Polyene platinum (II) complexes, processes for their preparation and use
Patent Information
- Application Number
- CN202611405885.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-09-10
- Publication Date
- 2026-10-27
AI Technical Summary
[0009]铂类药物（如顺铂）因其独特的作用机制、广泛的抗癌谱成为目前临床治疗恶性肿瘤最为有效的药物之一。铂类药物通过与肿瘤细胞DNA结合，形成铂-DNA加合物，从而干扰DNA复制，诱导细胞凋亡，但是铂类药物的抗菌活性报道很少。本发明通过结构设计，合成了一种新型的多烯铂（II）配合物，经验证具有良好的抗菌作用，对多种细菌和真菌均具有明显的抑制效果，能有效弥补抗生素滥用导致的耐药性问题，为开发新型铂类化合物在抗菌邻域的应用提供依据。
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of antibacterial drugs, and specifically relates to a polyene platinum(II) complex, its preparation method and application. Background Technology
[0002] With the widespread use of antibiotics, especially the unregulated overuse, bacterial resistance has become an increasingly prominent public health problem. Traditional antimicrobial drugs face enormous challenges, and finding antimicrobial compounds with novel structures and new mechanisms of action is the fundamental solution to the problem of antimicrobial resistance.
[0003] Small-molecule organometallic compounds, with their unique metal coordination modes, are primarily studied as anticancer and antimalarial drugs. From the early 20th century to the present, the main application of metal coordination compounds has been in the field of anticancer therapy. Metal coordination compounds possess two potential advantages in medicinal chemistry. First, the various states and multivalent nature of transition metals allow them to bind with countless different organic and inorganic ligands, forming highly diverse three-dimensional structures, thus opening up many previously inaccessible chemical spaces. Second, metal coordination compounds possess many unique reaction modes, including redox reactions, reactive oxygen species reactions, catalysis by other active substances, ligand exchange, or ligand release triggered by ligands. Currently, all antibacterial drugs and candidate antibacterial drugs are organic molecules, but practically applicable organometallic complexes for antibacterial use are still lacking. Summary of the Invention
[0004] To address the aforementioned problems in the prior art, the present invention provides a polyene platinum(II) complex having the following chemical structural formula:
[0005] .
[0006] This invention also provides a method for preparing the polyene platinum(II) complex, comprising the following preparation route:
[0007] .
[0008] The present invention also provides the use of the polyene platinum (II) complex in antibacterial and / or antifungal applications.
[0009] Platinum-based drugs (such as cisplatin) are among the most effective drugs for the clinical treatment of malignant tumors due to their unique mechanism of action and broad anticancer spectrum. Platinum-based drugs bind to tumor cell DNA, forming platinum-DNA adducts, thereby interfering with DNA replication and inducing apoptosis. However, reports on the antibacterial activity of platinum-based drugs are scarce. This invention synthesizes a novel polyene platinum(II) complex through structural design, which has been verified to have good antibacterial activity, showing significant inhibitory effects on various bacteria and fungi. This effectively addresses the drug resistance problem caused by antibiotic overuse and provides a basis for developing novel platinum compounds for application in the antibacterial field. Attached Figure Description
[0010] Figure 1 Compound 3 in Example 1 1 H NMR spectrum.
[0011] Figure 2 Compound 3 in Example 1 13 C NMR spectrum.
[0012] Figure 3 This is a high-resolution mass spectrum of compound 3 in Example 1.
[0013] Figure 4 The infrared spectrum of compound 3 in Example 1 is shown. Detailed Implementation
[0014] To make the technical solution, objectives, and advantages of the present invention clearer, the present invention will be further described in detail below through specific embodiments. It should be understood that the specific embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.
[0015] To further investigate the bioactivity of platinum complexes, this invention synthesizes a novel polyene platinum(II) complex molecule through structural design and evaluates its antibacterial activity, providing a basis for developing novel platinum compounds for application in the antibacterial field.
