A class of chiral Au 16 Metal complexes, their preparation methods and applications

Abstract

The application relates to the technical field of metal organic complexes, in particular to a chiral Au 16 Metal complex and preparation method and application thereof. By using a specific chiral 1,4-di (dithiocarbamate) -2-methyl piperazine potassium salt ligand, a specific chiral Au 16 Metal complex, 16 Au atoms in the structure of the metal complex form an Au 16 Macrocycle, 16 gold atoms form a polynuclear gold compound, and the chiral Au 16 Drug activity of the metal complex on cancer cells. In in-vitro cell experiments, the chiral Au 16 The metal complex has good in-vitro anticancer activity in different cancer cell lines. Meanwhile, due to the Au-Au bonding, a macrocycle structure is formed, and the chiral Au 16 Cytotoxicity of the metal complex on normal cells.

Description

Technical Field

[0001] This invention relates to the field of organometallic complex technology, and more particularly to a class of chiral Au compounds. 16 Metal complexes, their preparation methods, and applications. Background Technology

[0002] In recent years, metal-based drugs have shown unique potential in anti-tumor treatment. The successful clinical application of platinum-based drugs, such as cisplatin, has accelerated research on metal-based drugs. However, limiting factors such as drug resistance, toxicity, and insufficient targeting hinder the wider clinical application of platinum-based drugs.

[0003] Meanwhile, gold-based complexes have attracted widespread attention due to their unique chemical properties and potential antitumor effects. Au(I) can inhibit thioredoxin reductase (TrxR) through its high affinity for soft atoms (such as S and Se) in enzymes, thereby leading to excessive production of reactive oxygen species (ROS) that cause mitochondrial dysfunction and induce cell death, effectively inhibiting the proliferation of cancer cells. Based on these advantages, gold compounds have important research value in cancer treatment.

[0004] However, gold compounds also have some drawbacks, such as drug toxicity to normal cells. Summary of the Invention

[0005] In view of this, the present invention provides a class of chiral Au 16 Metal complexes, their preparation methods and applications, and the chiral Au provided by this invention. 16 Metal complexes significantly reduce drug toxicity to normal cells.

[0006] This invention provides a class of chiral Au 16 Metal complexes, with structures as shown in Formula I or Formula II: Formula I; Formula II; In Equations I and II, R1 is -H or -CH3, R2 is -H or -CH3, R3 is -H or -CH3, R4 is -H or -CH3, and X... - For Cl - or PF6 - .

[0007] Preferably, in Formulas I and II, R1 is -CH3, R2 is -CH3, R3 is -CH3, R4 is -CH3, and X is... - For Cl - or PF6 - .

[0008] Preferably, in formula I, R1 is -H, R2 is -CH3, R3 is -CH3, R4 is -H, and X... - For Cl - or PF6 - .

[0009] Preferably, in formula II, R1 is -CH3, R2 is -H, R3 is -CH3, R4 is -H, and X... - For Cl - or PF6 - .

[0010] Preferably, in formula I, R1 is -H, R2 is -H, R3 is -H, R4 is -H, and X is... - For Cl - or PF6 - .

[0011] The present invention also provides the chiral Au described in the above-described scheme. 16 The preparation method of metal complexes includes the following steps: (1) A piperazine compound, a base, carbon disulfide and a mixed solvent were mixed to carry out a di-substitution reaction to obtain the potassium salt (K2L) ligand of 1,4-bis(dithiocarbamate)-2-methylpiperazine; (2) The diphenylphosphine methane solution was added dropwise to the chloroauric acid tetrahydrate (AuCl3·HCl·4H2O) solution to carry out the first coordination reaction, and a binuclear gold complex (dppmAu2Cl2) was obtained. (3) The 1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt ligand, the binuclear gold complex, and the alcohol solution were mixed to carry out a second coordination reaction to obtain chiral Au. 16 Metal complexes; There is no requirement for the time order of steps (1) and (2).

[0012] Preferably, the piperazine compounds include one or more of R-(-)-2-methylpiperazine, S-(+)-2-methylpiperazine, piperazine, and homopiperazine.

[0013] Preferably, the temperature of the di-substitution reaction is 38-42 degrees Celsius, and the holding time is 11-13 hours.

[0014] Preferably, the second coordination reaction further includes a third post-treatment of the obtained product; when the third post-treatment is performed, the anion exchange includes the following steps: mixing the product obtained from the second coordination reaction with potassium hexafluorophosphate (KPF6) and an alcohol solution to carry out anion exchange reaction; when the third post-treatment is not performed, the anion exchange includes the following steps: mixing the product obtained from the second coordination reaction with potassium hexafluorophosphate to carry out anion exchange reaction.

[0015] The present invention also provides the chiral Au described in the above-described scheme. 16 Metal complexes or the chiral Au described in the above scheme 16 Application of metal complexes in the preparation of drugs for treating platinum-resistant cancers.

[0016] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention provides a class of chiral Au 16 Metal complexes. This invention synthesizes chiral Au compounds with specific chirality via a specific chiral 1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt ligand. 16 Metal complexes, in which 16 Au atoms in the structure form an Au atom through Au-Au bonding. 16 A macrocyclic ring, consisting of 16 gold atoms forming a polynuclear gold compound, can enhance the chiral nature of Au. 16 Drug activity of metal complexes against cancer cells. In in vitro cell experiments, chiral Au... 16 The metal complexes exhibited good in vitro anticancer activity in various cancer cell lines. Furthermore, the Au-Au bonding forms a large ring structure, effectively reducing the chiral Au content. 16 The cytotoxicity of metal complexes to normal cells.

[0017] The present invention also provides the chiral Au described in the above-described scheme. 16 A method for preparing metal complexes. The preparation method provided by this invention is simple in steps, convenient in operation, safe, and stable, making it suitable for industrial-scale production applications.

