Antitumor compound and its preparation method and application

Abstract

The present invention discloses an anti-tumor compound, the general structural formula of which is: wherein: M is P(PH)3, 1,1-bis(diphenylphosphine)methylene, 1,2-bis(diphenylphosphine)vinyl, 1,2-bis(diphenylphosphine)phenyl; R is any one of the following: CH3COO ‑ ,Ac ‑ 、F ‑ , Cl ‑ Br ‑ ,I ‑ 、NO2 ‑ 、[Ag(Hmna)2(mna)4] 4‑ The present invention also discloses a preparation method of the anti-tumor compound and its application in preparing a drug for inhibiting breast tumor cells.

Description

Technical Field

[0001] The invention belongs to the technical field of compound preparation, and specifically relates to a class of anti-tumor compounds (dihydrate-triammine-triphenylphosphine ruthenium salt compounds) and a preparation method and application thereof. Background Art

[0002] Cancer poses a serious threat to human health, with morbidity and mortality rates rising year by year, causing nearly 10 million deaths worldwide in 2020. Currently, it is treated mainly through three approaches: surgery, radiotherapy, chemotherapy, as well as molecular targeting, immunotherapy, and traditional Chinese medicine. Chemotherapy is chemical drug therapy, which is currently one of the most effective ways to treat cancer. In 1978, cisplatin was approved for marketing as the first inorganic anti-tumor drug, becoming the first generation of metal complex anti-tumor drugs. It is one of the most widely used drugs in the clinical treatment of testicular cancer, ovarian cancer, head and neck tumors, bladder cancer and other cancers. However, cisplatin is prone to cause side effects such as nephrotoxicity, neurotoxicity, ototoxicity, and drug resistance problems, which limit its application.

[0003] In order to overcome the above problems, searching for new metal compounds with anti-tumor activity has become one of the hot areas in new drug research and development today.

[0004] The currently available ruthenium complex is [CpRu(L)PPH3], and its structural formula is: The currently known function is that it has good antibacterial effect. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a class of anti-tumor compounds and their preparation method and application.

[0006] In order to solve the above technical problems, the present invention provides a class of anti-tumor compounds (dihydrate-triammine-triphenylphosphine ruthenium salt compounds), characterized in that the general structural formula is:

[0007]

[0008] Wherein: M is P(PH)3, 1,1-bis(diphenylphosphine)methylene, 1,2-bis(diphenylphosphine)vinyl, 1,2-bis(diphenylphosphine)phenyl;

[0009] R is any of the following: CH3COO - ,Ac - 、F - , Cl - Br - ,I - 、NO2 - 、[Ag(Hmna)2(mna)4] 4- .

[0010] Note: When the cation is +2, R is a -1 ion, so R2 represents two R anions.

[0011] The present invention also provides a method for preparing the above anti-tumor compound, comprising the following steps:

[0012] 1) Mixing a tris(triphenylphosphine)ruthenium dichloride raw material with acetic acid (acetic acid) and reacting at 60-150° C. for 3-8 hours to obtain an intermediate product;

[0013] The tris(triphenylphosphine)ruthenium dichloride raw material is tris(triphenylphosphine)ruthenium dichloride or tris(triphenylphosphine) derivative ruthenium dichloride;

[0014] For every 0.050mmol of tris(triphenylphosphine)ruthenium dichloride raw material, add 30±10ml of acetic acid;

[0015] 2) Add ethanol to dissolve the intermediate product, add ammonia water (add ammonia water slowly in batches), and continue the reaction at room temperature for 7±0.5 hours;

[0016] The molar ratio of the intermediate product to ammonia is 1:3-5, and the volume ratio of water to ethanol is 1:1-5.

