Cyanide-bridged binuclear metal organic compound as well as preparation method and application thereof

Abstract

The invention discloses a cyanogen-bridged binuclear metal organic compound as well as a preparation method and application thereof, and belongs to the technical field of biological medicines. The cyanide-bridged binuclear metal organic compound formed through cyano bridging has a Fe < II > / Fe < III > mixed valence state, electrons are delocalized between binuclear through Fe < II >-Fe < III > charge transfer, the binding capacity of the cyanide-bridged binuclear metal organic compound and DNA is remarkably improved, and then the DNA damage capacity to tumor cells is remarkably improved; in addition, the ligand L in the cyanogen-bridged binuclear metal organic compound can target tumor cells, so that the toxicity to normal tissues is reduced; meanwhile, Fe < 2 + > / Fe < 3 + > redox pairs in the cyanogen-bridged binuclear metal organic compound cooperate with high oxidability of a tumor microenvironment to trigger a Fenton reaction to generate active oxygen and selectively damage tumor cell mitochondria, so that the anti-tumor activity is further improved; therefore, the method has remarkable technical advancement and industrial application prospect in the field of biological medicines.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a cyanide-bridged binuclear organometallic compound, its preparation method, and its application. Background Technology

[0002] Cancer has become one of the leading causes of disease-related morbidity and mortality worldwide. A 2024 report by the World Health Organization (WHO) shows that more than 20 million new cases of malignant tumors are diagnosed globally each year, with solid tumors accounting for 78%. Treatment of common cancers such as lung cancer, breast cancer, and colorectal cancer still relies heavily on chemotherapy drugs. While platinum-based drugs, represented by cisplatin, have been widely used as first-line chemotherapy for solid tumors since their approval in 1978, their inherent limitations severely restrict treatment efficacy. Cisplatin primarily inhibits tumor cell proliferation through DNA cross-linking, but more than 30% of patients experience grade III or higher nephrotoxicity after treatment, and approximately 50% of ovarian and lung cancer patients develop resistance. Carboplatin, a second-generation platinum-based drug, has reduced nephrotoxicity, but about 60% of patients experience bone marrow suppression reactions such as thrombocytopenia, and the drug's resistance mechanism cannot be overcome. Oxaliplatin, while significantly effective against colorectal cancer, suffers from dose-dependent neurotoxicity (such as numbness in the extremities, exacerbated by cold), forcing 20%-30% of patients to discontinue treatment prematurely. Data from the National Cancer Institute (NCI) in the United States indicates that clinical limitations of platinum-based drugs prevent approximately 40% of patients with advanced solid tumors from receiving effective treatment. Therefore, the development of low-toxicity, highly active non-platinum metal anti-tumor drugs has become an urgent need in the international pharmaceutical field.

[0003] In the past three decades, significant progress has been made in the antitumor research of metal complexes such as ruthenium (Ru), copper (Cu), and titanium (Ti). Ruthenium complexes, such as KP1019, induce apoptosis by binding to the N7 position of guanine in DNA, achieving an objective response rate of 16% in a phase II clinical trial of advanced renal cell carcinoma, with significantly lower hepatotoxicity than cisplatin. NAMI-A, by inhibiting angiogenesis in tumor metastases, reduced the number of metastatic lesions by 40% in a breast cancer lung metastasis model. However, cellular uptake of ruthenium complexes depends on transferrin receptors, and high expression of this receptor in normal hepatocytes leads to elevated liver enzymes in approximately 15% of patients. Copper complexes, such as the Cu(II)-phen complex, can damage tumor cell mitochondria by generating reactive oxygen species (ROS), but the non-specific distribution of copper ions results in a high incidence of hemolytic toxicity.

[0004] Compared with other metals, iron-based complexes exhibit unique advantages in the field of anti-tumor therapy. Biocompatibility: The human body needs to ingest 10-15 mg of iron daily, and serum transferrin (Tf) has a high iron-binding constant of up to 10. 20 This ensures that iron-based compounds can be transported via natural iron metabolism pathways, reducing systemic toxicity. Redox activity: Fe 2+ / Fe3+ Standard electrode potential ( E θ A redox potential (=0.77V) matches the intracellular redox potential of tumor cells, allowing it to generate reactive oxygen species via the Fenton reaction, selectively damaging tumor cells containing high concentrations of glutathione peroxidase. Targeted delivery potential: Transferrin receptor (TfR1) expression in breast cancer MCF-7 cells reaches 2.3 × 10⁻⁶. 5 The number of cells per cell is 12 times that of normal mammary epithelial cells, providing a natural target for receptor-mediated endocytosis of iron-based compounds. Research at Stanford University in the United States shows that the endocytosis efficiency of the iron complex-TfR1 complex is 3.2 times that of the ruthenium complex.

[0005] However, existing metal complexes have poor activity in antitumor activity. Summary of the Invention

[0006] The purpose of this invention is to provide a cyanide-bridged binuclear organometallic compound, its preparation method, and its applications. This addresses the problem of poor activity of existing metal complexes in antitumor activity.

[0007] In a first aspect, the present invention provides a cyanide-bridged binuclear organometallic compound, the molecular formula of which is Na[ cis -Fe(L)2(CN)2][FeN(Cl)(CH2COO)3]; wherein L includes at least one of 2,2′-bipyridine or its derivatives, 2,2′-biquinoline, 1,10-o-phenanthroline or its derivatives.

