophene ligand and, based on this ligand, a conjugated bithiophene metal complex. This complex exhibits excellent singlet oxygen yield, biotoxicity, and photothermal conversion capabilities, and has broad application prospects in the preparation of two-photon infrared photodynamic photosensitizers and photothermal agents for tumors.

[0007] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0008] A conjugated bithiophene ligand, the structural formula of which is shown in Formula I:

[0009]

[0010] A conjugated bithiophene metal complex is composed of anions and cations, wherein the structural formulas of the cations are shown in Formula II, Formula III, and Formula IV:

[0011]

[0012] In Formula II, represents the auxiliary ligand L1, and the auxiliary ligand L1 is any one of the ligands with the following structures:

[0013]

[0014]

[0015] In Formula II, represents the auxiliary ligand L2, and the auxiliary ligand L2 is any one of the ligands of the following structures:

[0016]

[0017]

[0018] In Formula IV, represents the auxiliary ligand L3, and the auxiliary ligand L3 is any one of the ligands of the following structures:

[0019]

[0020] The present invention also provides a method for preparing the conjugated bithiophene ruthenium complex described in the above scheme, comprising the following steps:

[0021] (i) mixing the auxiliary ligand L1, ruthenium trichloride, lithium chloride and an organic solvent to perform a first coordination reaction to obtain a precursor compound having a structure shown in formula d;

[0022]

[0023] (ii) mixing the precursor compound having the structure shown in formula d, the bithiophene ligand dtdppz and the solvent to perform a second coordination reaction to obtain an anion of Cl - A conjugated bithiophene ruthenium complex, wherein the cation structure of the conjugated bithiophene ruthenium complex is shown in Formula II.

[0024] Preferably, the molar ratio of the auxiliary ligand L1 to ruthenium trichloride is 2:1; and the molar ratio of the precursor compound having the structure shown in formula d to the bithiophene ligand dtdppz is 1:1.

[0025] Preferably, the solvent in step (ii) is an ethylene glycol-water mixed solvent.

[0026] Preferably, the temperature of the second coordination reaction in step (ii) is 80-180° C., and the time is 2-72 hours.

[0027] Preferably, in the step (ii), after the second coordination reaction is completed, the step further comprises adding an aqueous solution containing an anion compound to the obtained reaction solution to convert Cl in the conjugated bithiophene ruthenium complex into - Make a replacement.

[0028] The present invention also provides a method for preparing the conjugated bithiophene osmium complex described in the above scheme, comprising the following steps:

[0029] (i) mixing the auxiliary ligand L2, ammonium hexachloroosmate, and an organic solvent to perform a first coordination reaction to obtain a precursor compound having a structure shown in Formula e;

[0030]

[0031] (ii) mixing the precursor compound having the structure shown in formula e, the bithiophene ligand dtdppz and the solvent to perform a second coordination reaction to obtain an anion of Cl - A conjugated bithiophene osmium complex, wherein the cation structure of the conjugated bithiophene osmium complex is shown in Formula III.

[0032] Preferably, the molar ratio of the auxiliary ligand L2 to ammonium hexachloroosmate is 2:1; and the molar ratio of the precursor compound having the structure shown in formula e to the bithiophene ligand dtdppz is 1:1.

[0033] Preferably, the solvent in step (ii) is ethylene glycol or an ethylene glycol-water mixed solvent.

[0034] Preferably, the temperature of the second coordination reaction in step (ii) is 80-180° C., and the time is 2-72 hours.

[0035] Preferably, in the step (ii), after the second coordination reaction is completed, the step further comprises adding an aqueous solution containing an anion compound to the obtained reaction solution to convert the Cl - Make a replacement.

[0036] The present invention also provides a method for preparing the conjugated bithiophene iridium complex described in the above scheme, comprising the following steps:

[0037] (i) mixing the auxiliary ligand L3, iridium trichloride, and an organic solvent to perform a first coordination reaction to obtain a precursor compound having a structure shown in Formula VI;

[0038]

[0039] (ii) mixing the precursor compound having the structure shown in formula f, the bithiophene ligand dtdppz and the solvent to perform a second coordination reaction to obtain an anion of Cl - A conjugated bithiophene iridium complex, wherein the cationic structure of the conjugated bithiophene iridium complex is shown in Formula IV.

[0040] Preferably, the molar ratio of the auxiliary ligand L3 to iridium trichloride is 2:1; the molar ratio of the precursor compound having the structure shown in formula f to the bithiophene ligand dtdppz is 1:2.

[0041] Preferably, the solvent in step (ii) is a mixed solvent of methanol and dichloromethane.

[0042] Preferably, the temperature of the second coordination reaction in step (ii) is 30-80° C., and the time is 2-72 hours.

[0043] Preferably, in the step (ii), after the second coordination reaction is completed, the step further includes adding an aqueous solution containing an anion compound to the obtained reaction solution to convert Cl in the conjugated bithiophene metal iridium complex into - Make a replacement.

[0044] The present invention also provides the use of the conjugated bithiophene metal complex described in the above scheme in the preparation of photosensitizers and photothermal agents for tumor photodynamic therapy.

[0045] The present invention also provides a conjugated bithiophene metal complex composed of anions and cations, wherein the cations have structures shown in Formula II, Formula III, and Formula IV. Based on the bithiophene ligand dtdppz, the present invention designs and invents conjugated bithiophene metal complexes in which the cations have structures shown in Formula II, Formula III, and Formula IV. The conjugated bithiophene metal complexes have the following advantages: (1) extremely high stability; (2) when 808nm infrared light is used as the excitation light, they have excellent singlet oxygen yield, cytotoxicity, and photothermal conversion efficiency, and can effectively kill cancer cells. The conjugated bithiophene metal complex provided by the present invention has certain biological toxicity and photothermal conversion ability, and is a potential new type of two-photon infrared photodynamic photosensitizer and photothermal agent, with broad application prospects in photodynamic therapy and photothermal therapy of tumors.

[0046] The present invention also provides a method for preparing the conjugated bithiophene metal complex described in the above scheme. The preparation method provided by the present invention has simple steps and is easy to carry out industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The synthetic route of conjugated bithiophene ligand dtdppz is shown below;

[0048] Figure 2 The reaction formula for synthesizing the precursor compound [Ru(L)2Cl2] is shown below;

[0049] Figure 3 The reaction formula for synthesizing conjugated bithiophene ruthenium complexes is:

[0050] Figure 4 The reaction formula for synthesizing the precursor compound [Os(L)2Cl2] is shown below;

[0051] Figure 5 The reaction formula for synthesizing conjugated bithiophene osmium complexes is shown below:

[0052] Figure 6 The reaction formula for synthesizing the precursor compound [Ir2(L)4(μ-Cl)2] is shown below;

[0053] Figure 7 The reaction formula for synthesizing conjugated bithiophene iridium complexes is shown below;

[0054] Figure 8 The figure shows the change in ultraviolet absorption of singlet oxygen scavenger ABDA in the solution after irradiation with 400 / 450nm light in the presence of conjugated bithiophene metal complex.