[0016] In a first aspect, the present invention provides a polyene platinum(II) complex having the following chemical structural formula:
[0017] .
[0018] According to a first aspect of the present invention, the polyene platinum(II) complex is named dichloro(3,7-dimethyl-1,6-octadiene)platinum, and its molecular formula is C2. 10 H 18 Cl2Pt.
[0019] In a second aspect, the present invention provides a method for preparing the polyene platinum(II) complex provided in the first aspect of the present invention, the method comprising the following preparation route:
[0020] .
[0021] According to a second aspect of the present invention, specifically, the method includes the following steps:
[0022] Step 1, Preparation of Compound 2:
[0023] Compound 2 was prepared from compound 1 in the presence of tetrahydrofuran (THF), sodium hydride (NaH), and methyl iodide (MeI) under anhydrous and oxygen-free conditions.
[0024] Compound 1 is named 3,7-dimethyl-1,6-octadien-3-ol, with the molecular formula C1. 10 H 18 O can be a product purchased from Heins Corporation with product number D-74430.
[0025] Compound 2 is named 3-methoxy-3,7-dimethyl-1,6-octadiene, with the molecular formula C2. 11 H 20 O.
[0026] Furthermore, the preparation of compound 2 may include the following operations:
[0027] Under anhydrous and oxygen-free conditions, compound 1 and THF were mixed at a weight / volume ratio (g:mL) of 1:(18-24) (preferably 1:22), and the mixture was stirred at 0°C for 0.5-2 h (preferably 1 h).
[0028] Then, add NaH to the reaction solution according to the molar ratio of compound 1 to NaH of 1:(0.5-2) (preferably 1:1.3), heat the reaction solution to 40°C, and continue stirring the reaction for 1-2 hours (preferably 1 hour).
[0029] Then, add MeI at a molar ratio of 1:(2-3) (preferably 1:2.2) of compound 1 and continue stirring the reaction for 10-14 h (preferably 12 h) to obtain the reaction product containing compound 2;
[0030] The reaction product containing compound 2 was poured into a saturated ammonium chloride solution and allowed to stand to separate into layers. The oil layer and the water layer were separated using a separatory funnel. The water layer was extracted with ethyl acetate to obtain the ethyl acetate extract layer.
[0031] The ethyl acetate extract and the aforementioned oil layer were combined and dried (the purpose of drying is to remove moisture, which can be done with anhydrous sodium sulfate), filtered to obtain the filtrate, and the filter cake (the main component of the filter cake is sodium sulfate) was discarded. The filtrate was concentrated to obtain the crude product of compound 2. The crude product of compound 2 was purified by silica gel chromatography to obtain purified compound 2.
[0032] Step 2, Preparation of Compound 3:
[0033] Compound 3 was prepared by reacting compound 2 with chloroplatinic acid under anhydrous and oxygen-free conditions.
[0034] Furthermore, the preparation of compound 3 may include the following operations:
[0035] Under anhydrous and oxygen-free conditions, chloroplatinic acid (PtCl6H2) and anhydrous acetic acid are stirred at 75°C for 1 h at a weight / volume ratio (g:mL) of 1:(7-10) (preferably 1:8) until the chloroplatinic acid is completely dissolved.
[0036] Then, according to the molar ratio of chloroplatinic acid to compound 2 of 1:(8-12) (preferably 1:10), compound 2 is added dropwise to the reaction solution, and the mixture is stirred at 70-80℃ (preferably 75℃) for 1.2-1.8h (preferably 1.5h) to obtain a reaction product containing compound 3;
[0037] After cooling the reaction product containing compound 3 to room temperature, add water, let stand for 0.8-3 hours (preferably 1 hour), filter, discard the filtrate, and collect the filter residue;
[0038] The obtained filter residue is first washed with ether, filtered and the liquid (i.e., the ether used as washing liquid) is discarded. Then, dichloromethane (DCM) is added to the container containing the filter residue, stirred thoroughly and allowed to stand. The filtrate is collected and the filter residue is discarded.