[0008] In this invention, the inventors discovered that cyanide-bridged binuclear organometallic compounds formed through cyano bridging possess Fe... Ⅱ / Fe Ⅲ The mixed valence states of Fe, where Fe Ⅱ →Fe Ⅲ The charge transfer delocalizes electrons between the binucleates, significantly enhancing the binding affinity of this cyanide-bridged binucleated organometallic compound to DNA, thereby significantly increasing its ability to damage tumor cells' DNA. Furthermore, the ligand L in this cyanide-bridged binucleated organometallic compound can target tumor cells and reduce toxicity to normal tissues. Simultaneously, the Fe in this cyanide-bridged binucleated organometallic compound... 2+ / Fe 3+ Redox pairs synergistically interact with the high oxidative activity of the tumor microenvironment, triggering the Fenton reaction to generate reactive oxygen species (ROS), which selectively damage tumor cell mitochondria and further enhance antitumor activity.

[0009] In some embodiments, the 2,2′-bipyridine derivative includes 3-methyl-2,2′-bipyridine, 4-methyl-2,2′-bipyridine, 5-methyl-2,2′-bipyridine, 6-methyl-2,2′-bipyridine, 4-chloro-2,2′-bipyridine, 5-chloro-2,2′-bipyridine, 6-chloro-2,2′-bipyridine, 4-bromo-2,2′-bipyridine, 5-bromo-2,2′-bipyridine, 6-bromo-2,2′-bipyridine, 4-methyl ... 2,2′-Bipyridine, 5-methoxy-2,2′-bipyridine, 6-methoxy-2,2′-bipyridine, 4-cyano-2,2′-bipyridine, 5-cyano-2,2′-bipyridine, 6-cyano-2,2′-bipyridine, 4-tert-butyl-2,2′-bipyridine, 5-tert-butyl-2,2′-bipyridine, 6-tert-butyl-2,2′-bipyridine, 4,4'-dimethyl-2,2′-bipyridine, 5,5'-dimethyl-2,2′-bipyridine '-Bipyridine, 6,6'-dimethyl-2,2'-bipyridine, 4,4'-dicyano-2,2'-bipyridine, 5,5'-dicyano-2,2'-bipyridine, 6,6'-dicyano-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, 5,5'-dimethoxy-2,2'-bipyridine, 6,6'-dimethoxy-2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine, 5,5'- At least one of the following: di-tert-butyl-2,2′-bipyridine, 6,6′-di-tert-butyl-2,2′-bipyridine, 4,4′-dichloro-2,2′-bipyridine, 5,5′-dichloro-2,2′-bipyridine, 6,6′-dichloro-2,2′-bipyridine, 4,4′-dibromo-2,2′-bipyridine, 5,5′-dibromo-2,2′-bipyridine, 6,6′-dibromo-2,2′-bipyridine, and 4,4′-diphenyl-2,2′-bipyridine.

[0010] Understandably, the types of 2,2′-bipyridine derivatives can be conventionally selected according to the needs of use, as long as they contain bipyridine as a ligand.

[0011] In some embodiments, the 1,10-phenanthroline derivative includes 2-chloro-1,10-phenanthroline, 3-chloro-1,10-phenanthroline, 4-chloro-1,10-phenanthroline, 5-chloro-1,10-phenanthroline, 2-bromo-1,10-phenanthroline, 3-bromo-1,10-phenanthroline, 4-bromo-1,10-phenanthroline, 5-bromo-1,10-phenanthroline, 2-methyl-1,10-phenanthroline, 3-methyl-1,10-phenanthroline, 4-methyl-1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 2-methoxy-1,10-phenanthroline, 3-methoxy-1,10-phenanthroline, 4-methoxy-1,10-phenanthroline, 5-methoxy -1,10-o-phenanthroline, 2-cyano-1,10-o-phenanthroline, 3-cyano-1,10-o-phenanthroline, 4-cyano-1,10-o-phenanthroline, 5-cyano-1,10-o-phenanthroline, 2-nitro-1,10-o-phenanthroline, 3-nitro-1,10-o-phenanthroline, 4-nitro-1,10-o-phenanthroline, 5-nitro-1,10-o-phenanthroline 0-Phenanthroline, 2-tert-butyl-1,10-phenanthroline, 3-tert-butyl-1,10-phenanthroline, 4-tert-butyl-1,10-phenanthroline, 5-tert-butyl-1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 3,8-dimethyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5,6-Dimethyl-1,10-phenanthroline, 3,4,7,8-Tetramethyl-1,10-phenanthroline, 2,9-Dichloro-1,10-phenanthroline, 3,8-Dichloro-1,10-phenanthroline, 4,7-Dichloro-1,10-phenanthroline, 5,6-Dichloro-1,10-phenanthroline, 3,4,7,8-Tetrachloro-1,10-phenanthroline, 2,9-Dibromo-1,10-phenanthroline, 3,8-Dibromo-1,10-phenanthroline, 4,7-Dibromo-1,10-phenanthroline, 5,6-Dibromo-1,10-phenanthroline, 3,4,7,8-Tetrabromo-1,10-phenanthroline, 2,9-Dimethoxy-1,10-phenanthroline, 3,8-Dimethoxy-1, 10-Phenanthroline, 4,7-Dimethoxy-1,10-Phenanthroline, 5,6-Dimethoxy-1,10-Phenanthroline, 3,4,7,8-Tetramethoxy-1,10-Phenanthroline, 2,9-Dicyano-1,10-Phenanthroline, 3,8-Dicyano-1,10-Phenanthroline, 4,7-Dicyano-1,10-Phenanthroline, 5 6-Dinitro-1,10-phenanthroline, 3,4,7,8-Tetracyano-1,10-phenanthroline, 2,9-dinitro-1,10-phenanthroline, 3,8-dinitro-1,10-phenanthroline, 4,7-dinitro-1,10-phenanthroline, 5,6-dinitro-1,10-phenanthroline, 3,4,7,8-tetranitro-1,At least one of 10-phenanthroline.