[0018] The present invention also provides the chiral Au described in the above-described scheme. 16 Metal complexes or the chiral Au described in the above scheme 16 Application of metal complexes in the preparation of drugs for treating platinum-resistant cancers. The present invention provides chiral Au. 16 Metal complexes are suitable for preparing drugs to treat platinum-resistant cancers, and have broad application prospects. The chiral Au provided by this invention... 16 Au(I) in metal complexes can inhibit thioredoxin reductase (TrxR) by having a high affinity for soft atoms (such as S and Se) in enzymes. This leads to excessive production of reactive oxygen species (ROS), causing mitochondrial dysfunction and inducing cell death, thereby effectively inhibiting the proliferation of cancer cells. Attached Figure Description

[0019] To more clearly illustrate the technical solutions of this invention, the accompanying drawings used in the embodiments of this invention or in the prior art are briefly described below. For those skilled in the art, other drawings can be derived from the following drawings without creative effort, and all such drawings are within the protection scope of this invention.

[0020] Figure 1 chiral Au 16 Metal complexes ( M R,R M’ R,R )-Au 16 A schematic diagram of the crystal structure of Cl8 (for clarity, all counter anions Clˉ have been omitted); Figure 2 chiral Au 16 Metal complexes ( P S,S P’ S,S )-Au 16 A schematic diagram of the crystal structure of Cl8 (for clarity, all counter anions Clˉ have been omitted); Figure 3 chiral Au 16 Percentage of apoptotic and necrotic cells in late-stage breast cancer after treatment with metal complexes (A), semi-quantitative analysis of apoptosis (B), intracellular lipid peroxidation level (C), and semi-quantitative analysis of LPO (D). Figure 4 For R-type and S-type chiral Au 16 Cytotoxicity analysis of metal complexes on normal human hepatic stellate cells (LX-2) at different time points; where A is an S-type chiral Au. 16 The metal complex exhibited 24-hour cytotoxicity against normal hepatic stellate cells (LX-2); B is an S-type chiral Au. 16 The metal complex exhibited cytotoxicity against normal hepatic stellate cells (LX-2) after 48 hours; C represents S-type chiral Au. 16 The metal complex exhibited cytotoxicity against normal hepatic stellate cells (LX-2) after 72 hours; D represents R-type chiral Au. 16 The metal complex exhibits 24-hour cytotoxicity against normal hepatic stellate cells (LX-2); E represents R-type chiral Au. 16 The metal complex exhibited cytotoxicity against normal hepatic stellate cells (LX-2) after 48 hours; F represents R-type chiral Au. 16 The cytotoxicity of metal complexes on normal hepatic stellate cells LX-2 after 72 hours; Figure 5 This invention provides some types of chiral Au. 16 Flowchart of the preparation process for metal complexes; Figure 6This invention provides some types of chiral Au. 16 Flowchart of the preparation process for metal complexes; Figure 7 This invention provides some types of chiral Au. 16 Flowchart of the preparation process for metal complexes. Detailed Implementation

[0021] This invention provides a class of chiral Au 16 Metal complexes, with structures as shown in Formula I or Formula II: Formula I; Formula II; In Equations I and II, R1 is -H or -CH3, R2 is -H or -CH3, R3 is -H or -CH3, R4 is -H or -CH3, and X... - For Cl - or PF6 - .

[0022] In this invention, in Formulas I and II, R1 is preferably -CH3, R2 is preferably -CH3, R3 is preferably -CH3, R4 is preferably -CH3, and X... - Cl is preferred - or PF6 - .

[0023] In this invention, in Formula I, R1 is preferably -H, R2 is preferably -CH3, R3 is preferably -CH3, R4 is preferably -H, and X... - Cl is preferred - or PF6 - .

[0024] In this invention, in Formula II, R1 is preferably -CH3, R2 is preferably -H, R3 is preferably -CH3, R4 is preferably -H, and X - Cl is preferred - or PF6 - .

[0025] In this invention, in Formula I, R1 is preferably -H, R2 is preferably -H, R3 is preferably -H, R4 is preferably -H, and X - Cl is preferred - or PF6 - .

[0026] The present invention also provides the chiral Au described in the above-described scheme. 16 The preparation method of metal complexes includes the following steps: (1) A piperazine compound, a base, carbon disulfide and a mixed solvent were mixed to carry out a di-substitution reaction to obtain the potassium salt (K2L) ligand of 1,4-bis(dithiocarbamate)-2-methylpiperazine; (2) The diphenylphosphine methane solution was added dropwise to the chloroauric acid tetrahydrate (AuCl3·HCl·4H2O) solution to carry out the first coordination reaction, and a binuclear gold complex (dppmAu2Cl2) was obtained. (3) The 1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt ligand, the binuclear gold complex, and the alcohol solution were mixed to carry out a second coordination reaction to obtain chiral Au. 16 Metal complexes; There is no requirement for the time order of steps (1) and (2).

[0027] This invention involves mixing piperazine compounds, a base, carbon disulfide, and a mixed solvent to carry out a di-substitution reaction, yielding a 1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt ligand.

[0028] In this invention, the piperazine compounds preferably include one or more of R-(-)-2-methylpiperazine, S-(+)-2-methylpiperazine, piperazine, and homopiperazine.

[0029] In this invention, the alkali is preferably an alkali metal hydroxide; the alkali metal hydroxide is preferably potassium hydroxide (KOH).

[0030] In this invention, the molar ratio of the piperazine compound to the base is preferably 3.8 to 4.2:5, more preferably 4:5.

[0031] In this invention, the molar ratio of the piperazine compound to carbon disulfide is preferably 0.8 to 1.2:2, more preferably 1:2.

[0032] In this invention, the mixed solvent preferably includes water and alcohol; the alcohol is preferably methanol; the volume ratio of water to alcohol is preferably 0.8~1.2:2, more preferably 1:2.