[0039] Add silica gel (100-200 mesh, which can be purchased from Anhui Liangchen Silicon Source Material) to the filtrate and let it stand to adsorb and remove color; then filter and collect the filtrate, and wash the filter residue with DCM again and collect the washing liquid.
[0040] The filtrate collected after adding silica gel and letting it stand and filtering was combined with the washing liquid collected after washing with DCM to obtain a liquid containing compound 3. The liquid containing compound 3 was treated with a rotary evaporator to remove most of the solvent (i.e., DCM), and a solid was observed to precipitate out (this solid is compound 3), thus obtaining a mixture containing compound 3.
[0041] Then, add diethyl ether to the mixture containing compound 3 for washing, filter, and collect the filter residue to obtain the yellow compound 3.
[0042] Thirdly, the present invention provides the use of the polyene platinum (II) complex provided in the first aspect of the present invention in antibacterial and / or antifungal applications.
[0043] According to a third aspect of the present invention, the bacteria may be Gram-positive or Gram-negative bacteria; for example, the bacteria may be methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300), Staphylococcus aureus standard strain (S. Aureus ATCC 25923), Escherichia coli standard strain (E. Coli ATCC 25922), Klebsiella pneumoniae standard strain (K. Pneumoniae ATCC 13883), or Pseudomonas aeruginosa standard strain (P. Aeruginosa ATCC 27853).
[0044] According to a third aspect of the invention, the fungus may be, for example, Candida albicans (C. albicans ATCC90028), Cryptococcus neoformans (C. neoformans ATCC32045), or Candida glabrata (C. glabrata ATCC15126).
[0045] The application of the polyene platinum(II) complex provided by this invention in the preparation of antibacterial and / or antifungal drugs is also within the scope of protection of this invention.
[0046] Unless otherwise specified, all reagents and materials used in the following examples are products that can be obtained from commercial channels; unless otherwise specified, all testing and detection methods used in the following examples are conventional testing and detection methods in the field and can be obtained from textbooks, reference books or academic journals.
[0047] In the following embodiments:
[0048] Dichloro(3,7-dimethyloctyl-1,6-dienyl)platinum (i.e., compound 3) was prepared into a 1000 µg / mL solution using 5% DMSO for later use.
[0049] Both Pt(COD)Cl2 and Pt(NOD)Cl2 were purchased from the Kunming Institute of Precious Metals and were prepared into a 1000 µg / mL solution using 5% DMSO for later use.
[0050] Cisplatin, carboplatin, sunipin, and heptaplatin were all purchased from the Kunming Institute of Precious Metals and were prepared into a 1000 µg / mL solution using 5% DMSO for later use.
[0051] All antibiotics were prepared using 0.9% sterile saline to a solution of 125 µg / mL for later use.
[0052] The standard bacterial strains used are:
[0053] Candida albicans (C. albicans ATCC90028), Cryptococcus neoformans (C. neoformans ATCC32045), and Candida glabrata (C. glabrata ATCC15126).
[0054] The standard fungal strain used is:
[0055] Staphylococcus aureus (S. Aureus ATCC 25923), methicillin-resistant Staphylococcus aureus (MRSA ATCC 43300), Escherichia coli (E. Coli ATCC 25922), Klebsiella pneumoniae (K. Pneumoniae ATCC 13883), and Pseudomonas aeruginosa (P. Aeruginosa ATCC 27853).
[0056] The aforementioned bacterial and fungal standard strains were all purchased from Shanghai Luwei Technology Co., Ltd.
[0057] Example 1
[0058] This example illustrates the preparation of compound 3.