[0017] illustrate:

[0018] When the tris(triphenylphosphine)ruthenium dichloride raw material is tris(triphenylphosphine)ruthenium dichloride, the product obtained in step 2) is di-hydrate-tri-ammonia-triphenylphosphine ruthenium acetate;

[0019] When the tris(triphenylphosphine)ruthenium dichloride raw material is tris(triphenylphosphine) derivative ruthenium dichloride, the product obtained in step 2) is acetate di-water-triammine-triphenyl derivative phosphine ruthenium;

[0020] As an anti-tumor compound.

[0021] As a further improvement of the preparation method of the antitumor compound of the present invention, it comprises the following step 3):

[0022] 3) The product obtained in step 2) is mixed with ammonium salt (NH4R) in a molar ratio of 1:1 to 3 and reacted at 20 to 50°C for 3 to 10 hours. The reaction product is dried (after drying at 70°C to constant weight) to obtain a dihydrate-triammine-triphenylphosphine ruthenium salt compound as an anti-tumor compound (the target product is a dark green, slightly shiny crystalline powder).

[0023] Note: This step 3) is to replace the anion of the product obtained in step 2) with other anions.

[0024] As a further improvement of the preparation method of the antitumor compound of the present invention:

[0025] When the tris(triphenylphosphine)ruthenium dichloride raw material is tris(triphenylphosphine)ruthenium dichloride,

[0026] The general formula of the product obtained in step 2) and step 3) is:

[0027] (molecular formula: [Ru(H2O)2(NH3)3(P(C6H5)3)]R2) or

[0028] Step 2) The R of the obtained product is CH3COO - ;

[0029] Step 3) R of the obtained product is any of the following: Ac - 、F - , Cl - Br - ,I - 、NO2 - 、[Ag(Hmna)2(mna)4] 4- .

[0030] That is, the intermediate product obtained in step 1) is a diacetate triphenylphosphine ruthenium complex,

[0031] The product obtained in step 2) is dihydrate acetate-triammine-triphenylphosphine ruthenium;

[0032] Step 3) The product obtained is a salt product in which the acetate group in dihydrate acetate-triammine-triphenylphosphine ruthenium is replaced by other anions.

[0033] As a further improvement of the preparation method of the anti-tumor compound of the present invention: the tris(triphenylphosphine)ruthenium dichloride raw material is tris(triphenylphosphine derivative)ruthenium dichloride;

[0034] The details are as follows:

[0035] When the tris(triphenylphosphine derivative) ruthenium dichloride is tris{(1,1-bis(diphenylphosphine)methylene ruthenium dichloride, the intermediate product obtained in step 1) is diacetate{(1,1-bis(diphenylphosphine)methylene ruthenium complex, and the product obtained in step 2) is acetate dihydrate-triammine-1,1-bis(diphenylphosphine)methylene phosphine ruthenium;

[0036] When the tris(triphenylphosphine derivative) ruthenium dichloride is tris[1,2-bis(diphenylphosphine)vinyl]ruthenium dichloride, the intermediate product obtained in step 1) is diacetate[1,2-bis(diphenylphosphine)vinyl]ruthenium complex, and the product obtained in step 2) is acetate dihydrate-triammine-1,2-bis(diphenylphosphine)vinylphosphine ruthenium;

[0037] When tris(triphenylphosphine derivative) ruthenium dichloride is tris[1,2-bis(diphenylphosphine)phenyl]ruthenium dichloride, the intermediate product obtained in step 1) is diacetate[1,2-bis(diphenylphosphine)phenyl]ruthenium complex, and the product obtained in step 2) is acetate dihydrate-triammine-1,2-bis(diphenylphosphine)phenyl]ruthenium.

[0038] The present invention also provides the use of the anti-tumor compound in preparing a drug for inhibiting breast tumor cells.

[0039] As an improvement of the application of the present invention: it is used for inhibiting the proliferation and metastasis of breast malignant tumor cells.

[0040] The anti-tumor compound (dihydrate-triammine-triphenylphosphine ruthenium salt compound) has strong killing power on malignant breast cancer tumor cells, but has weak toxicity on normal breast cells.