[0033] In this invention, the mass ratio of the piperazine compound to the volume ratio of the mixed solvent is preferably (190~210) g:20 L, more preferably 200 g:20 L.

[0034] In this invention, the temperature of the di-substitution reaction is preferably 38-42 degrees Celsius, more preferably 40 degrees Celsius, and the holding time is preferably 11-13 hours, more preferably 12 hours.

[0035] In this invention, the disubstituted reaction preferably further includes a first post-treatment of the obtained product; the first post-treatment preferably includes the following steps: sequentially cooling, concentrating, filtering and collecting the filtrate, evaporating, washing the solid, drying and crystallizing.

[0036] In this invention, the cooling is preferably natural cooling; the final temperature of the cooling is preferably room temperature (20~38 degrees Celsius).

[0037] In this invention, the concentration ratio is preferably 2 to 3, more preferably 2.2.

[0038] In this invention, the temperature of the rotary drying is preferably 55-65 degrees Celsius, more preferably 60 degrees Celsius, and the vacuum degree is preferably 20-50 mbar, more preferably 30-50 mbar.

[0039] In this invention, the washing reagent is preferably acetone; the amount of acetone used is preferably 20 ml.

[0040] In this invention, the drying temperature is preferably 55-65 degrees Celsius, more preferably 60 degrees Celsius, and the holding time is preferably 11-13 hours, more preferably 12 hours; the drying is preferably vacuum drying; the vacuum degree of the vacuum drying is preferably 100-150 mbar, more preferably 120-130 mbar.

[0041] In this invention, the crystallization is preferably carried out in a mixed solution of methanol and ethylene diether; the volume ratio of methanol to ethylene diether is preferably 1:1.

[0042] In this invention, the 1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt ligand preferably includes one or more of the following: R-(-)-1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt ligand, S-(+)-1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt ligand, 1,4-bis(dithiocarbamate)-piperazine potassium salt ligand, and 1,4-bis(dithiocarbamate)-homoperazine potassium salt ligand.

[0043] In this invention, a diphenylphosphine methane solution is added dropwise to a chloroauric acid tetrahydrate solution to carry out a first coordination reaction, thereby obtaining a binuclear gold complex.

[0044] In this invention, the solvent of the diphenylphosphine methane solution is preferably an alcohol; the alcohol is preferably ethanol; the concentration of the diphenylphosphine methane solution is preferably 83~88 mol / L, more preferably 85 mmol / L.

[0045] In this invention, the solvent of the chloroauric acid tetrahydrate solution is preferably an alcohol; the alcohol is preferably ethanol; the concentration of the chloroauric acid tetrahydrate solution is preferably 83~88 mol / L, more preferably 85 mmol / L.

[0046] In this invention, the molar ratio of diphenylphosphine methane in the diphenylphosphine methane solution to chloroauric acid tetrahydrate in the chloroauric acid tetrahydrate solution is preferably 0.8~1.2:1, more preferably 0.9~1.1:1, and even more preferably 1:1.

[0047] In this invention, the dripping rate is preferably 3 to 4 drops / second, more preferably 3 drops / second; during the dripping, the temperature of the diphenylphosphine methane solution is preferably 58 to 62 degrees Celsius, more preferably 60 degrees Celsius.

[0048] In this invention, the first coordination reaction is preferably carried out under stirring conditions; the time of the first coordination reaction is preferably 5.5 to 6.6 hours, more preferably 6 hours.

[0049] In this invention, the first coordination reaction preferably includes a second post-processing of the obtained product; the second post-processing preferably includes the following steps: sequentially performing solid-liquid separation and solid drying on the obtained product.

[0050] In this invention, the solid-liquid separation is preferably filtration; the drying temperature is preferably 55-65 degrees Celsius, more preferably 60 degrees Celsius, and the holding time is preferably 11-13 hours, more preferably 12 hours; the drying is preferably vacuum drying; the vacuum degree of the vacuum drying is preferably 100-150 mbar, more preferably 120 mbar.

[0051] After obtaining the 1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt ligand and the binuclear gold complex, the present invention mixes the 1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt ligand, the binuclear gold complex, and an alcohol solution (denoted as the first mixture) to carry out a second coordination reaction to obtain chiral Au. 16 Metal complexes.

[0052] In this invention, the first mixing preferably includes the following steps: mixing 1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt ligand and a portion of alcohol solution to obtain a ligand solution, mixing the binuclear gold complex and the remaining alcohol solution to obtain a complex solution, and adding the ligand solution dropwise to the complex solution.

[0053] In this invention, the molar ratio of the 1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt ligand to the binuclear gold complex is preferably 1:1.8 to 2.2, more preferably 1:2.

[0054] In this invention, the alcohol solution is preferably methanol.

[0055] In this invention, the volume ratio of the partial alcohol solution to the remaining alcohol solution is preferably 0.8 to 1.2:1, and more preferably 1:1.

[0056] In this invention, the mass ratio of the binuclear gold complex to the volume ratio of the alcohol solution is preferably (169~170) g:10 L, more preferably 169.6 g:10 L.

[0057] In this invention, the temperature of the second coordination reaction is preferably room temperature, and the holding time is preferably 11 to 13 hours, more preferably 12 hours.

[0058] In this invention, the second coordination reaction preferably includes a third post-processing of the resulting product.

[0059] In this invention, the third post-processing preferably includes the following steps: sequentially subjecting the obtained product to rotary drying, water washing, redissolving, and crystallization.

[0060] In this invention, the temperature of the rotary drying is preferably 38-42 degrees Celsius, more preferably 40 degrees Celsius, and the vacuum degree is preferably 150-200 mbar, more preferably 180 mbar.

[0061] In this invention, the solvent used for redissolution is preferably methanol; the amount of methanol used is preferably 10 mL.

[0062] In this invention, the crystallization is preferably carried out in a mixed solution of methanol and ethylene diether.