[0012] Understandably, the types of 1,10-phenanthroline derivatives can be conventionally selected according to the needs of use, as long as they contain phenanthroline as a ligand.

[0013] In some implementations, the cyanide-bridged binuclear organometallic compound is monoclinic. P twenty one / n Space group.

[0014] In some implementations, an asymmetric unit in the cyanide-bridged binuclear organometallic crystal structure contains a [ cis -Fe(L)2(CN)2][FeN(Cl)(CH2COO)3] - An anion, a sodium ion, and two uncoordinated water molecules.

[0015] In some implementation schemes, [ cis -Fe(L)2(CN)2][FeN(Cl)(CH2COO)3] - Anions are composed of [ cis -Fe(L)2(CN)2] and [FeN(Cl)(CH2COO)3] - Formed via cyano bridging; wherein, [ cis In the [Fe(L)2(CN)2] fragment, iron has a distorted six-coordinate octagonal configuration, where four positions are occupied by the four nitrogen atoms of the two L ligands, and the remaining two positions are occupied by the carbon atoms of the cyano group in the cis position; [FeN(Cl)(CH2COO)3] - The fragment has a six-coordinate octahedral configuration, with four positions occupied by one nitrogen atom from the nitrotriacetate group and three oxygen atoms from the carboxylate group, and the remaining two positions occupied by a nitrogen atom from the cyano group and a chlorine atom from the cyano group, respectively.

[0016] In a second aspect, the present invention provides a method for preparing a cyanobridged binuclear organometallic compound as described in any of the above claims, comprising the following steps: dissolving ferric chloride and trisodium nitrilotriacetate in water to carry out a first reaction, and then adding a compound containing... cis The second reaction is carried out in the first organic solvent of -Fe(L)2(CN)2. The resulting product is filtered and dried to obtain the target precipitate. The organic ether solvent is diffused into the second organic solvent containing the target precipitate to obtain a cyanide-bridged binuclear organometallic compound.

[0017] The method for preparing cyanide-bridged binuclear organometallic compounds provided by this invention is simple, uses inexpensive and readily available raw materials, and operates under mild reaction conditions. It does not require inert gas protection or high-pressure equipment, making it suitable for large-scale industrial production. Furthermore, by utilizing the difference in miscibility between organic ether solvents and a second organic solvent, uniform crystal nuclei are formed through slow diffusion, thereby obtaining high-purity cyanide-bridged binuclear organometallic compound crystals.

[0018] In some implementation schemes, ferric chloride, trisodium nitrilotriacetate, and cis The molar ratio of Fe(L)2(CN)2 is 1:(0.5-2):(0.5-2); the mass-volume ratio of ferric chloride to water, the first organic solvent, the organic ether solvent, and the second organic solvent is 1g:(10-200ml):(10-200ml):(40-800ml):(10-200ml); wherein the first organic solvent includes methanol, the organic ether solvent includes methyl tert-butyl ether, and the second organic solvent includes N,N-dimethylformamide.

[0019] In this invention, by controlling ferric chloride, trisodium nitrilotriacetate, and cis Within specific ranges, the molar ratio of Fe(L)2(CN)2 and the amounts of the first organic solvent, organic ether solvent, and second organic solvent can ensure complete reaction and avoid the generation of impurities.

[0020] In some implementation schemes, the temperature of the first reaction is 15-25°C and the time is 0.2-2 hours; the temperature of the second reaction is 45-55°C and the time is 4-12 hours.

[0021] In this invention, by controlling the temperature and time of the first reaction and the temperature and time of the second reaction within a specific range, a cyanobridged binuclear organometallic compound with good performance is obtained.

[0022] In a third aspect, the present invention provides the use of cyanide-bridged binuclear organometallic compounds prepared by any of the above-described cyanide-bridged binuclear organometallic compounds or by any of the above-described preparation methods in the preparation of antitumor drugs.

[0023] In some implementation schemes, the tumor includes at least one of cervical cancer, lung adenocarcinoma, and breast cancer.

[0024] The beneficial effects of this invention are: unlike the prior art, the cyanide-bridged binuclear organometallic compounds formed by cyanide bridging in this invention contain Fe Ⅱ / Fe Ⅲ The mixed valence states of Fe, where Fe Ⅱ →Fe ⅢThe charge transfer delocalizes electrons between the binucleates, significantly enhancing the binding affinity of this cyanide-bridged binucleated organometallic compound to DNA, thereby significantly increasing its ability to damage tumor cells' DNA. Furthermore, the ligand L in this cyanide-bridged binucleated organometallic compound can target tumor cells and reduce toxicity to normal tissues. Simultaneously, the Fe in this cyanide-bridged binucleated organometallic compound... 2+ / Fe 3+ The redox pair synergizes with the high oxidative activity of the tumor microenvironment to trigger the Fenton reaction, generating reactive oxygen species (ROS) that selectively damage tumor cell mitochondria, thereby further enhancing anti-tumor activity. Therefore, it has significant technological advantages and promising industrial application prospects in the biomedical field. Attached Figure Description