[0041] The present invention also provides a method for preparing the above compound. The overall reaction is carried out in three steps, as shown below:

[0042] Ru(PPH3)3Cl2+2HAc=Ru(Ac)2(PPH3)+2[HPPH3]Cl;

[0043] Ru(Ac)2(PPH3)+3NH3+2H2O=[Ru(NH3)3(H2O)2(PPH3)]Ac2

[0044] [Ru(NH3)3(H2O)2(PPH3)]Ac2+NH4R=[Ru(NH3)3(H2O)2(PPH3)]R+NH4Ac.

[0045] Ruthenium belongs to Group VIII in the periodic table together with platinum. Its chemical properties are similar to those of iron to a certain extent, and it can play a role similar to that of iron ions in the body. Ruthenium complexes have a stable oxidation state under physiological conditions, are easily absorbed by tumor tissues, have low toxicity, and its unique hexacoordinate structure gives it structural diversity. In most cases, its anti-tumor activity mechanism is different from that of platinum compounds, and it can solve the drug resistance problem of anti-tumor drugs well, so it has good development prospects. The present invention provides a class of mononuclear ruthenium lead compounds with simple structure and strong anti-tumor activity.

[0046] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in: the preparation method and the equipment used are simple, the post-processing is convenient, the product yield is high, the compound has high lethal activity and high metastasis inhibition on breast cancer tumor cells, and is expected to become a lead compound for breast cancer treatment.

[0047] In actual use, the usage can refer to the usage of cisplatin, and the dosage is also about 20% to 30% of the dosage of cisplatin. DETAILED DESCRIPTION

[0048] The present invention is further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto:

[0049] In the following cases, the stirring speed is about 300-400 rpm.

[0050] Embodiment 1, the synthesis method of acetic acid dihydrate-triammine-triphenylphosphine ruthenium compound, carries out the following steps in sequence:

[0051] 1) 0.480 g (0.050 mmol) of tris(triphenylphosphine)ruthenium dichloride was added to 30.0 mL of glacial acetic acid in 6 times, with an interval of 10 minutes between each time, and stirred and refluxed at 100°C for 8 hours. After the reaction time was reached, it was cooled to room temperature under stirring, and 200 ml of water was added. Solid matter precipitated, the upper liquid was removed by centrifugation, and the solid was washed with water until it was neutral. The intermediate product, Ru(Ac)2(PPH3) (0.043 mol), was obtained by centrifugation;

[0052] Note: The PPH3 generated by the reaction will further react with HCl to generate [HPPH 3 ] + Cl - .

[0053] 2) All the intermediate products obtained in step 1) - Ru(Ac)2(PPH3) (0.043 mol) were dissolved by adding 5 mL of ethanol, and then 18.0% (mass %) ammonia water (about 15 μL) containing 0.129 mol of NH3 was slowly added. The slow addition was to control the system temperature not to exceed 25°C, and the reaction was continued at room temperature for 7 hours.

[0054] 3) The reaction product of step 2) was dried at 70° C. to constant weight to obtain dihydrate acetate-triammine-triphenylphosphine ruthenium (0.0416 mol) with a yield of 83.21% and a purity of 99.10%.

[0055] The structural formula is:

[0056]

[0057] Where: R = CH3COO - .

[0058] Acetic acid dihydrate-triammine-triphenylphosphine ruthenium complex is a green crystalline solid with a yield of 83.21%; mp322℃; 1 H NMR(500MHz,CD3OD)δ7.22–7.69(m,15H,ArH),2.09(,3H,CH3COO- ).Elemental anal.ForRuC 22 H 34 N3O6P (%), calculated: C, 46.47; H, 6.03; N, 7.39; found: C, 46.56; H, 6.09; N, 7.35.

[0059] Example 2: Change step 3) in Example 1 to:

[0060] 3) Add NH4F (0.043 mol) of the same mass as the intermediate product of step 2) to the reaction product of step 2), stir well at room temperature for 2 hours, and then dry at 70°C to constant weight. The rest is the same as in Example 1 to obtain di-hydrate-tri-ammonia-triphenylphosphine ruthenium fluoride (0.035 mol).