[0063] In this invention, the second coordination reaction or the third post-treatment preferably further includes anion exchange of the resulting product.

[0064] In this invention, when performing the third post-processing, the anion exchange preferably includes the following steps: mixing the product obtained from the second coordination reaction with potassium hexafluorophosphate (KPF6) and an alcohol solution to carry out anion exchange reaction.

[0065] In this invention, the molar ratio of the product obtained from the second coordination reaction to potassium hexafluorophosphate is preferably 1:38~42, more preferably 1:40.

[0066] In this invention, the alcohol solution is preferably methanol.

[0067] In this invention, the preferred ratio of the mass of potassium hexafluorophosphate to the volume of the alcohol solution is (183~185) g:10 L, more preferably 183.93 g:10 L.

[0068] In this invention, the temperature of the anion exchange reaction is preferably room temperature, and the reaction time is preferably 12 hours.

[0069] In this invention, the anion exchange reaction preferably further includes centrifugation, precipitate washing, redissolution, and crystallization of the resulting product in sequence.

[0070] In this invention, the solvent used for redissolution is preferably acetonitrile; the crystallization is preferably carried out in a mixed solution of acetonitrile and diethyl ether.

[0071] In this invention, when no third post-processing is performed, the anion exchange preferably includes the following steps: mixing the product obtained from the second coordination reaction with potassium hexafluorophosphate (KPF6) to carry out anion exchange reaction.

[0072] In this invention, the molar ratio of the potassium ligand of 1,4-bis(dithiocarbamate)-2-methylpiperazine to potassium hexafluorophosphate is preferably 1:9 to 11, more preferably 1:10.

[0073] In this invention, the reaction conditions and post-treatment steps for anion exchange without the third post-treatment are preferably the same as those with the third post-treatment, and will not be repeated here.

[0074] The present invention also provides the chiral Au described in the above-described scheme. 16 Metal complexes or the chiral Au described in the above scheme 16 Application of metal complexes in the preparation of drugs for treating platinum-resistant cancers.

[0075] The chiral Au provided by this invention 16 Metal complexes are suitable for preparing drugs to treat platinum-resistant cancers, and have broad application prospects. The chiral Au provided by this invention... 16 Au(I) in metal complexes can inhibit thioredoxin reductase by having a high affinity for soft atoms in enzymes, thereby causing excessive production of reactive oxygen species, leading to mitochondrial dysfunction, inducing cell death, and thus effectively inhibiting the proliferation of cancer cells.

[0076] To further illustrate the present invention, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings and embodiments.

[0077] In a specific embodiment of the present invention, chiral Au is prepared. 16 The process flow of metal complexes is as follows: Figures 5-7 As shown.

[0078] Example 1: In this embodiment, potassium ligands of 1,4-bis(dithiocarbamate)-2-methylpiperazine with different chiralities were prepared. The synthetic route is as follows: .

[0079] S1) Synthesis of R-(-)-1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt ligand: R-(-)-2-methylpiperazine (200.0 mg, 2 mmol) and KOH (100 mg, 2.5 mmol) were dissolved in methanol (20 mL). CS2 (150.0 mg, 4 mmol) was dissolved in a mixture of water (5 mL) and methanol (10 mL) and added to the above solution. The reaction was carried out at 40°C for 12 hours. After the reaction was completed, the solution was naturally cooled to room temperature and concentrated to 10 mL. After filtering off the white solid, the solvent was evaporated at 60°C under a vacuum of 20–50 mbar. The solid was washed with acetone (20 mL) and dried under vacuum at 60°C for 12 hours under a vacuum of 100–150 mbar. The obtained compound was crystallized in methanol / diethyl ether (1:1 v / v) to give the target compound (yield: 565 mg, 86%) as a white crystalline solid. 1 H NMR (400 MHz, d 6 -DMSO), δ (ppm): 5.87-5.83 (m, 1H), 5.37-5.32 (m, 2H), 5.11 (d, J = 8.08 Hz, 1H),3.30-3.19 (m, 3H), 1.03 (d, J = 6.6 Hz, 3H). 13 C NMR (100 MHz, d 6 -DMSO), δ (ppm): 214.9, 213.9, 53.1, 53.05, 49.7, 44.9, 16.3. ESI-MS (C7H 10 N2S4K3): calcd for m / z= 366.8638, found: m / z = 366.8630 (M+K + ).

[0080] S2) Synthesis of S-(+)-1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt ligand: S-(+)-2-methylpiperazine (200.0 mg, 2 mmol) and KOH (100 mg, 2.5 mmol) were dissolved in methanol (20 mL). CS2 (150.0 mg, 4 mmol) was dissolved in a mixture of water (5 mL) and methanol (10 mL) and added to the above solution. The reaction was carried out at 40°C for 12 hours. After the reaction, the solution was allowed to cool naturally to room temperature and concentrated to 10 mL. After filtering off the white solid, the solvent was evaporated at 60°C under a vacuum of 20–50 mbar. The solid was washed with acetone (20 mL) and dried under vacuum at 60°C under a vacuum of 100–150 mbar for 12 hours. The resulting compound was crystallized in methanol / diethyl ether (1:1 v / v) to obtain the target compound (yield: 564 mg, 86%) as a white crystalline solid. 1 H NMR (400 MHz, d 6 -DMSO), δ (ppm): 5.86-5.83 (m, 1H), 5.34-5.31 (m, 2H), 5.11 (d, J = 11.12 Hz, 1H),3.32-3.19 (m, 3H), 1.03 (d, J = 6.6 Hz, 3H). 13 C NMR (100 MHz, d 6 -DMSO), δ (ppm): 214.9, 213.9, 53.1, 53.05, 49.7, 44.9, 16.3. ESI-MS (C7H 10 N2S4K3): calcd for m / z= 366.8638, found: m / z = 366.8630 (M+K + ).