[0055] Figure 9 This is the UV absorption change of the singlet oxygen scavenger ABDA in the solution after irradiation with 808nm laser in the presence of conjugated bithiophene metal complex;

[0056] Figure 10 The photothermal conversion diagrams of the conjugated bithiophene ruthenium complex prepared in the present invention and the control group PBS under 808nm infrared light irradiation for different times;

[0057] Figure 11 The photothermal conversion diagrams of the conjugated bithiophene osmium complex prepared in the present invention and the control group PBS under 808nm infrared light irradiation for different times;

[0058] Figure 12 The photothermal conversion diagrams of the conjugated bithiophene iridium complex prepared in the present invention and the control group PBS under 808nm infrared light irradiation for different times;

[0059] Figure 13 Real-time thermal imaging (a), tumor volume (b), and changes in mouse weight (c) during photodynamic therapy of melanoma mice treated with conjugated bithiophene ruthenium complex Ru7.

[0060] Figure 14 The real-time thermal imaging (a), tumor volume (b), and weight (c) changes of mice during photodynamic therapy of melanoma mice with conjugated bithiophene osmium complex Os2.

[0061] Figure 15 Real-time thermal imaging (a), tumor volume (b) and changes in mouse weight (c) during photodynamic therapy of melanoma mice with conjugated bithiophene iridium complex Ir2. DETAILED DESCRIPTION

[0062] The present invention provides a conjugated bithiophene ligand, characterized in that the structural formula is as shown in Formula I:

[0063]

[0064] The present invention also provides a method for preparing the conjugated bithiophene ligand described in the above scheme, comprising the following steps:

[0065] (1) mixing a compound having a structure represented by formula a, oxalyl chloride, and an organic solvent to react to obtain a compound having a structure represented by formula b;

[0066]

[0067] (2) mixing the compound having the structure shown in formula b, the compound having the structure shown in formula c, and an organic solvent to carry out a condensation reaction to obtain a conjugated bithiophene ligand having the structure shown in formula I.

[0068]

[0069] In the present invention, the synthesis route of the conjugated bithiophene ligand having the structure shown in Formula I is as follows: Figure 1 As shown below, combined Figure 1 Provide detailed explanation.

[0070] The present invention comprises reacting a compound having a structure represented by formula a, oxalyl chloride and an organic solvent to obtain a compound having a structure represented by formula b. In the present invention, the chemical name of the compound having a structure represented by formula a is 3,3'-bithiophene.

[0071] In the present invention, the method for synthesizing the compound having the structure shown in formula a preferably comprises the following steps: 3-bromothiophene (structural formula shown in Figure 1 ), 3-thiophene boronic acid (structural formula see Figure 1 ), tetrakis(triphenylphosphine)palladium, an aqueous potassium carbonate solution, and an organic solvent are mixed and reacted to obtain a compound having the structure shown in Formula a. In the present invention, the organic solvent is preferably tetrahydrofuran; the molar ratio of 3-bromothiophene to 3-thiopheneboronic acid is preferably 1:1; the reaction is preferably carried out under reflux conditions, and the reaction time is preferably 12 to 36 hours; the reaction is preferably carried out under argon protection conditions. In a specific embodiment of the present invention, 3-bromothiophene, 3-thiopheneboronic acid, and an aqueous potassium carbonate solution are preferably added to the organic solvent, and then tetrakis(triphenylphosphine)palladium is added under argon protection and refluxed for 24 hours. After the reaction is completed, the present invention preferably cools the reaction solution to room temperature, then adds a saturated aqueous sodium chloride solution, extracts with dichloromethane, and the collected organic phase is dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain a crude product, which is purified on a silica gel column to obtain a compound having the structure shown in Formula a. In the present invention, the eluent for silica gel column purification is preferably petroleum ether.

[0072] After obtaining the compound having the structure represented by Formula a, the present invention mixes the compound having the structure represented by Formula a, oxalyl chloride, and an organic solvent for reaction to obtain a compound having the structure represented by Formula b. In the present invention, the organic solvent for the reaction is preferably dichloroethane; the amount ratio of the compound having the structure represented by Formula a to oxalyl chloride is preferably 12.0 mmol:3-5 mL; the reaction temperature is preferably 60-140° C., and the reaction time is preferably 1-5 days; in a specific embodiment of the present invention, the reaction is preferably carried out under reflux conditions.

[0073] In the present invention, the obtained reaction solution is preferably cooled, filtered, washed and vacuum dried in sequence, and the obtained crude product is directly subjected to the next reaction without further treatment.

[0074] After obtaining the compound having the structure shown in Formula b, the present invention mixes the compound having the structure shown in Formula b, the compound having the structure shown in Formula c (chemical name: 5,6-diaminophenanthroline) and an organic solvent to carry out a condensation reaction to obtain a compound having the structure shown in Formula I. In the present invention, the organic solvent used in the condensation reaction is preferably acetic acid; the molar ratio of the compound having the structure shown in Formula c to the compound having the structure shown in Formula b is preferably 1:1.

[0075] The present invention has no special requirements for the preparation method of the compound having the structure shown in formula c, and a method well known to those skilled in the art can be used. In a specific embodiment of the present invention, the preparation method of the compound having the structure shown in formula c preferably includes the following steps: mixing 1,10-o-phenanthroline, concentrated nitric acid and concentrated sulfuric acid to perform reaction a to obtain 5-nitro-1,10-o-phenanthroline, then performing reaction b with hydroxylamine hydrochloride, potassium hydroxide and ethanol to obtain 5-amino-6-nitro-o-phenanthroline, and finally performing reaction c with hydrazine hydrate, palladium carbon and anhydrous ethanol to obtain a compound having the structure shown in formula c; in the present invention, the amount ratio of the 1,10-o-phenanthroline, concentrated nitric acid and concentrated sulfuric acid is preferably 27.7mmol:30mL:15mL; the temperature of the reaction a is preferably 150°C, and the time is preferably 1 to 3h; the temperature of the reaction b is preferably 90°C, and the time is preferably 0.5 to 1h; the temperature of the reaction c is preferably 90°C, and the time is preferably 1 to 3h. After the reaction is completed, the obtained reaction solution is cooled and added into petroleum ether, and then filtered, washed and dried to obtain 5,6-diaminophenanthroline.

[0076] After obtaining the compound having the structure represented by Formula C, the present invention mixes the compound having the structure represented by Formula C with the compound having the structure represented by Formula B and an organic solvent to carry out a condensation reaction to obtain a conjugated bithiophene ligand having the structure represented by Formula I. In the present invention, the organic solvent used in the condensation reaction is preferably acetic acid, and the molar ratio of the compound having the structure represented by Formula C to the compound having the structure represented by Formula B is preferably 1:1. The condensation reaction temperature is preferably 80-120°C, and the reaction time is preferably 1-8 hours, more preferably 4-5 hours. In a specific embodiment of the present invention, the condensation reaction is preferably carried out under reflux conditions. After completion of the reaction, the present invention preferably cools the resulting reaction solution to room temperature, then sequentially filters, washes with water, ethanol, and diethyl ether, and then dries to obtain a conjugated bithiophene ligand having the structure represented by Formula I (denoted as dtdppz).