[0061]

[0062] Where R=F.

[0063] Ruthenium fluoride dihydrate-triammine-triphenylphosphine is a light green crystalline solid with a yield of 70%; mp550℃; 1 H NMR(500MHz,CD3OD)δ7.20–7.71(m,15H,ArH).Elemental anal.For RuC 18 H 28 N3O2F2P (%), calculated: C, 44.25; H, 5.78; N, 8.60; found: C, 44.43; H, 5.84; N, 8.57.

[0064] Example 3: Compared with Example 2, NH4F is replaced by NH4Cl, the molar amount remains unchanged at 0.043 mol, and the rest is the same as Example 2, to obtain dihydrate-triammine-triphenylphosphine ruthenium chloride (0.037 mol).

[0065]

[0066] Where R = Cl.

[0067] Chloride dihydrate-triammine-triphenylphosphine ruthenium is a green crystalline solid with a yield of 74.01%; mp 496℃; 1 H NMR(500MHz,CD3OD)δ7.21–7.74(m,15H,ArH).Elemental anal.For RuC 18 H 28N3O2Cl2P (%), calculated: C, 41.46; H, 5.41; N, 8.06; found: C, 41.34; H, 5.57; N, 8.12.

[0068] Example 4: Compared with Example 2, NH4F is replaced by NH4Br, the molar amount remains unchanged at 0.043 mol, and the rest is the same as Example 2, to obtain dihydrate bromide-triammine-triphenylphosphine ruthenium (0.036 mol).

[0069]

[0070] Wherein R = Br.

[0071] Ruthenium bromide dihydrate-triammine-triphenylphosphine is a green crystalline solid with a yield of 72%; mp 468℃; 1 H NMR(500MHz,CD3OD)δ7.19–7.71(m,15H,ArH).Elemental anal.For RuC 18 H 28 N3O2Br2P (%), calculated: C, 35.42; H, 4.62; N, 6.89; found: C, 35.31; H, 4.73; N, 6.96.

[0072] Example 5: Compared with Example 2, NH4F is replaced by NH4I, the molar amount remains unchanged at 0.043 mol, and the rest is the same as Example 2, to obtain dihydrate iodide-triammine-triphenylphosphine ruthenium (0.033 mol).

[0073]

[0074] Where R=I.

[0075] Ruthenium iodide dihydrate triammine triphenylphosphine is a green crystalline solid with a yield of 66.01%; mp 437℃; 1 H NMR(500MHz,CD3OD)δ7.22–7.71(m,15H,ArH).Elemental anal.For RuC 18 H 28 N3O2I2P (%), calculated: C, 30.69; H, 4.01; N, 5.97; found: C, 30.55; H, 4.14; N, 5.83.

[0076] Example 6: Compared with Example 2, NH4F is replaced by NH4NO2, the molar amount remains unchanged at 0.043 mol, and the rest is the same as Example 2, to obtain nitrite dihydrate-tri-triphenylphosphine ruthenium (0.309 mol).

[0077]

[0078] Where R = NO2 - .

[0079] Nitrite dihydrate-triamminium-triphenylphosphine ruthenium complex is a green crystalline solid with a yield of 61.81%; mp 422℃; 1 HNMR(500MHz,CD3OD)δ7.20–7.75(m,15H,ArH).Elemental anal.For RuC 18 H 28 N5O6P (%), calculated: C, 39.84; H, 5.20; N, 12.91; found: C, 39.77; H, 5.38; N, 12.84.

[0080] Example 7: Compared with Example 2, NH4F was replaced by (NH4)4[Ag6(Hmna)2(mna)4], and the rest was referred to Example 2 to obtain 2-mercaptonicotinic acid silver dihydrate-triammine-triphenylphosphine ruthenium (0.0298 mol).