[0025] Figure 1 The compound Na in Example 1 of this invention [ cis Crystal structure diagram of the molecule -Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3; Figure 2 The compound Na in Example 1 of this invention [ cis Infrared spectrum of [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3]; Figure 3 The compound Na in Example 1 of this invention [ cis The electronic absorption spectrum of [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3], where 1 represents the compound Na[ cis -Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3]; Figure 4 The results of cell viability changes during 24 hours of co-culturing HeLa cells with samples in the application test examples of this invention are shown. The Control group received 100 μL / well of complete culture medium; the cisplatin group received 100 μL / well of cisplatin working solution at a concentration of 50 μg / mL; Na[ cis The [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] group was treated with 100 μL / well of the corresponding sample working solution with concentrations of 1 μg / mL, 10 μg / mL, 50 μg / mL, 250 μg / mL, and 1000 μg / mL, respectively. Each treatment group was replicated in 3 wells. Figure 5 In the application test examples of this invention, HeLa cells were subjected to different concentrations of Na[ cis Curve showing the change in cell viability after co-culturing with [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] for 24 hours; Figure 6The results of cell viability changes after HeLa cells were co-cultured with samples for 48 hours in the application test examples of this invention are shown. The Control group received 100 μL / well of complete culture medium; the cisplatin group received 100 μL / well of cisplatin working solution at a concentration of 50 μg / mL; Na[ cis The [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] group was treated with 100 μL / well of the corresponding sample working solution with concentrations of 1 μg / mL, 10 μg / mL, 50 μg / mL, 250 μg / mL, and 1000 μg / mL, respectively. Each treatment group was replicated in 3 wells. Figure 7 In the application test examples of this invention, HeLa cells were subjected to different concentrations of Na[ cis Curve showing the change in cell viability after co-culturing with [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] for 48 h; Figure 8 The results show the changes in cell viability of A549 cells after co-culturing with the sample for 24 hours in the application test examples of this invention. The Control group received 100 μL / well of complete culture medium; the cisplatin group received 100 μL / well of cisplatin working solution at a concentration of 50 μg / mL; Na[ cis The [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] group was treated with 100 μL / well of the corresponding sample working solution with concentrations of 1 μg / mL, 10 μg / mL, 50 μg / mL, 250 μg / mL, and 1000 μg / mL, respectively. Each treatment group was replicated in 3 wells. Figure 9 In the application test examples of this invention, A549 cells were subjected to different concentrations of Na[ cis Curve showing the change in cell viability after co-culturing with [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] for 24 hours; Figure 10 The results show the changes in cell viability of A549 cells after co-culturing with the sample for 48 hours in the application test examples of this invention. The Control group received 100 μL / well of complete culture medium; the cisplatin group received 100 μL / well of cisplatin working solution at a concentration of 50 μg / mL; Na[ cis The [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] group was treated with 100 μL / well of the corresponding sample working solution with concentrations of 1 μg / mL, 10 μg / mL, 50 μg / mL, 250 μg / mL, and 1000 μg / mL, respectively. Each treatment group was replicated in 3 wells. Figure 11 In the application test examples of this invention, A549 cells were subjected to different concentrations of Na[ cisCurve showing the change in cell viability after co-culturing with [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] for 48 h; Figure 12 The results show the changes in cell viability of MCF-7 cells after co-culturing with the sample for 24 hours in the application test examples of this invention. The Control group received 100 μL / well of complete culture medium; the cisplatin group received 100 μL / well of cisplatin working solution at a concentration of 50 μg / mL; Na[ cis The [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] group was treated with 100 μL / well of the corresponding sample working solution with concentrations of 1 μg / mL, 10 μg / mL, 50 μg / mL, 250 μg / mL, and 1000 μg / mL, respectively. Each treatment group was replicated in 3 wells. Figure 13 In the application test examples of this invention, MCF-7 cells were subjected to different concentrations of Na[ cis Curve showing the change in cell viability after co-culturing with [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] for 24 hours; Figure 14 The results of cell viability changes in MCF-7 cells co-cultured with samples for 48 hours in the application test examples of this invention are shown. The Control group received 100 μL / well of complete culture medium; the cisplatin group received 100 μL / well of cisplatin working solution at a concentration of 50 μg / mL; Na[ cis The [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] group was treated with 100 μL / well of the corresponding sample working solution with concentrations of 1 μg / mL, 10 μg / mL, 50 μg / mL, 250 μg / mL, and 1000 μg / mL, respectively. Each treatment group was replicated in 3 wells. Figure 15 In the application test examples of this invention, MCF-7 cells were subjected to different concentrations of Na[ cis The curve showing the change in cell viability after co-culturing with [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] for 48 hours. Detailed Implementation

[0026] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0027] Experimental methods not specified in the examples are generally performed under conventional conditions and as described in the manual, or as recommended by the manufacturer. Unless otherwise specified, the general equipment, materials, reagents, etc. used are commercially available.

[0028] The main instruments and equipment used in this invention are as follows: CO2 constant temperature incubator (Beijing Sangyi Experimental Instrument Research Institute, model: WIGGENSWCI-180); ultra-clean workbench (Shanghai Dut Scientific Instrument Co., Ltd., model: SW-CJ-2FD); centrifuge (Shanghai Luxiangyi Centrifuge Instrument Co., Ltd., model: TD5); microplate reader (TECAN, model: SPARK 10M).