[0077] The present invention also provides a conjugated bithiophene metal complex composed of anions and cations, wherein the structural formulas of the cations are shown in Formula II, Formula III, and Formula IV:

[0078]

[0079] In Formula II, represents the auxiliary ligand L1, and the auxiliary ligand L1 is any one of the ligands with the following structures:

[0080]

[0081]

[0082] In Formula II, represents the auxiliary ligand L2, and the auxiliary ligand L2 is any one of the ligands of the following structures:

[0083]

[0084]

[0085] In Formula IV, represents the auxiliary ligand L3, and the auxiliary ligand L3 is any one of the ligands of the following structures:

[0086]

[0087] In the present invention, the chemical names of the auxiliary ligands L1 are: 2,2'-bipyridine (bpy), 4,4'-dimethylbipyridine (dmbpy), 4,4'-di-tert-butyl-2,2'-bipyridine (tbubpy), 1,10-phenanthroline (phen), 2,9-dimethyl-1,10-phenanthroline (dmp), 3,4,7,8-tetramethyl-1,10-phenanthroline (tmp) and 4,7-diphenyl-1,10-phenanthroline (dip); the chemical names of the auxiliary ligands L2 are: The chemical names of the auxiliary ligands L3 are: 2-phenylpyridine (ppy) and 2-(2,4-difluorophenyl)pyridine (Fppy). The present invention has no special requirements on the source of the auxiliary ligands. The commercially available ligands can be used or they can be synthesized by methods well known to those skilled in the art.

[0088] The present invention has no special requirements for the anions in the conjugated bithiophene metal complex. Conventional anions in the art can achieve the purpose of the present invention. In a specific embodiment of the present invention, the anions are preferably inorganic salt anions, more preferably PF6 - 、ClO4 - or Cl - PF6 is the most preferred - .

[0089] The present invention also provides a method for preparing the conjugated bithiophene ruthenium complex described in the above scheme, comprising the following steps:

[0090] (i) mixing an auxiliary ligand L1, ruthenium trichloride, lithium chloride, and an organic solvent to perform a first coordination reaction to obtain a precursor compound having a structure shown in formula d;

[0091]

[0092] (ii) mixing the precursor compound having the structure shown in formula d, the conjugated bithiophene ligand having the structure shown in formula I and a solvent to carry out a second coordination reaction to obtain an anion of Cl - A conjugated bithiophene ruthenium complex, wherein the cation structure of the conjugated bithiophene ruthenium complex is shown in Formula II.

[0093] The present invention combines an auxiliary ligand L1, ruthenium trichloride, lithium chloride, and an organic solvent for a first coordination reaction to obtain a precursor compound having the structure shown in Formula d. In the present invention, the molar ratio of the auxiliary ligand L1 to ruthenium trichloride is preferably 2:1; the molar ratio of the lithium chloride to ruthenium trichloride is preferably 14:3; the organic solvent used in the coordination reaction is preferably N,N'-dimethylformamide; the temperature of the coordination reaction is preferably 140°C, and the duration is preferably 8 hours; and the first coordination reaction is preferably carried out under argon protection. After completion of the reaction, the present invention cools the resulting reaction solution to room temperature, adds acetone, and then freezes it overnight. The solution is then filtered, washed, and vacuum-dried to obtain the precursor compound [Ru(L1)2Cl2] having the structure shown in Formula d.

[0094] In the present invention, the chemical reaction formula for preparing the precursor compound [Ru(L1)2Cl2] is as follows: Figure 2 shown.

[0095] After obtaining the precursor compound having the structure shown in formula d, the present invention mixes the precursor compound having the structure shown in formula d, the conjugated bithiophene ligand having the structure shown in formula I and a solvent to perform a second coordination reaction to obtain an anion of Cl - A conjugated bithiophene ruthenium complex, wherein the cationic structure of the conjugated bithiophene ruthenium complex is shown in Formula II. In the present invention, the molar ratio of the precursor compound having the structure shown in Formula d to the conjugated bithiophene ligand having the structure shown in Formula I is preferably 1:1; the solvent is preferably an ethylene glycol-water mixed solvent; the volume ratio of ethylene glycol to water in the ethylene glycol-water mixed solvent is preferably 20:1; the temperature of the second coordination reaction is preferably 80-180°C, more preferably 130-140°C, and the time of the coordination reaction is preferably 2-72 hours, more preferably 6-12 hours; the second coordination reaction is preferably carried out under argon protection.

[0096] In the present invention, the reaction formula for preparing the conjugated bithiophene osmium complex is as follows: Figure 3 shown.

[0097] The present invention also provides a method for preparing the conjugated bithiophene osmium complex described in the above scheme, comprising the following steps:

[0098] (i) mixing the auxiliary ligand L2, ammonium hexachloroosmate, and an organic solvent to perform a first coordination reaction to obtain a precursor compound having a structure shown in Formula e;

[0099]

[0100] (ii) mixing the precursor compound having the structure shown in formula e, the conjugated bithiophene ligand having the structure shown in formula I and a solvent to carry out a second coordination reaction to obtain an anion of Cl - A conjugated bithiophene osmium complex, wherein the cation structure of the conjugated bithiophene osmium complex is shown in Formula III.

[0101] The present invention combines an auxiliary ligand L2, ammonium hexachloroosmate, and an organic solvent to perform a first coordination reaction, thereby obtaining a precursor compound having the structure shown in Formula e. In the present invention, the molar ratio of the auxiliary ligand L2 to ammonium hexachloroosmate is preferably 2:1; the organic solvent used in the coordination reaction is preferably ethylene glycol; the temperature of the coordination reaction is preferably 140°C, and the time is preferably 1.5 hours; the first coordination reaction is preferably carried out under argon protection. After the reaction is completed, the present invention cools the resulting reaction solution to room temperature, adds a saturated aqueous solution of sodium dithionite, and maintains it in an ice bath for 0.5 hours. The reaction is then filtered, washed, and vacuum-dried to obtain a precursor compound having the structure shown in Formula e [Os(L2)2Cl2].

[0102] In the present invention, the chemical reaction formula for preparing the precursor compound [Os(L2)2Cl2] is as follows Figure 4 shown.

[0103] After obtaining the precursor compound having the structure shown in formula e, the present invention mixes the precursor compound having the structure shown in formula e, the conjugated bithiophene ligand having the structure shown in formula I and a solvent to perform a second coordination reaction to obtain an anion of Cl -A conjugated bithiophene osmium complex having a cationic structure as shown in Formula III. In the present invention, the molar ratio of the precursor compound having the structure shown in Formula e to the conjugated bithiophene ligand having the structure shown in Formula I is preferably 1:1; the solvent is preferably an ethylene glycol-water mixed solvent; the volume ratio of ethylene glycol to water in the ethylene glycol-water mixed solvent is preferably 20:1; the temperature of the second coordination reaction is preferably 80 to 180°C, more preferably 130 to 140°C, and the time of the coordination reaction is preferably 2 to 72 hours, more preferably 6 to 12 hours; the second coordination reaction is preferably carried out under argon protection.

[0104] In the present invention, the reaction formula for preparing the conjugated bithiophene osmium complex is as follows: Figure 5 shown.

[0105] The present invention also provides a method for preparing the conjugated bithiophene iridium complex described in the above scheme, comprising the following steps:

[0106] (i) mixing the auxiliary ligand L3, iridium trichloride and an organic solvent to perform a first coordination reaction to obtain a precursor compound having a structure shown in Formula f;

[0107]

[0108] (ii) mixing the precursor compound having the structure shown in formula f, the conjugated bithiophene ligand having the structure shown in formula I and a solvent to carry out a second coordination reaction to obtain an anion of Cl - A conjugated bithiophene iridium complex, wherein the cationic structure of the conjugated bithiophene iridium complex is shown in Formula IV.