[0081] .

[0082] S3) Synthesis of 1,4-bis(dithiocarbamate)-piperazine potassium salt ligand: Piperazine (172.2 mg, 2 mmol) and KOH (100 mg, 2.5 mmol) were dissolved in methanol (20 mL). CS2 (150.0 mg, 4 mmol) was dissolved in a mixture of water (5 mL) and methanol (10 mL) and added to the above solution. The reaction was carried out at 40°C for 12 hours. After the reaction, the mixture was allowed to cool naturally to room temperature and concentrated to 10 mL. After filtering off the white solid, the solvent was evaporated at 60°C under a vacuum of 20–50 mbar. The solid was washed with acetone (20 mL) and dried under vacuum at 60°C under a vacuum of 100–150 mbar for 12 hours. The resulting compound was crystallized in methanol / diethyl ether (1:1 v / v) to obtain the target compound (yield: 534 mg, 85%) as a white crystalline solid. 1 H NMR (400 MHz, d 6 -DMSO), δ (ppm): 4.24 (s, 8H).

[0083] .

[0084] S4) Synthesis of 1,4-bis(dithiocarbamate)-periperazine potassium salt ligand: Piperazine (200 mg, 2 mmol) and KOH (100 mg, 2.5 mmol) were dissolved in methanol (20 mL). CS2 (150.0 mg, 4 mmol) was dissolved in a mixture of water (5 mL) and methanol (10 mL) and added to the above solution. The reaction was carried out at 40°C for 12 hours. After the reaction, the mixture was allowed to cool naturally to room temperature and concentrated to 10 mL. After filtering off the white solid, the solvent was evaporated at 60°C under a vacuum of 20–50 mbar. The solid was washed with acetone (20 mL) and dried under vacuum at 60°C under a vacuum of 100–150 mbar for 12 hours. The resulting compound was crystallized in methanol / diethyl ether (1:1 v / v) to obtain the target compound (yield: 565 mg, 86%) as a white crystalline solid. 1 H NMR (400 MHz, d 6 -DMSO), δ (ppm): 4.41-4.20 (s, 1H), 4.14-4.07 (m, 2H), 3.99-3.92 (t, 1H), 3.18-3.15 (d,J = 7.7 Hz, 6H).

[0085] Example 2: This embodiment synthesizes a binuclear dppmAu2Cl2, and the specific steps are as follows: Diphenylphosphine methane (326.7 mg, 0.85 mmol) was dissolved in ethanol (10 mL) and heated to 60°C to ensure complete dissolution. Next, AuCl3·HCl·4H2O (350 mg, 0.85 mmol) was added to ethanol (10 mL) and dissolved. Then, the 60°C diphenylphosphine methane solution was added dropwise to the AuCl3·HCl·4H2O ethanol solution at a rate of 3 drops / second. After the addition was complete, stirring was continued for 6 hours to ensure the reaction proceeded fully. Finally, the resulting white powder was filtered and dried under vacuum at 100–150 mbar and 60°C for 12 hours. After drying, approximately 310 mg of product was obtained, with a yield of 85%.

[0086] Example 3: In this embodiment, a class of chiral Au was synthesized using the 1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt ligand synthesized in Example 1 and the dinuclear dppmAu2Cl2 synthesized in Example 2. 16 Metal complexes, the specific steps are as follows: (A) Chiral Au 16 Metal complexes ( M R,R M’ R,R )-Au 16 Preparation of Cl8: A methanol solution (5 mL) of R-(-)-1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt (32.79 mg, 0.1 mmol) prepared in step S1 was slowly added to a methanol suspension (5 mL) of (dppm) Au2Cl2 (169.60 mg, 0.2 mmol) prepared in Example 2. The mixture was stirred at room temperature for 12 hours, and the mixture became a clear yellow-green solution. The solution was evaporated to dryness at 40°C and a vacuum of 150–200 mbar, washed with water, and the solid was dissolved in 10 mL of methanol. The resulting compound was crystallized in methanol / diethyl ether to obtain chiral Au. 16 Metal complexes, crystal structures such as Figure 1 As shown. 1 H NMR (400 MHz, d 6 -DMSO), δ (ppm): 7.78 (s, 16H), 7.44-7.35 (m, 24H), 5.32 (br, 1H), 4.81-3.93 (m,10H), 1.34-1.04 (m, 2H), 1.04 (d, J= 4.08 Hz, 1H). 13 C NMR (100 MHz, d 6 -DMSO), δ (ppm): 206.40, 133.80, 132.35, 130.05, 129.42, 67.79, 56.14, 54.11, 53.34,50.77, 46.53, 25.87, 23.31, 16.63.

[0087] (B) Chiral Au 16 Metal complexes ( P S,S P’ S,S )-Au 16 Preparation of Cl8: A methanol solution (5 mL) of S-(+)-1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt (32.79 mg, 0.1 mmol) prepared in step S2 was slowly added to a methanol suspension (5 mL) of (dppm) Au2Cl2 (169.60 mg, 0.2 mmol) prepared in Example 2. The mixture was stirred at room temperature for 12 hours, and the mixture became a clear yellow-green solution. The solution was evaporated to dryness at 40°C and a vacuum of 150–200 mbar, washed with water, and the solid was dissolved in 10 mL of methanol. The resulting compound was crystallized in methanol / diethyl ether to obtain chiral Au. 16 Metal complexes, crystal structures such as Figure 2 As shown. 1 H NMR (400 MHz, d 6 -DMSO), δ (ppm): 7.71 (br, 16H), 7.54-6.95 (m, 24H), 6.55-6.10 (br, 1H), 5.50-5.08 (br, 1H), 5.08-4.34 (br, 6H), 4.34-3.80 (br, 3H), 1.56-1.24 (br,2H), 1.04 (d, J = 5.99 Hz, 1H). 13 C NMR (100 MHz, d 6 -DMSO), δ(ppm): 206.15, 133.81,132.42, 129.91, 129.46, 67.78, 55.40, 54.21, 53.34, 51.05, 46.64, 25.75,23.31, 16.65.