[0059] Step 1, Preparation of Compound 2:
[0060] Under anhydrous and oxygen-free conditions, compound 1 (3,7-dimethyl-1,6-octadien-3-ol) (10.0 g, 64.8 mmol) was added to a 500 mL three-necked flask, followed by tetrahydrofuran (220 mL). The reaction was then cooled to 0 °C and stirred for 1 h.
[0061] Then add NaH (weigh 3.4 g of 60% NaH dispersion dissolved in mineral oil, containing 84.3 mmol of NaH), heat the reaction to 40°C, and continue stirring for 1 hour.
[0062] Then add iodomethane (20.4 g, 143.7 mmol) and continue stirring for 12 h.
[0063] Pour the reaction solution into saturated ammonium chloride (200 mL), and use a separatory funnel to separate the oil layer and the water layer; then extract the water layer with ethyl acetate (200 mL) to obtain the ethyl acetate extract layer;
[0064] After combining the ethyl acetate extract layer and the aforementioned oil layer, the mixture was dried with anhydrous sodium sulfate (the purpose of drying was to remove moisture), filtered, the filtrate was collected, and the filter cake (the main component of the filter cake was sodium sulfate) was discarded.
[0065] The filtrate was concentrated to obtain crude compound 2; the crude compound 2 was purified by silica gel chromatography to obtain purified compound 2 with a yield of 72%.
[0066] The structure of compound 2 is characterized as follows:
[0067] 1 H NMR (500MHz, Chloroform-d) δ 5.76 (dd,J=17.6,10.9Hz,1H), 5.19–5.06 (m,3H), 3.15 (s,3H), 1.98 (d,J=8.1Hz,2H), 1.70–1.65 (m, 3H), 1.62–1.58 (m, 3H), 1.58–1.49 (m, 2H), 1.23 (s, 3H).
[0068] 13 C NMR (126MHz, Chloroform-d) δ 142.85, 131.30, 124.48, 114.51, 85.96–74.62 (m), 49.90, 39.33, 25.61, 22.33, 21.53, 17.54.
[0069] Step 2, Preparation of Compound 3:
[0070] Under anhydrous and oxygen-free conditions, chloroplatinic acid (1.0 g, 2.4 mmol) was added to a 25 mL three-necked flask, followed by anhydrous acetic acid (8 mL). The mixture was heated to 75 °C and stirred for 1 h until all the chloroplatinic acid dissolved.
[0071] Compound 2 (3.9 g, 24.4 mmol) was then added dropwise to the above reaction solution. A small amount of yellow solid was observed to precipitate during the reaction, and the reaction was continued to be stirred at 75 °C for 1.5 h.
[0072] Stop stirring, cool to room temperature, add water (50 mL) and let stand for 1 hour. Discard the filtrate and collect the filter residue.
[0073] The obtained filter residue was first washed with ether (50 mL), filtered and the washing liquid (ether) was discarded. Then, dichloromethane (20 mL) was added to the container containing the filter residue, stirred thoroughly and allowed to stand. The filtrate was collected and the filter residue was discarded.
[0074] Add silica gel (3g, 100~200 mesh, purchased from Anhui Liangchen Silicon Source Materials) to the filtrate and let it stand to adsorb and remove color; then filter and collect the filtrate, wash the filter residue again with dichloromethane (20mL) and collect the washing liquid;
[0075] The filtrate collected after adding silica gel and letting it stand and filtering was combined with the washing liquid collected after washing with dichloromethane to obtain a liquid containing compound 3.
[0076] The liquid containing compound 3 was treated with a rotary evaporator to remove most of the solvent (i.e., dichloromethane). A solid was observed to precipitate out (which is compound 3), thus obtaining a mixture containing compound 3.
[0077] Then, 5 mL of ether was added to the mixture containing compound 3 for washing. After filtration, the residue was collected to obtain yellow compound 3 with a yield of 21%.