[0109] In the present invention, an auxiliary ligand L3, iridium trichloride, and an organic solvent are mixed to perform a first coordination reaction to obtain a precursor compound having the structure shown in Formula e. In the present invention, the molar ratio of the auxiliary ligand L3 to iridium trichloride is preferably 2:1; the organic solvent used in the coordination reaction is preferably ethylene glycol ethyl ether; the coordination reaction temperature is preferably 110°C and the reaction time is preferably 2 days; and the first coordination reaction is preferably carried out under argon protection. After the reaction is completed, the resulting reaction solution is cooled to room temperature and then filtered, washed, and vacuum dried to obtain the precursor compound [Ir2(L3)4(μ-Cl)2] having the structure shown in Formula e.

[0110] In the present invention, the chemical reaction formula for preparing the precursor compound [Ir2(L3)4(μ-Cl)2] is as follows Figure 6 shown.

[0111] After obtaining the precursor compound having the structure shown in formula e, the present invention mixes the precursor compound having the structure shown in formula e, the conjugated bithiophene ligand having the structure shown in formula I and a solvent to perform a second coordination reaction to obtain an anion of Cl - A conjugated bithiophene iridium complex, wherein the cationic structure of the conjugated bithiophene iridium complex is shown in Formula IV. In the present invention, the molar ratio of the precursor compound having the structure shown in Formula e to the conjugated bithiophene ligand having the structure shown in Formula I is preferably 1:2; the solvent is preferably a methanol-dichloromethane mixed solvent; the volume ratio of methanol and dichloromethane in the methanol-dichloromethane mixed solvent is preferably 1:1; the temperature of the second coordination reaction is preferably 30 to 80°C, more preferably 50 to 60°C, and the time of the coordination reaction is preferably 2 to 72 hours, more preferably 14 to 18 hours; the second coordination reaction is preferably carried out under argon protection conditions.

[0112] In the present invention, the reaction formula for preparing the conjugated bithiophene iridium complex is as follows: Figure 7 shown.

[0113] After the coordination reaction is completed, the post-treatment is carried out directly to obtain the anion Cl - Conjugated bithiophene ruthenium complex, conjugated bithiophene osmium complex and conjugated bithiophene iridium complex; In a specific embodiment of the present invention, when the target product is a conjugated bithiophene metal complex of other anions, it is also preferred to add an aqueous solution containing an anion compound to the obtained reaction solution, and the Cl in the conjugated bithiophene metal complex is - Replacement, and then post-treatment; the anion in the aqueous solution containing the anion compound is preferably PF6 - or ClO4 - In a specific embodiment of the present invention, the aqueous solution containing an anionic compound is preferably a saturated aqueous solution of ammonium hexafluorophosphate; after adding the aqueous solution containing an anionic compound, it is preferably allowed to stand for 0.5 hours before post-treatment.

[0114] In the present invention, the post-treatment method is preferably: for conjugated bithiophene ruthenium complex and conjugated bithiophene osmium complex, the obtained reaction solution is filtered, washed and vacuum dried in sequence to obtain a crude product, and the crude product is subjected to alumina column chromatography to obtain the corresponding conjugated bithiophene ruthenium complex and conjugated bithiophene osmium complex; for conjugated bithiophene iridium complex, the obtained reaction solution is filtered, washed and vacuum dried in sequence to obtain a crude product, and the crude product is subjected to silica gel column chromatography to obtain the corresponding conjugated bithiophene iridium complex; in the present invention, the eluent for alumina column chromatography is preferably a toluene-acetonitrile mixed solvent, and the volume ratio of toluene and acetonitrile in the toluene-acetonitrile mixed solvent is preferably 2:1 to 1:3; in the present invention, the eluent for silica gel column chromatography is preferably a methanol-dichloromethane mixed solvent, and the volume ratio of methanol and dichloromethane in the methanol-dichloromethane mixed solvent is preferably 10:1 to 1:1.

[0115] The present invention also provides the use of the conjugated bithiophene metal complex described in the above scheme in the preparation of infrared photodynamic therapy photosensitizers and photothermal agents for tumors. In the present invention, the tumor is preferably a melanoma. The conjugated bithiophene metal complex provided by the present invention not only has excellent two-photon absorption properties and excellent singlet oxygen yield, but also exhibits high phototoxicity and low dark toxicity towards melanoma cells, making it a potential new type of two-photon infrared photodynamic photosensitizer. Furthermore, the conjugated bithiophene metal complex provided by the present invention also has excellent photothermal conversion efficiency under infrared excitation light, making it a potential new type of infrared photothermal agent.

[0116] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions of the present invention. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0117] Example 1

[0118] The preparation of conjugated bithiophene ligand dtdppz is as follows:

[0119] (1) Weigh 5.0 g (27.7 mmol) of 1,10-phenanthroline, 30 mL of concentrated H2SO4, and 15 mL of concentrated HNO3 into a flask, reflux at 150°C for 2 h, cool, pour into a beaker containing 500 mL of ice water, and adjust the pH to neutral. Filter, wash, and vacuum dry to obtain a light yellow solid, 5-nitro-1,10-phenanthroline, with a yield of 4.4 g and a yield of 70%. Then, 2.0 g (9.0 mmol) of 5-nitro-1,10-phenanthroline and ethanol were weighed into a flask and heated under reflux at 90°C until the precipitate was completely dissolved. Then, 4.0 g (60.0 mmol) of hydroxylamine hydrochloride was added, and a large amount of yellow precipitate was produced. At the same time, an ethanol solution containing 4.5 g of KOH was slowly added dropwise, and reflux was continued for 0.5 h. After cooling, the solution was poured into a beaker containing 600 mL of ice water and allowed to stand overnight. The solution was filtered, washed, and vacuum dried to obtain a brown-yellow solid, namely 5-amino-6-nitro-phenanthroline, with a yield of 1.1 g and a yield of 48%. Finally, 0.408 g (1.7 mmol) of 5-amino-6-nitro-o-phenanthroline and 400 mL of anhydrous ethanol were weighed into a flask. The temperature was raised to 90°C, and 0.2 g (1.9 mmol) of Pd / C and 8 mL of hydrazine hydrate were added. After refluxing for 1 h, the mixture was filtered while hot and 400 mL of petroleum ether was added. The mixture was filtered, washed, and dried in vacuo to obtain a light yellow flocculent precipitate, namely 5,6-diamino-o-phenanthroline, with a yield of 0.256 g and a yield of 73%.

[0120] (2) 1.63 g (10.0 mmol) of 3-bromothiophene, 1.54 g (12.0 mmol) of 3-thiopheneboronic acid, 25 mL of THF, and 10 mL of a 2M aqueous solution containing 2.76 g of K2CO3 were weighed into a flask. Under an Ar atmosphere, 0.081 g of [Pd(Pph3)4] was quickly added. The mixture was heated to reflux at 80°C for 24 h. After cooling, 30 mL of a NaCl aqueous solution was added. The mixture was extracted three times with CH2Cl2. The organic phase was collected and dried overnight with anhydrous Na2SO4. The mixture was filtered and evaporated to dryness under reduced pressure. The crude product was purified on a silica gel column to obtain a white solid, 3,3'-bithiophene, with a yield of 1.38 g and a yield of 83%. Weigh 2.0 g (12.0 mmol) of 3,3'-bithiophene, 35 mL of 1,2-dichloroethane, and 4.2 mL of oxalyl chloride into a flask and heat under reflux at 80°C for 3 days. After cooling, filter, wash, and vacuum dry to obtain a red solid, namely benzo[1,2-b:4,3-b′]bithiophene-4,5-dione, with a yield of 1.872 g and a yield of 71%.