[0088] (C) Chiral Au 16 Metal complexes ( M R,R M’ R,R )-Au 16 Preparation of (PF6)8: The (prepared in step A) M R,R M’ R,R )-Au 16 Cl8 (187.60 mg, 0.025 mmol) was dissolved in methanol (10 mL), and excess KPF6 (183.93 mg, 1 mmol) was added. The reaction was carried out for 12 hours, yielding a yellow precipitate, which was separated by centrifugation. The precipitate was washed with water and dissolved in 10 mL of acetonitrile. The resulting compound was crystallized in acetonitrile / diethyl ether to give chiral Au. 16 Metal complexes. 1 H NMR (400 MHz, d 6 -DMSO), δ (ppm): 7.36 (br, 40H), 5.58-4.91 (m, 4H), 4.90-4.30 (m,5H), 4.10 (br, 2H), 1.57 (d, J = 5.75 Hz, 3H). 13 C NMR (100 MHz, d 6 -DMSO), δ (ppm):200.81, 162.79, 133.69, 132.61, 129.45, 74.01, 59.62, 53.84, 53.56, 48.91,46.70, 36.25, 31.25, 25.42, 15.71. ESI-MS (C 57 H 54 Au4N2P6S4F 12 ): calcd for m / z =2096.0066, found: m / z = 903.0278 [M-2PF6] 2+, found: m / z = 1951.0239 [M-PF6] + .

[0089] (D) Chiral Au 16 Metal complexes ( P S,S P’ S,S )-Au 16 Preparation of (PF6)8: Prepared in step B ( P S,S P’ S,S )-Au 16 Cl8 (187.60 mg, 0.025 mmol) was dissolved in methanol (10 mL), and excess KPF6 (183.93 mg, 1 mmol) was added. The reaction was carried out for 12 hours, yielding a yellow precipitate, which was separated by centrifugation. The precipitate was washed with water and dissolved in 10 mL of acetonitrile. The resulting compound was crystallized in acetonitrile / diethyl ether to give chiral Au. 16 Metal complexes. 1 H NMR (400 MHz, d 6 -DMSO), δ (ppm): 8.48-6.73 (m, 40H), 6.53-6.26 (br, 1H), 5.45-4.08(br, 2H), 5.04-4.46 (br, 5H), 4.42-4.40 (br, 3H), 1.72-1.35 (br, 3H). 13 C NMR (100 MHz, d 6 -DMSO), δ (ppm): 202.85, 162.77, 133.70, 132.59, 129.43, 73.99,58.81, 56.83, 53.91, 47.05, 29.48, 27.03, 25.54, 16.16. ESI-MS(C 57 H 54 Au4N2P6S4F 12 ): calcd for m / z = 2096.0066, found: m / z = 903.0271 [M-2PF6] 2+ , found: m / z = 1951.0234 [M-PF6] + .

[0090] (E) Chiral Au16 Metal complexes ( M R,R M’ A,A )-Au 16 Preparation of (PF6)8: A methanol solution (5 mL) containing a mixture of R-(-)-1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt (16.40 mg, 0.05 mmol) prepared in step S1 and 1,4-bis(dithiocarbamate)-piperazine potassium salt (15.70 mg, 0.05 mmol) prepared in step S3 was slowly added to a methanol suspension (5 mL) containing (dppm) Au2Cl2 (169.60 mg, 0.2 mmol) prepared in Example 2. The mixture was stirred at room temperature for 12 hours, and the mixture became a clear yellow-green solution. Excess KPF6 (183.93 mg, 1 mmol) was added and the reaction was continued for 12 hours, resulting in a yellow precipitate, which was then centrifuged. The precipitate was washed with water and dissolved in 10 mL of acetonitrile. The resulting compound was crystallized in acetonitrile / diethyl ether to obtain chiral Au. 16 Metal complexes. 1 H NMR (400 MHz, d 6 -DMSO), δ (ppm): 7.88 (m, 4H) 7.57 (m, 16H), 7.54 (br, 8H), 7.50 (br, 16H), 7.38 (m, 24H), 7.30-7.20 (br, 12H), 5.23 and 4.19 (m, 2H), 5.02 (m, 2H), 4.81(br, 8H), 4.66 (br, 1H), 4.55 4.70-4.68 (br, 8H), 4.46 and 4.35 (br, 2H),1.55 (d, 3H, J = 4.7 Hz). 13 C NMR (100 MHz, DMSO-d6, 25 °C, ppm): δ(ppm): 200.23,134.06, 133.73, 133.05, 132.83, 129.87, 129.68, 128.60, 128.33, 65.30, 51.38,15.63. ESI-MSI: (C 57 H 54 Au4N2P6S4F 12 ) (C 56 H 52 Au4N2P6S4F 12) calcd for m / z = 2081.6609, calcd for m / z = 2096.0066, found: m / z = 895.9957 [M-2PF6] 2+ , found: m / z =903.0032 [M-2PF6] 2+ .