[0078] The structure of compound 3 is characterized as follows:
[0079] 1 HNMR (500MHz, Chloroform-d) δ 5.73–5.52 (m,2H), 2.47–2.35 (m,1H), 2.15–2.01 (m,2H), 1.58 (s,3H), 1.26 (d,J=6.7Hz,3H), 1.17 (d,J=7.0Hz,3H), 1.06–0.93 (m,2H).
[0080] 13 C NMR (126MHz, Chloroform-d) δ 119.71, 107.80, 89.16, 88.21, 35.22, 28.01, 22.47, 22.35, 19.07.
[0081] HRMS (ESI-MS): Calculated for C 10 H 16 Cl2Pt [M+NH4] + = 419.0615, found:419.0622.
[0082] IR (film): 2962, 1505, 1480, 1434, 1418, 1369, 1295, 1199, 1076, 1066, 1023, 931, 897, 798, 752, 566, 455.
[0083] 1 H NMR spectrum as follows Figure 1 As shown; 13 C NMR spectrum as follows Figure 2 As shown; high-resolution mass spectrometry Figure 3 As shown; infrared spectrum as Figure 4 As shown.
[0084] Example 2
[0085] This example illustrates the resistance of compound 3 (i.e., dichloro(3,7-dimethyl-1,6-octadiene)platinum) to bacteria.
[0086] The minimum inhibitory concentrations (MICs) of compound 3 and other compounds (including Pt(COD)Cl2, Pt(NOD)Cl2, cisplatin, carboplatin, sunipin, heptaplatin, VA, AMP, and CAZ) against bacteria were determined using the following method.
[0087] According to the CLSI M100 antibacterial susceptibility testing reference standards, a sterile 96-well microplate was used. 100 μL of MH broth was added to the first well of each row as a blank control (no bacteria and no compound added). 50 μL of MH broth was added to wells 2-12. 50 μL of compound 3 (prepared with 5% DMSO) at a concentration of 1000 μg / mL or another compound at 125 μg / mL was added to the second well of each row. After mixing by pipetting, 50 μL was added to the third well. This serial dilution was continued up to the eleventh well. 50 μL of the diluted compound was discarded after mixing in the eleventh well. The eleventh well was left untreated (as a control with bacteria but no compound 3). Finally, 1.5 × 10⁻⁶ HCl (prepared with 0.9% physiological saline) was added to each of wells 2-12. 5 50 μL of bacterial suspension at CFU / mL (i.e., in wells 2-11, the final concentrations (working concentrations) of compound 3 are 500, 250, 125, 62.5, 31.25, 15.63, 7.81, 3.91, 1.95, and 0.98 μg / mL, respectively; wells with compound 3 are the experimental group; the final concentrations (working concentrations) of other compounds are 62.5, 31.25, 15.63, 7.81, 3.91, 1.95, 0.98, 0.49, 0.24, and 0.12 μg / mL, respectively; wells with other compounds are the reference control).
[0088] Simultaneously, the following solvent controls were set up: 50 μL of 5% DMSO in MH broth medium and 50 μL of 1.5 × 10⁻⁶ mol / L solution prepared with 0.9% physiological saline were added to each well. 5 CFU / mL bacterial suspension.
[0089] After incubating the culture plate in a 37℃ incubator for 24 hours, the experimental results were observed. The lowest compound concentration observed in wells 2-11, where the well was clear and free of visible turbidity, was the MIC of that compound. All experiments were performed with three replicates.
[0090] The results showed that the wells of the blank control without bacteria or compound 3 were clear and transparent with no visible turbidity; the wells of the control with bacteria but without compound 3 were the most turbid, indicating very vigorous bacterial growth and reproduction; the wells of the solvent control were similar to those of the control with bacteria but without compound 3, being relatively turbid, indicating very vigorous bacterial growth and reproduction.
[0091] The results for compound 3 and other compounds are shown in Table 1.