[0121] (3) Weigh 0.210 g (1.0 mmol) of 5,6-diaminophenanthroline, 0.264 g (1.2 mmol) of benzo[1,2-b:4,3-b′]bithiophene-4,5-dione, and 20 mL of glacial acetic acid in a 50 mL flask. Heat and reflux at 100°C for 2 h. The reaction solution turns brown and a large amount of precipitate is precipitated. After cooling, the solution is filtered, washed, and vacuum-dried to obtain a brown solid, which is the bithiophene ligand dtdppz. The yield is 0.230 g, and the yield is 81%.

[0122] Example 2

[0123] Synthesis method of precursor compound [Ru(bpy)2Cl2]:

[0124] 1.56 g (6 mmol) of ruthenium trichloride, 1.87 g (12 mmol) of auxiliary ligand bpy (2,2'-bipyridine), and 1.68 g (28 mmol) of lithium chloride were weighed into a two-necked flask, and 20 mL of N,N'-dimethylformamide was added. The mixture was heated to reflux at 140°C under argon for 8 h. After cooling to room temperature, 50 mL of acetone was added, and the mixture was frozen overnight. The mixture was filtered, washed, and vacuum-dried to obtain a purple-black solid, which was the precursor compound [Ru(bpy)2Cl2], with a yield of 1.12 g and a yield rate of 39%.

[0125] The auxiliary ligand bpy in the above scheme was replaced by dmbpy (4,4'-dimethylbipyridine), tbubpy (4,4'-di-tert-butyl-2,2'-bipyridine), phen (1,10-phenanthroline), dmp (2,9-dimethyl-1,10-phenanthroline), tmp (3,4,7,8-tetramethyl-1,10-phenanthroline) and dip (4,7-diphenyl-1,10-phenanthroline), respectively. The other conditions were the same as the above scheme, and the precursor compounds [Ru(dmbpy)2Cl2], [Ru(tbubpy)2Cl2], [Ru(phen)2Cl2], [Ru(dmp)2Cl2], [Ru(tmp)2Cl2] and [Ru(dip)2Cl2] were obtained respectively.

[0126] Example 3

[0127] Synthesis of conjugated bithiophene ruthenium complex Ru1:

[0128] 0.063 g (0.16 mmol) of the ligand dtdppz and 0.058 g (0.12 mmol) of the precursor [Ru(bpy)2Cl2] were weighed into a two-necked flask, and 6 mL of ethylene glycol and 1 mL of water were added. The mixture was stirred and refluxed at 140°C under argon for more than 12 h. After cooling to room temperature, 12 mL of water and a saturated aqueous solution of ammonium hexafluorophosphate were added. The mixture was allowed to stand for 0.5 h, filtered, washed, and dried in vacuo. The resulting black crude product was chromatographed on an alumina column using toluene:acetonitrile (1:2, v:v) as the eluent. The red component was collected to obtain the conjugated bithiophene ruthenium complex Ru1 with a yield of 0.086 g and a yield of 66%. 1 HNMR(400MHz,DMSO-d6)δ(ppm):9.60(d,J=8.2Hz,2H),8.90(dd,J=8.2,3.8Hz,4H),8 .31(d,J=5.2Hz,2H),8.29(d,J=5.6Hz,2H),8.22(d,J=8.0Hz,2H),8.20(d,J=5.0Hz, 2H),8.14(t,J=7.8Hz,2H),8.07(t,J=7.6Hz,2H),7.87(d,J=5.4Hz,2H),7.82(d,J=5 .4Hz,2H),7.61(t,J=6.8Hz,2H),7.40(t,J=6.4Hz,2H).HR-MS(MeOH,m / z):[M-2PF6] 2+ Calculated:(C 42 H 26 N8RuS2)404.0380; Found:404.0377.

[0129] Synthesis of conjugated bithiophene ruthenium complex Ru2:

[0130] The preparation steps are the same as Ru1, except that the precursor [Ru(bpy)2Cl2] is replaced by [Ru(dmbpy)2Cl2] 0.065 g (0.12 mmol). The other steps and operating conditions remain unchanged. The Ru2 yield is 0.032 g, with a yield of 23%. 1H NMR (400MHz, DMSO-d6) δ (ppm): 9.62 (d, J = 8.0, Hz, 2H), 8.77 (d, J = 14.2Hz, 4H), 8. 40(d,J=5.0Hz,2H),8.27(dd,J=5.4,1.0Hz,2H),8.24(d,J=5.0Hz,2H),8.06(dd,J =13.8,3.0Hz,2H),7.68(d,J=6.0Hz,2H),7.56(d,J=5.8Hz,2H),7.44(d,J=5.0Hz, 2H),7.21(d,J=5.2Hz,2H),2.57(s,6H),2.47(s,6H).HR-MS(MeOH,m / z):[M-2PF6] 2+ Calculated:(C 46 H 34 N8RuS2)432.0690; Found:432.0692.

[0131] Synthesis of conjugated bithiophene ruthenium complex Ru3:

[0132] The preparation steps are the same as Ru1, except that the precursor [Ru(bpy)2Cl2] is replaced by [Ru(tbubpy)2Cl2] 0.085 g (0.12 mmol). The other steps and operating conditions remain unchanged. The yield of Ru3 is 0.066 g, with a yield of 42%. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.65(d,J=8.0Hz,2H),8.90(dd,J=12.4,2.0Hz,4H),8 .36(d,J=5.0Hz,2H),8.24(d,J=5.4Hz,2H),8.19(dd,J=5.4,1.0Hz,2H),8.10(dd,J=1 3.4,2.8Hz,2H),7.70(d,J=6.0Hz,2H),7.68(d,J=2.0Hz,2H),7.65(d,J=2.0Hz,2H), 7.36(dd,J=6.0,1.8Hz,2H),1.45(s,18H),1.35(s,18H).HR-MS(MeOH,m / z):[M-2PF6] 2+ Calculated:(C 58 H 58 N8RuS2)516.1625; Found:516.1629.

[0133] Synthesis of conjugated bithiophene ruthenium complex Ru4:

[0134] The preparation steps are the same as Ru1, except that the precursor [Ru(bpy)2Cl2] is replaced by [Ru(phen)2Cl2] 0.064 g (0.12 mmol). The other steps and operating conditions remain unchanged. The yield of Ru4 is 0.046 g, with a yield of 33%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.60 (d, J = 8.4Hz, 2H), 8.82 (dd, J = 8.2, 3.0, Hz, 4H), 8.41 (s, 4H), 8.37 (t, J = 3.4Hz, 2H), 8.30 (d, J = 5.4H z,2H),8.22(t,J=5.8Hz,4H),8.11(td,J=5.2,1.0Hz,2H),7.94(dd,J=8.4,5.4Hz,2H),7.84-7.75(m,4H).HR-MS(MeOH,m / z):[M-2PF6] 2+ Calculated:(C 46 H 26 N8RuS2)428.0374; Found:428.0377.