[0091] (F) Chiral Au 16 Metal complexes ( P S,S P’ A,A )-Au 16 Preparation of (PF6)8: A methanol solution (5 mL) containing a mixture of S-(+)-1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt (16.40 mg, 0.05 mmol) prepared in step S2 and 1,4-bis(dithiocarbamate)-piperazine potassium salt (15.70 mg, 0.05 mmol) prepared in step S3 was slowly added to a methanol suspension (5 mL) containing (dppm) Au2Cl2 (169.60 mg, 0.2 mmol) prepared in Example 2. The mixture was stirred at room temperature for 12 hours, and the mixture became a clear yellow-green solution. Excess KPF6 (183.93 mg, 1 mmol) was added and the reaction was continued for 12 hours, resulting in a yellow precipitate, which was then centrifuged. The precipitate was washed with water and dissolved in 10 mL of acetonitrile. The resulting compound was crystallized in acetonitrile / diethyl ether to obtain chiral Au. 16 Metal complexes. 1 H NMR (400 MHz, d 6 -DMSO), δ (ppm): 7.88 (m, 4H) 7.67 (m, 16H), 7.54 (br, 8H), 7.50 (br, 16H), 7.38 (m, 24H), 7.30-7.20 (br, 12H), 5.23 and 4.19 (m, 2H), 5.02 (m, 2H), 4.81(br, 8H), 4.66 (br, 1H), 4.55 4.70-4.68 (br, 8H), 4.46 and 4.35 (br, 2H),1.56 (d, 3H, J = 4.7 Hz). 13 C NMR (100 MHz, DMSO- d6, 25 °C, ppm): δ (ppm): 200.25, 134.06, 133.77, 133.05, 132.83, 129.87, 129.68, 129.31, 65.36, 51.39, 26.43, 15.63. ESI-MSI: (C 57 H 54 Au4N2P6S4F 12 ) (C 56 H 52 Au4N2P6S4F 12 ) calcd for m / z =2081.6609, calcd for m / z = 2096.0066, found: m / z = 895.9856 [M-2PF6] 2+ , found:m / z = 902.9969 [M-2PF6] 2+ .

[0092] (G) Chiral Au 16 Metal complex rac-A4-Au 16 Preparation of Cl8: A methanol solution (5 mL) of 1,4-bis(dithiocarbamate)-periperazine potassium salt (32.79 mg, 0.1 mmol) prepared in step S4 was slowly added to a methanol suspension (5 mL) of (dppm) Au2Cl2 (169.60 mg, 0.2 mmol) prepared in Example 2. The mixture was stirred at room temperature for 12 hours, and the mixture became a clear yellow-green solution. The solution was evaporated to dryness at 40°C and a vacuum of 150–200 mbar, washed with water, and the solid was dissolved in 10 mL of methanol. The resulting compound was crystallized in methanol / diethyl ether to obtain chiral Au. 16 Metal complexes.

[0093] (H) Chiral Au 16 Metal complex A4-Au 16 Preparation of (PF6)8: The rac-A4-Au prepared in step G 16 Cl8 (187.60 mg, 0.025 mmol) was dissolved in methanol (10 mL), and excess KPF6 (183.93 mg, 1 mmol) was added. The reaction was carried out for 12 hours, yielding a yellow precipitate, which was separated by centrifugation. The precipitate was washed with water and dissolved in 10 mL of acetonitrile. The resulting compound was crystallized in acetonitrile / diethyl ether to give chiral Au. 16 Metal complexes. ESI-MS (C 57 H 54 Au4N2P6S4F12 ): calcd for m / z = 2096.0066, found: m / z = 903.0278 [M-2PF6] 2+ , found: m / z = 1951.0230 [M-PF6] + .

[0094] Test Example 1: The MTT assay was used to evaluate ( ) M R,R M’ R,R )-Au 16 Cl8 and ( P S,S P’ S,S )-Au 16 The anticancer activity of Cl8 in U87 and 4T1 cancer cells was shown in Table 1.

[0095] Table 1 Chiral Au 16 Metal complexes in different cancer cells 50 :

[0096] Note: The data in Table 1 are the mean ± standard deviation of three independent experiments.

[0097] As can be seen from Table 1, IC 50 The test results show that chiral Au 16 Metal complexes exhibit significantly different antitumor activities in different cell lines, with the R-configuration molecules generally showing superior cytotoxicity. In U87 and 4T1 cells, the IC50 values ​​of the two configurations of the drug decreased as the incubation time increased from 24 hours to 72 hours. 50 The values ​​all showed a significant decreasing trend, suggesting that their cytotoxicity is time-dependent. Comparisons between different cell lines revealed that, compared to U87 cells, these two chiral Au values ​​showed a more pronounced decreasing trend. 16 Metal complexes exhibit lower IC50 in 4T1 cells. 50 The value indicates that its anti-tumor effect is more significant in breast cancer cells. Furthermore, at the same time point and cell type, the IC50 value of the R-configuration molecule... 50 The value is consistently lower than that of the S configuration, further indicating that the R configuration has stronger antitumor potential. In summary, the R configuration chiral Au... 16 Metal complexes exhibit more efficient inhibitory activity in breast cancer cells and show promising potential for targeted therapy.

[0098] in conclusion:( M R,R M’R,R )-Au 16 Cl8 and ( P S,S P’ S,S )-Au 16 Cl8 showed potent cytotoxicity against both 4T1 and U87 tumor cells, and this effect was time- and concentration-dependent; in addition, ( M R,R M’ R,R )-Au 16 Cl exhibits a higher ( P S, S P’ S,S )-Au 16 Cl8 exhibits superior antitumor activity.

[0099] Test Example 2: Evaluation was performed using annexin V / PI staining and flow cytometry. M R,R M’ R,R )-Au 16 Cl8 and ( P S,S P’ S,S )-Au 16 After 24 hours of Cl8 treatment, the percentage of apoptotic and necrotic cells in advanced breast cancer and the semi-quantitative analysis of apoptosis were performed. Evaluation was conducted using Bodipy 581 / 591 C11 staining and flow cytometry. M R,R M’ R,R )-Au 16 Cl8 and ( P S,S P’ S,S )-Au 16 Intracellular lipid peroxidation levels and semi-quantitative LPO analysis after 24 hours of Cl8 treatment were as follows: Figure 3 As shown.