[0029] The main reagents and kits are as follows: fetal bovine serum (Procell, catalog number: 164210-50); F12K medium (Ginobio, catalog number: GMN21127-5); MEM medium (Corning, catalog number: 10-010-CV); DMEM high glucose medium (Corning, catalog number: 10-013-CVRC); PBS (Procell, catalog number: PB180327); trypsin (Biosharp, catalog number: BL512A); CCK8 (Invigentech, catalog number: IV08-100); cisplatin (MCE, catalog number: HY-17394); DMSO (Solepro, catalog number: D8371).

[0030] Cell lines: HeLa cells (human cervical cancer cells), purchased from Shanghai Saibaikang Biotechnology; A549 cells (human lung adenocarcinoma cells), purchased from Shanghai Saibaikang Biotechnology; MCF-7 cells (human breast cancer cells), purchased from Beina Biotechnology.

[0031] Cell culture medium preparation: A549 cell culture medium: prepared according to the ratio of F12K medium to fetal bovine serum of 9:1; HeLa cell culture medium: prepared according to the ratio of MEM medium to fetal bovine serum of 9:1; MCF-7 cell culture medium: prepared according to the ratio of DMEM high glucose medium to fetal bovine serum of 9:1.

[0032] Cell culture: A549, Hela, and MCF-7 cells were cultured in a 5% CO2 incubator at 37°C.

[0033] Example 1 This embodiment provides a method for preparing cyanide-bridged binuclear organometallic compounds.

[0034] For example, taking ligand L as 1,10-phenanthroline (phen) as an example, the synthetic molecular formula is Na[ cisA cyanide-bridged binuclear organometallic compound of the type Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3].

[0035] Specifically, it includes the following steps: At 20℃, ferric chloride (1.62 g, 0.01 mol) and trisodium nitrilotriacetate (CAS No.: 18662-53-8, molecular formula: C6H8NNa3O7, molecular weight: 275.099, 2.75 g, 0.01 mol) were dissolved in water (100 mL) and reacted for 0.5 h. Then, a solution containing... cis A methanol solution (50 ml) of Fe(phen)₂(CN)₂ (4.78 g, 0.01 mol) was prepared. The reaction mixture was reacted at 50 °C for 6 h, and the reaction was stopped. A large amount of brown precipitate was formed, which was filtered and dried to obtain a brown solid. Methyl tert-butyl ether (100 ml) was slowly diffused into a solution of N,N-dimethylformamide (50 ml) containing the brown solid, yielding 2.63 g of brown crystals, with a yield of 32.6%.

[0036] The chemical formula of the crystal was determined to be C. 32 H 26 ClFe2N7NaO8.

[0037] Elemental analysis: Theoretical values ​​(%): C, 47.64; H, 3.25; N, 12.15. Experimental values ​​(%): C, 46.94; H, 3.15; N, 12.09.

[0038] Infrared spectroscopy IR (KBr, cm⁻¹) -1 , Figure 2 ): 3409s, 3081vw, 3051vw, 2919w, 2850w, 2128w, 2105m, 2073s, 1657vw, 1651vw, 1643v w, 1633vw, 1625vw, 1601vw, 1578m, 1562vw, 1540w, 1518w, 1508w, 1489m, 1466w, 1453m, 1426s, 1411m, 1385s, 1340m, 1311w, 1294w, 1272w, 1252w, 1224m, 1206m, 1145m, 1104w , 1092w, 1053m, 1005w, 910m, 877w, 846s, 829w, 804w, 776m, 725s, 559vw, 540vw, 524vw.

[0039] UV-Vis (CH3CN) spectroscopy, λ max ,nm (ε,dm 3 mol-1 cm -1 ): 369(7921), 529(8134), 604(7392).

[0040] The molecular formula of this crystalline compound is Na[ cis -Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3].

[0041] The crystal structure of the prepared crystalline compound was determined using a Saturn 724+CCD diffractometer. Specifically, the Mo K₂ was monochromated using a graphite monochromator at 293 K. α ( λ =0.71073Å) rays, with ω - 2θ Independent diffraction points were collected using a variable-speed scanning method. The raw data underwent empirical absorption correction using CrystalClear, and the structure was analyzed using... SHELXL -2016 The procedure was derived via a direct method. Unless otherwise specified, all non-hydrogen atoms were anisotropically refined, and the parameters were obtained through... SHELXL The 2016 program underwent full-matrix least squares correction. Hydrogen atoms were generated theoretically through hydrogen addition, and the crystal structure was corrected using full-matrix least squares. The R value is defined as follows: w R = Σ || F o |−| F c || / Σ | F o |, w R =[ Σ [( F o 2 - F c 2 ) 2 ] / Σ [( F o 2 ) 2 ]] 1 / 2 . Compound Na[ cis The crystallographic data collection, structural determination, and refinement data of [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] are shown in Table 1 below.

[0042] Table 1 Compound Na[ cisCrystallographic data collection, structure determination, and refinement data for [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3]

[0043] Compound Na[ cis The partial bond lengths and bond angles of [-Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] are shown in Table 2 below.