[0135] Synthesis of conjugated bithiophene ruthenium complex Ru5:

[0136] The preparation steps are the same as Ru1, except that the precursor [Ru(bpy)2Cl2] is replaced by [Ru(dmp)2Cl2] 0.070 g (0.12 mmol). The other steps and operating conditions remain unchanged. The yield of Ru5 is 0.026 g, with a yield of 18%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.50 (d, J = 1.2Hz, 2H), 8.93 (d, J = 8.4Hz, 2H), 8.44 (t, J = 8.6Hz, 4H), 8.37 (d, J = 5.2Hz, 2H), 8.26 (t, J = 9.8Hz, 4H), 8.00 (d ,J=8.4Hz,2H),7.67(dd,J=13.6,2.6Hz,2H),7.56(dd,J=5.6,1.2Hz,2H),7 .41(d,J=8.6Hz,2H),1.96(s,6H),1.84(s,6H).HR-MS(MeOH,m / z):[M-2PF6] 2+ Calculated:(C 46 H 34 N8RuS2)456.0689; Found:456.0690.

[0137] Synthesis of conjugated bithiophene ruthenium complex Ru6:

[0138] The preparation steps are the same as Ru1, except that the precursor [Ru(bpy)2Cl2] is replaced by [Ru(tmp)2Cl2] 0.074 g (0.12 mmol). The other steps and operating conditions remain unchanged. The yield of Ru6 is 0.054 g, with a yield of 30%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.60 (d, J = 8.0, Hz, 2H), 8.51 (s, 4H), 8.42 (d, J = 5.2Hz, 2H), 8.26 (d, J = 5.2Hz, 2H), 8.14 (dd, J = 5.6, 1.0Hz, 2H ),7.95(dd,J=13.6,2.8Hz,2H),7.88(s,2H),7.76(s,2H),2.80(s,6H),2.78(s,6H),2.26(s,6H),2.23(s,6H).HR-MS(MeOH,m / z):[M-2PF6] 2+ Calculated:(C 54 H 42 N8RuS2)484.1000; Found:484.1003.

[0139] Synthesis of conjugated bithiophene ruthenium complex Ru7:

[0140] The preparation steps are the same as Ru1, except that the precursor [Ru(bpy)2Cl2] is replaced by [Ru(dip)2Cl2] 0.105 g (0.12 mmol). The other steps and operating conditions remain unchanged. The yield of Ru7 is 0.118 g, with a yield of 68%. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.73(d,J=8.2Hz,2H),8.43(d,J=5.2Hz,2H),8 .38(d,J=5.2Hz,4H),8.28(d,J=4.9Hz,4H),8.10–8.07(m,2H),7.86(dd,J=11. 3,6.6Hz,4H),7.80(d,J=5.5Hz,2H),7.75(d,J=8.3Hz,2H),7.69(d,J=6.6Hz, 8H),7.64(t,J=4.1Hz,8H),7.59(d,J=5.9Hz,4H).HR-MS(MeOH,m / z):[M-2PF6] 2+ Calculated:(C 70 H 42 N8RuS2)580.1003; Found:580.1007.

[0141] Example 4

[0142] Synthesis method of precursor compound [Os(bpy)2Cl2]:

[0143] 0.220 g (0.5 mmol) of ammonium hexachloroosmate and 0.172 g (1.1 mmol) of the auxiliary ligand bpy (2,2'-bipyridine) were weighed and added to a two-necked flask. 10 mL of ethylene glycol was added, and the mixture was refluxed at 120°C under argon for 1 h. After cooling to room temperature, 10 mL of a saturated aqueous solution of sodium dithionite was added and the mixture was kept in an ice bath for 0.5 h. The mixture was filtered, washed, and vacuum-dried to obtain a purple-black solid, which was the precursor compound [Os(bpy)2Cl2], with a yield of 0.236 g and a yield of 77%.

[0144] The auxiliary ligand bpy in the above scheme was replaced by tbubpy (4,4'-di-tert-butyl-2,2'-bipyridine), phen (1,10-phenanthroline) and dip (4,7-diphenyl-1,10-phenanthroline), respectively. The other conditions were the same as the above scheme to obtain the precursor compounds [Os(tbubpy)2Cl2], [Os(phen)2Cl2] and [Os(dip)2Cl2], respectively.

[0145] Example 5

[0146] Synthesis of conjugated bithiophene osmium complex Os1:

[0147] 0.079 g (0.2 mmol) of the ligand dtdppz and 0.109 g (0.19 mmol) of the precursor [Os(bpy)2Cl2] were weighed into a two-necked flask, and 6 mL of ethylene glycol and 1 mL of water were added. The mixture was stirred and refluxed at 150°C under argon for more than 24 h. After cooling to room temperature, 12 mL of water and a saturated aqueous solution of ammonium hexafluorophosphate were added. The mixture was allowed to stand for 0.5 h, filtered, washed, and dried in vacuo. The resulting dark green crude product was chromatographed on an alumina column using toluene:acetonitrile (1:1, v:v) as the eluent. The dark green component was collected to obtain the bithiophene mononuclear osmium complex Os1 with a yield of 0.086 g and a yield of 46%. 1H NMR (400MHz, DMSO-d6) δ (ppm): 9.47 (dd, J = 7.4Hz, 2H), 8.88 (td, J = 14.4, 8.3Hz, 4H), 8.43 (d, J=5.2Hz,2H),8.30(d,J=5.2Hz,2H),8.21(dd,J=7.4Hz,2H),8.05(td,J=8.1,5.4Hz,2H),8.0 0(td,J=8.1,5.7Hz,2H),7.95(td,J=8.2,5.7Hz,2H),7.77(d,J=5.5Hz,2H),7.66(d,J=6.1Hz ,2H),7.53(td,J=9.1,4.2Hz,2H),7.28(td,J=8.0,7.1Hz,2H).ESI-MS(MeOH,m / z):[M-2PF6] 2+ Calculated:(C 42 H 26 N8OsS2)449.07;Found:449.19.

[0148] Synthesis of conjugated bithiophene osmium complex Os2:

[0149] The preparation steps were the same as those for Os1, except that the precursor [Os(bpy)2Cl2] was replaced with [Os(tbubpy)2Cl2] 0.155 g (0.19 mmol). The remaining steps and operations remained unchanged. The yield of Os2 was 0.035 g, with a yield of 13%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.44 (d, J = 8.2 Hz, 2H), 8.87 (d, J = 15.6 Hz, 4H), 8.42 ( d,J=5.1Hz,2H),8.29(d,J=5.2Hz,2H),8.15(d,J=5.3Hz,2H),8.01(td,J=7.8,5.3H z,2H),7.60(d,J=7.8Hz,2H),7.57(dd,J=8.1,7.4Hz,2H),7.53(d,J=6.2Hz,2H),7. 27(dd,J=7.3,6.8Hz,2H),1.45(s,18H),1.35(s,18H).ESI-MS(MeOH,m / z):[M-2PF6] 2+ Calculated:(C 58 H 58 N8OsS2)561.19;Found:561.16.