[0100] according to Figure 3 It can be seen that chiral Au 16 Metal complexes have significant effects in inducing apoptosis and promoting lipid peroxidation in breast cancer cells, with the R-configuration being more effective than the S-configuration. Annexin V / PI double staining flow cytometry showed that chiral Au... 16 After 24 hours of treatment with metal complexes, the apoptosis rate followed the chiral Au 16The concentration of metal complexes increased significantly, with the R conformation inducing a higher proportion of apoptosis at the same dose. Further analysis using Bodipy 581 / 591 C11 staining to detect lipid peroxidation levels indicated that chiral Au... 16 Treatment with metal complexes significantly increased intracellular lipid peroxidation levels, exhibiting a dose-dependent increasing trend. The fluorescence intensity of the R-configuration group was higher than that of the S-configuration, suggesting that it more effectively induced lipid peroxidation. This phenomenon suggests the presence of chiral Au. 16 Metal complexes, especially the R configuration, may enhance antitumor activity by promoting lipid peroxidation-mediated ferroptosis. These results provide important experimental evidence for chiral metal drugs as a novel anticancer strategy.

[0101] in conclusion:( M R,R M’ R,R )-Au 16 Cl8 and ( P S,S P’ S,S )-Au 16 Cl8 can achieve anti-tumor effects through a dual cell death pathway: TrxR-induced apoptosis and GPX4-driven ferroptosis.

[0102] Test Example 3: right( M R,R M’ R,R )-Au 16 Cl8 and ( P S,S P’ S,S )-Au 16 The cytotoxicity of Cl8 on normal human hepatic stellate cells (LX-2) at different time points was analyzed, and the results are as follows: Figure 4 As shown.

[0103] according to Figure 4 It can be seen that R-type and S-type chiral Au 16 The metal complexes showed low cytotoxicity against normal LX-2 hepatic stellate cells at different time points (24 hours, 48 ​​hours, and 72 hours). The S-type molecule had almost no effect on cell viability after treatment at 24 and 48 hours, with only slight toxicity observed at a high dose at 72 hours. The R-type molecule showed a similar trend, but its cytotoxicity was slightly higher than that of the S-type molecule at 72 hours, manifested as a more significant decrease in cell viability. Overall, these results indicate that both R-type and S-type chiral Au... 16 Metal complexes have no significant toxicity to normal cells under low to medium doses and short-term exposure, and are relatively safe.

[0104] in conclusion:( M R,R M’ R,R )-Au 16 Cl8 and ( P S,S P’ S,S )-Au 16 Cl8 showed extremely low toxicity in LX-2 cells after 24 and 72 hours of treatment; indicating ( M R,R M’ R,R )-Au 16 Cl8 and ( P S,S P’ S,S )-Au 16 Cl8 has good biocompatibility.

[0105] The embodiments of the present invention have been described above; however, these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. All other embodiments obtained by those skilled in the art based on the above embodiments of the present invention without inventive effort are within the protection scope of the present invention.

Claims

1. A class of chiral Au 16 Metal complexes, characterized in that, The structure is shown in Equation I or Equation II: Formula I; Formula II; In Equations I and II, R1 is -H or -CH3, R2 is -H or -CH3, R3 is -H or -CH3, R4 is -H or -CH3, and X... - For Cl - or PF6 - .

2. The chiral Au according to claim 1 16 Metal complexes, characterized in that, In Equations I and II, R1 is -CH3, R2 is -CH3, R3 is -CH3, R4 is -CH3, and X is... - For Cl - or PF6 - .

3. The chiral Au according to claim 1 16 Metal complexes, characterized in that, In formula I, R1 is -H, R2 is -CH3, R3 is -CH3, R4 is -H, and X - For Cl - or PF6 - .

4. The chiral Au according to claim 1 16 Metal complexes, characterized in that, In formula II, R1 is -CH3, R2 is -H, R3 is -CH3, R4 is -H, and X... - For Cl - or PF6 - .

5. The chiral Au according to claim 1 16 Metal complexes, characterized in that, In Equation I, R1 is -H, R2 is -H, R3 is -H, R4 is -H, and X is... - For Cl - or PF6 - .

6. A chiral Au 16 The preparation method of the metal complex, wherein the chiral Au 16 The metal complex is the chiral Au as described in any one of claims 1 to 5. 16 Metal complexes, characterized in that, Includes the following steps: (1) Piperazine compounds, bases, carbon disulfide and mixed solvents were mixed to carry out a di-substitution reaction to obtain 1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt ligand; (2) A diphenylphosphine methane solution was added dropwise to a chloroauric acid tetrahydrate solution to carry out the first coordination reaction, resulting in a binuclear gold complex; (3) The 1,4-bis(dithiocarbamate)-2-methylpiperazine potassium salt ligand, the binuclear gold complex, and the alcohol solution were mixed to carry out a second coordination reaction to obtain chiral Au. 16 Metal complexes; There is no requirement for the time order of steps (1) and (2).

7. The preparation method according to claim 6, characterized in that, The piperazine compounds include one or more of R-(-)-2-methylpiperazine, S-(+)-2-methylpiperazine, piperazine, and homopiperazine.

8. The preparation method according to claim 6, characterized in that, The temperature for the di-substitution reaction is 38-42 degrees Celsius, and the holding time is 11-13 hours.

9. The preparation method according to claim 6, characterized in that, The second coordination reaction also includes a third post-processing of the resulting product; When performing the third post-processing, the anion exchange includes the following steps: mixing the product obtained from the second coordination reaction with potassium hexafluorophosphate and an alcohol solution to carry out anion exchange reaction; When no third post-processing is performed, the anion exchange includes the following steps: mixing the product obtained from the second coordination reaction with potassium hexafluorophosphate to carry out anion exchange reaction.

10. A chiral Au 16 The application of metal complexes in the preparation of drugs for treating platinum-resistant cancers, characterized in that, The chiral Au 16 The metal complex is the chiral Au as described in any one of claims 1 to 5. 16 Metal complexes or chiral Au obtained by the preparation method according to any one of claims 6 to 9 16 Metal complexes.

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