[0092] Table 1. MIC determination results of compound 3 and other compounds against standard bacteria (unit: μg / mL)
[0093]
[0094] Note: VA: Vancomycin; AMP: Ampicillin; CAZ: Ceftazidime.
[0095] As shown in Table 1, compound 3 exhibited antibacterial activity against a variety of standard bacteria tested, covering both Gram-positive and Gram-negative bacteria, demonstrating relatively broad-spectrum antibacterial properties. Specifically, compound 3 showed significant antibacterial activity against MRSA and Staphylococcus aureus (MIC) at 7.81 μg / mL, and against Escherichia coli and Klebsiella pneumoniae (MIC) at 31.25 μg / mL. However, its MIC against Pseudomonas aeruginosa reached 250 μg / mL, indicating relatively low antibacterial activity; a higher concentration was required to effectively inhibit the growth of Pseudomonas aeruginosa.
[0096] In addition, compared with the other two platinum complexes Pt(COD)Cl2 and Pt(NOD)Cl2, compound 3 showed significantly higher antibacterial activity against Escherichia coli and Klebsiella pneumoniae.
[0097] Example 3
[0098] This example illustrates the resistance of compound 3 (i.e., dichloro(3,7-dimethyl-1,6-octadiene)platinum) to fungi.
[0099] The minimum inhibitory concentrations (MICs) of compound 3 and other compounds (including Pt(COD)Cl2, Pt(NOD)Cl2, cisplatin, carboplatin, sunipin, heptaplatin, FLU, and MCFG) against fungi were determined using the following method.
[0100] According to the CLSI M27-A4 antifungal susceptibility testing reference standard, a sterile 96-well microplate was used. 100 μL of liquid Sabouraud medley medium was added to the first well of each row as a negative control. 50 μL of liquid Sabouraud medley medium was added to wells 2-12. 50 μL of compound 3 (prepared with 5% DMSO) at a concentration of 1000 μg / mL or another compound at 125 μg / mL was added to the second well of each row. After mixing by pipetting, 50 μL was added to the third well, and so on, serially diluted up to the eleventh well. 50 μL of the diluted compound was discarded after mixing in the eleventh well. Well 12 was left untreated (as a control with fungus added but without compound 3). Finally, 1.5 × 10⁻⁶ oz. prepared with 0.9% physiological saline was added to wells 2-12. 3 50 μL of fungal suspension containing CFU / mL (i.e., in wells 2-11, the final concentrations (working concentrations) of compound 3 are 500, 250, 125, 62.5, 31.25, 15.63, 7.81, 3.91, 1.95, and 0.98 μg / mL, respectively; the final concentrations (working concentrations) of other compounds are 62.5, 31.25, 15.63, 7.81, 3.91, 1.95, 0.98, 0.49, 0.24, and 0.12 μg / mL, respectively; wells containing other compounds serve as reference controls).
[0101] Simultaneously, the following solvent controls were set up: 50 μL of 5% DMSO with liquid Sabouraud broth as the solvent and 50 μL of 1.5 × 10⁻⁶ mol / L of DMSO prepared with 0.9% physiological saline were added to each well. 3 Fungal suspension at CFU / mL.
[0102] After incubating the culture plates in a 25°C incubator for 24 h (48 h for Cryptococcus neoformans), the experimental results were observed. The lowest compound concentration observed in wells 2-11, where the well was clear and free of visible turbidity, was the MIC of that compound. All experiments were performed with three replicates.
[0103] The results showed that the wells of the blank control without fungi or compound 3 were clear and transparent with no visible turbidity; the wells of the control with fungi but without compound 3 were the most turbid, indicating very vigorous fungal growth and reproduction; the wells of the solvent control were similar to those of the control with fungi but without compound 3, being relatively turbid, indicating very vigorous fungal growth and reproduction.
[0104] The results for compound 3 and other compounds are shown in Table 2.