[0150] Synthesis of conjugated bithiophene osmium complex Os3:

[0151] The preparation steps were the same as those for complex Os1, except that the precursor [Os(bpy)2Cl2] was replaced by [Os(phen)2Cl2] 0.118 g (0.19 mmol). The remaining steps and operations remained unchanged. The yield of Os3 was 0.082 g, with a yield of 35%. 1 H NMR(400MHz, DMSO-d6)δ(ppm):9.41(t,J=8.2Hz,2H),8.59(td,J=8.2,7.8Hz,4H),8.40(t,J=11.4Hz,6H),8.30(t,J=7.6Hz,2H),8.20(d,J=4.1Hz,2H) ,8.16(d,J=5.4Hz,2H),8.01(t,J=4.8Hz,2H),7.86(td,J=8.1,7.9Hz,2H), 7.75(t,J=6.6Hz,2H),7.73(d,J=7.6Hz,2H).ESI-MS(MeOH,m / z):[M-2PF6] 2+ Calculated:(C 46 H 26 N8OsS2)473.07;Found:473.03.

[0152] Synthesis of conjugated bithiophene osmium complex Os4:

[0153] The preparation steps were the same as those for complex Os1, except that the precursor [Os(bpy)2Cl2] was replaced by [Os(dip)2Cl2] 0.183 g (0.19 mmol). The remaining steps and operations remained unchanged. The yield of Os4 was 0.105 g, with a yield of 36%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.55 (d, J = 8.1Hz, 2H), 8.46 (d, J = 4.0Hz, 2H), 8.35 (t, J = 10.9Hz, 12H), 8.04 (d, J = 8.9Hz, 2H) ,7.83(d,J=4.9Hz,2H),7.77(d,J=6.9Hz,2H),7.70(d,J=9.2Hz,18H),7.67(d,J=8.9Hz,2H).ESI-MS(MeOH,m / z):[M-2PF6] 2+ Calculated:(C 70 H 42 N8OsS2)625.13;Found:625.21.

[0154] Example 6

[0155] Synthesis method of precursor compound [Ir2(ppy)4(μ-Cl)2]:

[0156] Weigh 0.597 g (2.0 mmol) of iridium trichloride and 0.775 g (5.0 mmol) of auxiliary ligand ppy (2-phenylpyridine) into a two-necked flask, add 45 mL of ethylene glycol ethyl ether and 15 mL of water, reflux at 110 ° C under argon for 48 h, cool to room temperature, filter, wash, and vacuum dry to obtain a yellow solid, which is the precursor compound [Ir2(ppy)4(μ-Cl)2].

[0157] The auxiliary ligand ppy in the above scheme was replaced by Fppy (2-(2,4-difluorophenyl)pyridine), and the other conditions were the same as the above scheme to obtain the precursor compound [Ir2(Fppy)4(μ-Cl)2].

[0158] Example 7

[0159] Synthesis method of conjugated bithiophene iridium complex Ir1:

[0160] 0.059 g (0.15 mmol) of the ligand dtdppz and 0.054 g (0.05 mmol) of the precursor [Ir2(ppy)4(μ-Cl)2] were weighed into a two-necked flask, and 8 mL of methanol and 8 mL of dichloromethane were added. The mixture was stirred and refluxed at 50°C under argon for more than 16 h. After cooling to room temperature, 12 mL of water and a saturated aqueous solution of ammonium hexafluorophosphate were added. The mixture was allowed to stand for 0.5 h, filtered, washed, and dried in vacuo. The resulting orange-yellow crude product was chromatographed on a silica gel column using methanol:dichloromethane (10:1, v:v) as the eluent. The orange-yellow component was collected to obtain the conjugated bithiophene iridium complex Ir1 with a yield of 0.040 g and a yield of 89%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.79 (d, J = 8.2 Hz, 2H), 8.33 (d, J = 5.2, Hz, 2H), 8. 08(td,J=5.0,3.0Hz,2H),8.02(d,J=5.6Hz,4H),7.92(d,J=5.2Hz,2H),7.77(d,J =7.6Hz,2H),7.73(d,J=9.0Hz,2H),7.48(d,J=5.6Hz,2H),7.05(t,J=7.4Hz,2H) ,6.89(dt,J=7.4,7.2Hz,4H),6.33(d,J=7.4Hz,2H).ESI-MS(MeOH,m / z):[M-PF6] + Calculated:(C 44 H 26 N6IrS2)895.12;Found:895.12.

[0161] Synthesis method of conjugated bithiophene iridium complex Ir2:

[0162] The preparation steps are the same as Ir1, except that the precursor [Ir2(ppy)4(μ-Cl)2] is replaced by [Ir2(Fppy)4(μ-Cl)2] 0.061g (0.05mmol). The other steps and operations remain unchanged. The yield of Ir2 is 0.036g, with a yield of 75%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.79 (d, J = 8.0 Hz, 2H), 8.43 (d, J = 4.6 Hz, 2H), 8.3 7(d,J=5.0Hz,2H),8.34(d,J=8.8Hz,2H),8.25(t,J=5.4Hz,2H),8.22(d,J=5.8H z,2H),8.02(t,J=7.8Hz,2H),7.73(d,J=5.6Hz,2H),7.12(t,J=6.6Hz,2H),7.06 (dd,J=2.2,2.6Hz,2H),5.75(dd,J=8.4,2.2Hz,2H).ESI-MS(MeOH,m / z):[M-PF6] + Calculated:(C 44 H 22 F4IrN6S2)967.09; Found:967.09.

[0163] Example 8

[0164] Singlet oxygen generation properties of conjugated bithiophene metal complexes:

[0165] ABDA (9,10-anthracenediyl-bis(methylene)dimalonic acid) was used as singlet oxygen ( 1 The singlet oxygen generation efficiency of the complex was studied by measuring the absorption spectrum of ABDA solution containing conjugated bithiophene metal complexes (Ru1-7, Os1-4 and Ir1-2) using a UV / visible spectrophotometer. The UV absorption spectrum of the singlet oxygen scavenger ABDA in the solution after irradiation with 400 / 450nm and 808nm lasers in the presence of conjugated bithiophene metal complexes is shown in the figure below. Figure 8-9 shown.

[0166] When measuring the singlet oxygen yield, the complex solution was prepared with pure water. The complex concentration was 10 μM and the ABDA concentration was 100 μM. The [Ru(bpy)3] 2+ and [Os(bpy)3] 2+For comparison, the singlet oxygen yields were obtained by linear fitting. Under 400 / 450nm and 808nm light excitation, the singlet oxygen generation rates of the conjugated bithiophene metal complexes (Ru1-7, Os1-4 and Ir1-2) were all higher than those of the control complex [Ru(bpy)3] 2+ , and the singlet oxygen yields of the complexes Ru3 and Ru6 under 808nm light reached [Ru(bpy)3] 2+ The results show that the ruthenium complex provided by the present invention has an excellent ability to induce the production of singlet oxygen under infrared light excitation.

[0167] Example 9

[0168] Infrared photothermal conversion capability of conjugated bithiophene metal complexes:

[0169] Using PBS buffer containing 10% DMSO as a control, 808nm infrared light was used to illuminate the 10μM conjugated bithiophene metal complexes (Ru1-7, Os1-4 and Ir1-2, all solvents were PBS buffer containing 10% DMSO), and thermal imaging of the solution was performed at 0 minutes, 1 minute, 2 minutes, 5 minutes and 10 minutes ( Figure 10-12 ), and the heat Q generated by the conjugated bithiophene metal complex and the photothermal conversion efficiency η were calculated.

[0170] according to Figure 10-12 The recorded temperature data shows that the conjugated bithiophene metal complexes of the present invention generate a certain amount of heat under 808nm illumination, compared to the control PBS. Linear fitting shows that Ir2 has the highest photothermal conversion efficiency (PCE) at 808nm illumination, reaching 36.2%, followed by Ru7, with a PCE of 32.0%. These results demonstrate that the conjugated bithiophene metal complexes Ru7 and Ir2 provided by the present invention have excellent infrared photothermal conversion capabilities at 808nm.