[0044] Table 2 Compound Na[ cis Partial bond lengths and bond angles of [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3]

[0045] Furthermore, the compound Na[ prepared above] cis [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] is a monoclinic crystal system. P twenty one / n Space group, see Figure 1 An asymmetric unit in the crystal structure of this compound contains a [ cis -Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] - An anion, one sodium ion, and two uncoordinated water molecules. cis -Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] - Anions are composed of [ cis [Fe(phen)2(CN)2] and [FeN(Cl)(CH2COO)3] - Formed via cyano bridging; wherein, [ cis In the [Fe(phen)2(CN)2] fragment, iron has a distorted six-coordinate octahedral configuration, with four positions occupied by the four nitrogen atoms of the two 1,10-phenanthroline groups, and the remaining two positions occupied by the carbon atoms of the cyano group in the cis position; [FeN(Cl)(CH2COO)3] - The fragment has a six-coordinate octahedral configuration, with four positions occupied by one nitrogen atom from the nitrotriacetate group and three oxygen atoms from the carboxylate group, and the remaining two positions occupied by a nitrogen atom from the cyano group and a chlorine atom from the cyano group, respectively.

[0046] Among them, in [ cis In the [Fe(phen)2(CN)2] fragment, Fe1 The C bond lengths are 1.897(14) Å and 1.894(14) Å, respectively, and the Fe1-N bond lengths are 1.967(11)-2.015(11) Å. The C bond lengths are 1.159(15) Å and 1.132(16) Å, respectively. In [FeN(Cl)(CH2COO)3] - In the fragment, the bond lengths of Fe2-O are 1.983(10)-2.037(11) Å, the bond length of Fe2-Cl1 is 2.130(14) Å, the bond length of Fe2-N7 is 2.194(12) Å, the bond length of Fe2-N1 is 2.040(11) Å, and the bond angle of C1-Fe1-C2 is 86.8(6). o The bond angle of Cl1-Fe2-N1 is 92.3° (5) o C1 The bond angle of N1-Fe2 is 167.6 (12) o N The bond angle of C-Fe1 is 176.4° (13) o And 176.1(13) o .

[0047] The compound Na[ prepared above] cis Electronic absorption spectroscopy was performed on [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3]. Specifically, acetonitrile was used for the test on a Perkin-Elmer Lambda 900 UV-vis-NIR spectrometer, and the results are as follows: Figure 3 As shown.

[0048] from Figure 3 It can be seen from this that compound Na[ cis -Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] at 369nm ( ε= 7921dm 3 ·mol -1 ·cm -1 ), 529 nm ( ε= 8134dm 3 ·mol -1 ·cm -1 ) and 604nm ( ε= 7392dm 3 ·mol -1 ·cm -1 The maximum absorption wavelength appears at ( ). Compound Na[ cisThe maximum absorption bands of [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] at 369 nm and 529 nm can be attributed to metal-ligand charge transfer, while the absorption of the maximum absorption band at 604 nm can be attributed to Fe II →Fe III Metal-to-metal charge transfer.

[0049] Application test cases This application test example uses the compound Na[ prepared in Example 1]. cis The cytotoxicity of [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] to cancer cell lines was tested.

[0050] Specifically, the CCK-8 assay was used to detect the presence of the compound Na in HeLa (human cervical cancer cells), A549 (human lung adenocarcinoma cells), MCF-7 cells (human breast cancer cells). cis Changes in cell viability after co-culturing with [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] for 24h and 48h.

[0051] First, prepare the solution: Accurately weigh 100 mg of the compound powder sample prepared in Example 1, sterilize by UV irradiation for 30 min, and dissolve in DMSO to a concentration of 100 mg / mL. For cisplatin (1 mg / mL): Weigh 10 mg of the solid powder sample, dissolve in complete culture medium to a concentration of 1 mg / mL, filter to sterilize, and set aside. Dilute the above solution with complete culture medium to prepare the working solution.

[0052] Then, the experiments were divided into groups: Control group, cisplatin group, 1% DMSO group, and Na[ cis The [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] group comprised four subgroups. The Control group received 100 μL / well of complete culture medium; the cisplatin group received 100 μL / well of 50 μg / mL sample working solution; the 1% DMSO group received 100 μL / well of 1% DMSO sample working solution; and the Na[ cis The [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] group was treated with 100 μL / well of working solution at concentrations of 1, 10, 50, 100, 250, 500, and 1000 μg / mL. Each treatment group was replicated in triplicate.

[0053] Finally, the CCK8 experiment was performed: A549, HeLa, and MCF-7 cells in logarithmic growth phase were collected, cell counts were performed, and cell concentrations were adjusted to 4 × 10⁻⁶ cells / cells.3 Inoculate each well into a 96-well plate and incubate overnight at 37°C with 5% CO2. Continue incubation for 48 hours following the same grouping process. Remove the culture medium. Wash each well three times with PBS, add 120 μL / well of medium containing 10% CCK-8, and incubate at 37°C with 5% CO2 for 2 hours. Transfer 100 μL / well of the supernatant to a new 96-well plate and measure the absorbance at 450 nm using a microplate reader.

[0054] The absorbance values ​​of each group were entered into Excel and the relative activity was calculated (relative activity % = (experimental group OD value - background OD value) / (control group mean OD value - background OD value) × 100), where the background OD value is the absorbance with only CCK8 reagent and culture medium added.

[0055] The results are as follows: Figure 4-15 As shown.