[0105] Table 2. MIC determination results of compound 3 and other compounds against standard fungi (unit: μg / mL)
[0106]
[0107] Note: FLU: Fluconazole, MCFG: Micafungin.
[0108] As shown in Table 2, compound 3 exhibited antifungal activity against all three standard fungal strains, but its MIC values were relatively high. The MIC against *Candida albicans* was 125 μg / mL, while the MICs against *Cryptococcus neoformans* and *Candida glabrata* both reached 250 μg / mL, indicating that compound 3 required relatively high concentrations to inhibit the growth of these two fungal strains. The data in Table 2 also show that the inhibitory effects of compound 3 on different fungal strains were not significantly different, suggesting that its inhibitory effect on these three fungi lacked obvious selectivity and may possess relatively broad-spectrum but weak antifungal properties.
[0109] Example 4
[0110] This example illustrates the hemolytic properties of compound 3 (i.e., dichloro(3,7-dimethyl-1,6-octadiene)platinum).
[0111] Preparation of 5% red blood cell suspension: Centrifuge the blood at 1000 rpm, discard the supernatant, wash the precipitated red blood cells with 0.9% NaCl physiological saline until the supernatant is clear and transparent to obtain the precipitated human red blood cells, and prepare a 5% red blood cell physiological saline suspension.
[0112] Take 7 clean EP tubes and add samples according to Table 3. The final concentrations of compound 3 in tubes 1-5 are 15.63, 7.81, 3.91, 1.95, and 0.98 μg / mL, respectively. Tube 6 is not added with compound 3 but with physiological saline (negative control), and tube 7 is not added with compound 3 but with 0.1% Trition X-100 (positive control).
[0113] After thorough mixing, immediately place the EP tube in a 37℃ water bath. After 1 hour, remove the liquid from the EP tube and centrifuge at 1000 rpm for 5 minutes. Observe the cells in the test tube to determine whether red blood cells have dissolved or aggregated. Take 100 μL of the supernatant and measure the OD value at 530 nm using an ELISA reader. Calculate the hemolysis rate using the following formula: Hemolysis rate (%) = (A test sample - A negative control) / (A positive control - A negative control) × 100%, where "A test sample" represents the OD value at 530 nm for tubes 1-5, "A negative control" represents the OD value at 530 nm for tube 6, and "A positive control" represents the OD value at 530 nm for tube 7. The evaluation criterion is: a hemolysis rate > 5% is considered to indicate significant hemolysis.
[0114] Table 3. Sample dosing table for hemolysis test (unit: mL)
[0115]
[0116] The results showed that the hemolysis rate was 0% in the negative control and 100% in the positive control. The hemolysis rate results at different concentrations of compound 3 are shown in Table 4.
[0117] Table 4 Results of hemolysis rate test
[0118]
[0119] Normal red blood cells have an intact cell membrane structure and a certain degree of stability. When exposed to chemical substances, the structure and function of the red blood cell membrane are disrupted, leading to the release of hemoglobin into the incubation solution. As shown in Table 4, the hemolysis rate decreased significantly with decreasing concentration of compound 3 (from 15.63 μg / mL to 0.98 μg / mL). At a concentration of 15.63 μg / mL, the hemolysis rate was 49.19%, while at 0.98 μg / mL, the hemolysis rate was only 0.61%, indicating a significant reduction in hemolytic activity. At a concentration of 7.81 μg / mL, the hemolysis rate of compound 3 was less than 5%, showing no hemolytic effect. This concentration is precisely the MIC value of compound 3 against MRSAATCC43300 and S. Aureus ATCC25923. Compound 3, within its effective range for inhibiting the growth of MRSA and S. Aureus strains, does not disrupt the integrity of the red blood cell membrane and exhibits good safety for red blood cells.
[0120] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.