[0171] Example 10

[0172] Conjugated bithiophene metal complexes Ru7, Os2, and Ir2 induce photothermal conversion in vivo and inhibit melanoma activity in vivo

[0173] All animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Yunnan University (approval number: YNU20220269). BALB / c female nude mice were purchased from Gem Pharmatech, aged 6–8 weeks and weighing 18–20 g.

[0174] Mice were housed in an individually ventilated cage (IVC) system with a constant temperature (20-26°C) and humidity (40-70%), with 5 mice per cage. Each mouse was injected subcutaneously in the right posterior flank with 0.1 ml of PBS (containing approximately 5 × 10 6 A375 tumor cells). When the average tumor size reached 63 mm 3 Start drug treatment when

[0175] For the complex Ru7, mice were randomly divided into 6 groups (5 mice in each group): Group 1, injected with PBS only; Group 2, injected with PBS and then illuminated with a 450 nm LED (50 mW / cm 2 , light dose is 30.0J / cm 2 ) irradiation; Group 3, injected with PBS, then irradiated with 808 nm laser (0.1 W / cm 2 , light dose is 30.0J / cm 2 ) irradiation; Group 4, injection of Ru7 (20 μL, 10 μM) only; Group 5, injection of Ru7 (20 μL, 10 μM) followed by 450 nm LED (50 mW / cm 2 , light dose is 30.0J / cm 2 ) irradiation; Group 6, injection of Ru7 (20 μL, 10 μM), followed by 808 nm laser (0.1 W / cm 2 , light dose is 30.0J / cm 2 ) irradiation.

[0176] For the complex Os2, mice were randomly divided into 4 groups (5 mice in each group): Group 1, injected with PBS only; Group 2, injected with PBS and then irradiated with 808 nm laser (0.1 W / cm 2 , light dose is 30.0J / cm 2 ) irradiation; Group 3, injected with Os2 (20 μL, 10 μM) only; Group 4, injected with Os2 (20 μL, 10 μM) and then irradiated with 808 nm laser (0.1 W / cm 2 , light dose is 30.0J / cm 2 ) irradiation.

[0177] For the complex Ir2, mice were randomly divided into 4 groups (5 mice in each group): Group 1, injected with PBS only; Group 2, injected with PBS and then irradiated with 808 nm laser (0.1 W / cm 2 , light dose is 30.0J / cm 2 ) irradiation; Group 3, injected with Ir2 (20 μL, 10 μM) only; Group 4, injected with Ir2 (20 μL, 10 μM) and then irradiated with 808 nm laser (0.1 W / cm 2 , light dose is 30.0J / cm2 ) irradiation.

[0178] During the treatment program, body weight and tumor volume data were recorded every 2 to 3 days. Tumor volume was expressed in mm 3 The formula is: V = 0.5a × b 2 , where a and b are the long and short diameters of the tumor, respectively. Tumor weights were measured at the end of the study. The entire dosing and tumor and body weight measurement procedures were performed in a laminar flow cabinet. Relative tumor volume was calculated as V / V0 (V is the tumor volume on the day the data was recorded, and V0 is the tumor volume on the day treatment started).

[0179] The results are as follows Figure 13-15 As shown in the figure, (a) is the real-time thermal imaging of mice during the treatment process, (b) is the change of tumor volume during the treatment process, and (c) is the change of mouse weight during the treatment process.

[0180] Depend on Figure 13-15 As can be seen, under 808nm infrared light, the conjugated bithiophene metal complexes Ru7, Os2, and Ir2 all significantly increased the temperature of the mouse tumor site and effectively inhibited melanoma growth in the mice. The therapeutic effect was far superior to that under 450nm visible light and no light conditions. At the same time, physiological parameters such as mouse weight were not affected. This shows that the conjugated bithiophene metal complexes Ru7, Os2, and Ir2 provided by the present invention also function as photothermal agents in tumor photodynamic therapy, which can further enhance the tumor treatment effect.

[0181] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A conjugated bithiophene ligand, characterized in that: The structural formula is shown in Formula I:

2. The method for preparing the conjugated bithiophene ligand according to claim 1, characterized in that: The following steps are involved: (i) mixing a compound having a structure represented by formula a, oxalyl chloride, and an organic solvent to react to obtain a compound having a structure represented by formula b; (ii) mixing the compound having the structure shown in Formula b, the compound having the structure shown in Formula c, and an organic solvent to carry out a condensation reaction to obtain a conjugated bithiophene ligand having the structure shown in Formula I; 3. The preparation method according to claim 2, characterized in that The reaction temperature in step (i) is 60-140° C. and the reaction time is 1-5 days; The condensation reaction in step (ii) is carried out at a temperature of 80 to 120° C. and for a time of 1 to 8 hours.

4. A conjugated bithiophene metal complex consisting of anions and cations, characterized in that: The structural formulas of the cations are shown in Formula II, Formula III and Formula IV: In Formula II, represents the auxiliary ligand L1, and the auxiliary ligand L1 is any one of the ligands with the following structures: In formula III, represents the auxiliary ligand L2, and the auxiliary ligand L2 is any one of the ligands of the following structures: In Formula IV, represents the auxiliary ligand L3, and the auxiliary ligand L3 is any one of the ligands of the following structures:

5. The method for preparing the conjugated bithiophene ruthenium complex according to claim 4, characterized in that: The following steps are involved: (i) mixing the auxiliary ligand L1, ruthenium trichloride, lithium chloride and an organic solvent to perform a first coordination reaction to obtain a precursor compound having a structure shown in formula d; (ii) mixing the precursor compound having the structure shown in formula d, the conjugated bithiophene ligand shown in formula I and a solvent to perform a second coordination reaction to obtain an anion of Cl - A conjugated bithiophene ruthenium complex, wherein the cation structure of the conjugated bithiophene ruthenium complex is shown in Formula II.

6. The method for preparing the conjugated bithiophene osmium complex according to claim 4, characterized in that: The following steps are involved: (i) mixing the auxiliary ligand L2, ammonium hexachloroosmate, and an organic solvent to perform a first coordination reaction to obtain a precursor compound having a structure shown in Formula e; (ii) mixing the precursor compound having the structure shown in formula e, the conjugated bithiophene ligand shown in formula I and a solvent to carry out a second coordination reaction to obtain an anion of Cl - A conjugated bithiophene osmium complex, wherein the cation structure of the conjugated bithiophene osmium complex is shown in Formula III.

7. The method for preparing the conjugated bithiophene iridium complex according to claim 4, characterized in that: The following steps are involved: (i) mixing the auxiliary ligand L3, iridium trichloride and an organic solvent to perform a first coordination reaction to obtain a precursor compound having a structure shown in Formula f; (ii) mixing the precursor compound having the structure shown in formula f, the conjugated bithiophene ligand shown in formula I and a solvent to carry out a second coordination reaction to obtain an anion of Cl - A conjugated bithiophene iridium complex, wherein the cationic structure of the conjugated bithiophene iridium complex is shown in Formula IV.

8. Use of the conjugated bithiophene metal complex according to claim 4 in the preparation of photosensitizers and photothermal agents for tumor photodynamic therapy.

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