[0056] from Figure 4-7 As can be seen from the above, the compound Na[ prepared by this invention] cis [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] exhibits good cytotoxicity against HeLa cells, and with the addition of Na[ cis The increased concentration of [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] and the increased co-culture time further enhanced the cytotoxicity of HeLa cells. After 24 hours of co-culture, 1000 μg / mL of the compound reduced the relative viability of HeLa cells to 76.30%, and after 48 hours of co-culture, 1000 μg / mL of the compound reduced the relative viability of HeLa cells to 46.07%.

[0057] from Figure 8-11 As can be seen from the above, the compound Na[ prepared by this invention] cis [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] exhibits good cytotoxicity against A549 cells, and with the addition of compound Na[ cis The increased concentration of [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] and the increased co-culture time further enhanced the cytotoxicity of A549 cells. After 24 hours of co-culture, 1000 μg / mL of the compound reduced the relative viability of A549 cells to 70.82%, and after 48 hours of co-culture, 1000 μg / mL of the compound reduced the relative viability of A549 cells to 69.00%.

[0058] from Figure 12-15 As can be seen from the above, the compound Na[ prepared by this invention] cis[Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] exhibits good cytotoxicity against MCF-7 cells, and with the addition of compound Na[ cis The increased concentration of [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] and the increased co-culture time further enhanced the cytotoxicity of MCF-7 cells. After 24 hours of co-culture, 1000 μg / mL of the compound reduced the relative viability of MCF-7 cells to 34.15%, and after 48 hours of co-culture, 1000 μg / mL of the compound reduced the relative viability of MCF-7 cells to 28.30%; and the cytotoxicity of the compound to MCF-7 cells was significantly higher than that of cisplatin.

[0059] In summary, the compound Na[ in this invention] cis [Fe(phen)2(CN)2][FeN(Cl)(CH2COO)3] exhibits good cytotoxicity against HeLa, A549, and MCF-7 cells, thus showing promising application prospects in the preparation of antitumor drugs.

[0060] It should be noted that all the above embodiments belong to the same inventive concept, and the descriptions of each embodiment have different focuses. Where the description in a particular embodiment is not detailed, please refer to the description in other embodiments.

[0061] The embodiments described above are merely illustrative of implementation methods of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A cyanide-bridged binuclear organometallic compound, characterized in that, The molecular formula of the cyanide-bridged binuclear organometallic compound is Na[ cis -Fe(L)2(CN)2][FeN(Cl)(CH2COO)3]; Wherein, L includes at least one of 2,2′-bipyridine or its derivatives, 2,2′-biquinoline, 1,10-o-phenanthroline or its derivatives.

2. The cyanide-bridged binuclear organometallic compound according to claim 1, characterized in that, The 2,2′-bipyridine derivatives include 3-methyl-2,2′-bipyridine, 4-methyl-2,2′-bipyridine, 5-methyl-2,2′-bipyridine, 6-methyl-2,2′-bipyridine, 4-chloro-2,2′-bipyridine, 5-chloro-2,2′-bipyridine, 6-chloro-2,2′-bipyridine, 4-bromo-2,2′-bipyridine, 5-bromo-2,2′-bipyridine, 6-bromo-2,2′-bipyridine, and 4-methoxy-2, 2′-Bipyridine, 5-methoxy-2,2′-bipyridine, 6-methoxy-2,2′-bipyridine, 4-cyano-2,2′-bipyridine, 5-cyano-2,2′-bipyridine, 6-cyano-2,2′-bipyridine, 4-tert-butyl-2,2′-bipyridine, 5-tert-butyl-2,2′-bipyridine, 6-tert-butyl-2,2′-bipyridine, 4,4'-dimethyl-2,2′-bipyridine, 5,5'-dimethyl-2,2′-bipyridine Pyridine, 6,6'-dimethyl-2,2'-bipyridine, 4,4'-dicyano-2,2'-bipyridine, 5,5'-dicyano-2,2'-bipyridine, 6,6'-dicyano-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, 5,5'-dimethoxy-2,2'-bipyridine, 6,6'-dimethoxy-2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine, 5,5'-di At least one of tert-butyl-2,2′-bipyridine, 6,6′-ditert-butyl-2,2′-bipyridine, 4,4′-dichloro-2,2′-bipyridine, 5,5′-dichloro-2,2′-bipyridine, 6,6′-dichloro-2,2′-bipyridine, 4,4′-dibromo-2,2′-bipyridine, 5,5′-dibromo-2,2′-bipyridine, 6,6′-dibromo-2,2′-bipyridine, and 4,4′-diphenyl-2,2′-bipyridine.