Claims
1. A polyene platinum(II) complex having the following chemical structural formula: 。 2. The method for preparing the polyene platinum(II) complex according to claim 1, comprising the following preparation route: 。 3. The method according to claim 2, characterized in that: The method includes the following steps for preparing compound 2: Compound 2 was prepared by reacting compound 1 with tetrahydrofuran, sodium hydride and iodomethane under anhydrous and oxygen-free conditions. Compound 1 is 3,7-dimethyl-1,6-octadien-3-ol, with the molecular formula C1. 10 H 18 O; The method includes the following steps for preparing compound 3: Compound 3 was prepared by reacting compound 2 with chloroplatinic acid under anhydrous and oxygen-free conditions.
4. The method according to claim 3, characterized in that: In the preparation steps of compound 2: Under anhydrous and oxygen-free conditions, compound 1 and THF were mixed at a weight / volume ratio (g:mL) of 1:22 and stirred at 0°C for 1 h. Then, NaH was added to the reaction solution at a molar ratio of 1:1.3 between compound 1 and NaH, the reaction solution was heated to 40°C, and the reaction was stirred for 1 hour. Then, MeI was added at a molar ratio of 1:2.2 to compound 1, and the reaction was stirred for 12 hours to obtain a reaction product containing compound 2. In the preparation steps of compound 3: Under anhydrous and oxygen-free conditions, chloroplatinic acid and anhydrous acetic acid were stirred at 75°C for 1 hour at a weight / volume ratio (g:mL) of 1:8 until the chloroplatinic acid was completely dissolved. Then, compound 2 was added dropwise to the reaction solution at a molar ratio of 1:10 for chloroplatinic acid and compound 2, and the mixture was stirred at 75°C for 1.5 h to obtain a reaction product containing compound 3.
5. The method according to claim 4, characterized in that: The reaction product containing compound 2 was poured into a saturated ammonium chloride solution and allowed to stand to separate into layers, resulting in an oil layer and an aqueous layer; the aqueous layer was then extracted with ethyl acetate to obtain an ethyl acetate extract layer. The ethyl acetate extract layer and the aforementioned oil layer were combined, dried, and filtered to obtain a filtrate. The filter cake was discarded, and the filtrate was concentrated to obtain the crude product of compound 2. The crude compound 2 was purified using a silica gel chromatography column to obtain purified compound 2.
6. The method according to claim 5, characterized in that: The drying process is carried out using anhydrous sodium sulfate.
7. The method according to claim 6, characterized in that: After cooling the reaction product containing compound 3 to room temperature, add water, let stand for 0.8-3 hours, filter, discard the filtrate, and collect the filter residue; The obtained filter residue was first washed with ether, filtered and the liquid was discarded. Then, dichloromethane was added to the container containing the filter residue, stirred thoroughly and allowed to stand. The filtrate was collected and the filter residue was discarded. Add 100-200 mesh silica gel to the filtrate and let it stand; then filter and collect the filtrate, and wash the filter residue again with DCM and collect the washing liquid. The filtrate collected after adding silica gel and letting it stand and filtering was combined with the washing liquid collected after washing with DCM to obtain a liquid containing compound 3; the liquid containing compound 3 was treated with a rotary evaporator to obtain a mixture containing compound 3. Then, add diethyl ether to the mixture containing compound 3 for washing, filter, and collect the filter residue to obtain the yellow compound 3.
8. The use of the polyene platinum (II) complex of claim 1 in antibacterial and / or antifungal applications.
9. The application according to claim 8, characterized in that: The bacteria are at least one of the following: methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300), Staphylococcus aureus standard strain (S. aureus ATCC 25923), Escherichia coli standard strain (E. coli ATCC 25922), Klebsiella pneumoniae standard strain (K. pneumoniae ATCC 13883), and Pseudomonas aeruginosa standard strain (P. aeruginosa ATCC 27853); The fungus is at least one of Candida albicans (C. albicans ATCC90028), Cryptococcus neoformans (C. neoformans ATCC32045), and Candida glabrata (C. glabrata ATCC15126).