3. The cyanide-bridged binuclear organometallic compound according to claim 1, characterized in that, The 1,10-phenanthroline derivatives include 2-chloro-1,10-phenanthroline, 3-chloro-1,10-phenanthroline, 4-chloro-1,10-phenanthroline, 5-chloro-1,10-phenanthroline, 2-bromo-1,10-phenanthroline, 3-bromo-1,10-phenanthroline, 4-bromo-1,10-phenanthroline, 5-bromo-1,10-phenanthroline, 2-methyl-1,10-phenanthroline, 3-methyl-1,10-phenanthroline, 4-methyl-1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 2-methoxy-1,10-phenanthroline, 3-methoxy-1,10-phenanthroline, 4-methoxy-1,10-phenanthroline, 5-methoxy-1,10-phenanthroline, 2-methoxy-1,10-phenanthroline, 3-methoxy-1,10-phenanthroline, 4-methoxy-1,10-phenanthroline, and 5-methoxy-1,10-phenanthroline. Phospho-1,10-phenanthroline, 3-cyano-1,10-phenanthroline, 4-cyano-1,10-phenanthroline, 5-cyano-1,10-phenanthroline, 2-nitro-1,10-phenanthroline, 3-nitro-1,10-phenanthroline, 4-nitro-1,10-phenanthroline, 5-nitro-1,10-phenanthroline, 2-tert- Butyl-1,10-o-phenanthroline, 3-tert-butyl-1,10-o-phenanthroline, 4-tert-butyl-1,10-o-phenanthroline, 5-tert-butyl-1,10-o-phenanthroline, 2,9-dimethyl-1,10-o-phenanthroline, 3,8-dimethyl-1,10-o-phenanthroline, 4,7-dimethyl-1,10-o-phenanthroline, 5,6-dimethyl-1, 10-Phenanthroline, 3,4,7,8-Tetramethyl-1,10-Phenanthroline, 2,9-Dichloro-1,10-Phenanthroline, 3,8-Dichloro-1,10-Phenanthroline, 4,7-Dichloro-1,10-Phenanthroline, 5,6-Dichloro-1,10-Phenanthroline, 3,4,7,8-Tetrachloro-1,10-Phenanthroline, 2,9-Dibromo -1,10-o-phenanthroline, 3,8-dibromo-1,10-o-phenanthroline, 4,7-dibromo-1,10-o-phenanthroline, 5,6-dibromo-1,10-o-phenanthroline, 3,4,7,8-tetrabromo-1,10-o-phenanthroline, 2,9-dimethoxy-1,10-o-phenanthroline, 3,8-dimethoxy-1,10-o-phenanthroline, 4,7- At least one of the following: dimethoxy-1,10-phenanthroline, 5,6-dimethoxy-1,10-phenanthroline, 3,4,7,8-tetramethoxy-1,10-phenanthroline, 2,9-dicyano-1,10-phenanthroline, 3,8-dicyano-1,10-phenanthroline, 4,7-dicyano-1,10-phenanthroline, 5,6-dicyano-1,10-phenanthroline, 3,4,7,8-tetracyano-1,10-phenanthroline, 2,9-dinitro-1,10-phenanthroline, 3,8-dinitro-1,10-phenanthroline, 4,7-dinitro-1,10-phenanthroline, 5,6-dinitro-1,10-phenanthroline, and 3,4,7,8-tetranitro-1,10-phenanthroline.

4. The cyanide-bridged binuclear organometallic compound according to claim 1, characterized in that, The cyanide-bridged binuclear organometallic compound is monoclinic. P twenty one / n Space group.

5. The cyanide-bridged binuclear organometallic compound according to claim 1, characterized in that, An asymmetric unit in the cyanide-bridged binuclear organometallic compound crystal structure contains a [ cis -Fe(L)2(CN)2][FeN(Cl)(CH2COO)3] - An anion, a sodium ion, and two uncoordinated water molecules.

6. The cyanide-bridged binuclear organometallic compound according to claim 5, characterized in that, The [ cis -Fe(L)2(CN)2][FeN(Cl)(CH2COO)3] - Anions are composed of [ cis -Fe(L)2(CN)2] and [FeN(Cl)(CH2COO)3] - Formed via cyano bridging; Among them, the [ cis In the [Fe(L)2(CN)2] fragment, iron has a distorted six-coordinate octagonal configuration, where four positions are occupied by the four nitrogen atoms of the two L ligands, and the remaining two positions are occupied by the carbon atoms of the cyano group in the cis position; [FeN(Cl)(CH2COO)3] - The fragment has a six-coordinate octahedral configuration, with four positions occupied by one nitrogen atom from the nitrotriacetate group and three oxygen atoms from the carboxylate group, and the remaining two positions occupied by a nitrogen atom from the cyano group and a chlorine atom from the cyano group, respectively.

7. A method for preparing a cyanide-bridged binuclear organometallic compound as described in any one of claims 1-6, characterized in that, Includes the following steps: After dissolving ferric chloride and trisodium nitrilotriacetate in water, the first reaction is carried out, followed by the addition of... cis The second reaction is carried out in a first organic solvent containing Fe(L)2(CN)2. The resulting product is filtered and dried to obtain the target precipitate. An organic ether solvent is diffused into a second organic solvent containing the target precipitate to obtain the cyanide-bridged binuclear organometallic compound.

8. The preparation method according to claim 7, characterized in that, The ferric chloride, the trisodium triamcinolone acetonide and the cis The molar ratio of Fe(L)2(CN)2 is 1:(0.5-2):(0.5-2). The mass-volume ratio of the ferric chloride to the water, the first organic solvent, the organic ether solvent, and the second organic solvent is 1g:(10-200ml):(10-200ml):(40-800ml):(10-200ml). Wherein, the first organic solvent includes methanol, the organic ether solvent includes methyl tert-butyl ether, and the second organic solvent includes N,N-dimethylformamide.

9. The preparation method according to claim 7, characterized in that, The temperature of the first reaction is 15-25℃ and the time is 0.2-2h; the temperature of the second reaction is 45-55℃ and the time is 4-12h.

10. The use of the cyanobridged binuclear organometallic compound according to any one of claims 1-6 or the cyanobridged binuclear organometallic compound prepared by the preparation method according to any one of claims 7-9 in the preparation of antitumor drugs.

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