[0081]

[0082] Where R = [Ag6(Hmna)2(mna)4] 4- ,mna=2-mercaptonicotinate

[0083] 2-Mercaptonicotinic acid silver dihydrate-triammine-triphenylphosphine ruthenium is a green crystalline solid with a yield of 59.62%; mp551℃; 1 H NMR(500MHz,CD3OD)δ7.20–7.75(m,15H,ArH), δ6.83-7.68(m,18H,mna).Elemental anal.For Ru2C 72 H 76 N 12 O 16 P2S6Ag6 (%), calculated: C, 35.02; H, 3.10; N, 6.81; found: C, 33.13; H, 3.15; N, 6.75,

[0084] Example 8-1,

[0085] The tris(triphenylphosphine)ruthenium dichloride used as the raw material in step 1) of Example 1 was replaced with tris{(1,1-bis(diphenylphosphine)methyleneruthenium dichloride, and the molar amount remained unchanged; and the subsequent steps were carried out using the intermediate product obtained from this raw material accordingly, and the rest were the same as Example 1.

[0086] Acetic acid dihydrate-triammine-1,1-bis(diphenylphosphine)methylenephosphine ruthenium (0.0336 mol) was obtained.

[0087] The structural formula is:

[0088]

[0089] R is 1,1-bis(diphenylphosphino)methylene;

[0090]

[0091] Acetic acid dihydrate-triammine-1,1-bis(diphenylphosphine)methylenephosphine ruthenium, yield 67.2%, 1 H NMR (500MHz, CD3OD) δ7.13–7.88(m,20H,ArH), δ2.83(m,2H,P-CH), δ2.10(,3H,CH3COO - ). Elementalanal.For RuC 17 H 31 N3O6P2 (%), calculated: C, 38.05; H, 5.82; N, 7.83; found: C, 38.16; H, 5.95; N, 7.71.

[0092] Example 8-2

[0093] The tris(triphenylphosphine)ruthenium dichloride used as the raw material in step 1) of Example 1 was replaced with [1,2-bis(diphenylphosphine)vinyl]ruthenium dichloride, and the molar amount remained unchanged; and the subsequent steps were carried out accordingly using the intermediate product obtained from this raw material, and the rest was the same as Example 1.

[0094] Acetic acid dihydrate-triammine-1,2-bis(diphenylphosphine)vinylphosphine ruthenium (0.0302 mol) was obtained.

[0095] The structural formula is:

[0096]

[0097] R is 1,2-bis(diphenylphosphine)vinyl;

[0098]

[0099] The yield of ruthenium acetate dihydrate-triammine-1,2-bis(diphenylphosphino)vinylphosphine is 60.4%, δ7.21–8.26 (m, 20H, ArH), δ5.53 (s, 2H, C=CH), δ6.41 (s, 2H, C=CH), δ2.10 (s, 3H, CH3COO - ),Elementalanal.For RuC 30 H 41 N3O6P2 (%), calculated: C, 51.26; H, 5.88; N, 5.98; found: C, 51.33; H, 5.75; N, 5.90.

[0100] Example 8-3

[0101] The tris(triphenylphosphine)ruthenium dichloride used as the raw material in step 1) of Example 1 was replaced with tris[1,2-bis(diphenylphosphine)phenyl]ruthenium dichloride, and the molar amount remained unchanged; and the subsequent steps were carried out accordingly using the intermediate product obtained from this raw material, and the rest was the same as Example 1.

[0102] Acetic acid dihydrate-triammine-(1,2-bis(diphenylphosphine)phenylruthenium (0.0269 mol) was obtained.

[0103] The structural formula is:

[0104]

[0105] R is 1,2-bis(diphenylphosphino)phenyl;

[0106]

[0107] The yield of dihydrate acetate-triammine-(1,2-bis(diphenylphosphine)phenylruthenium was 53.8%; δ7.30–8.52 (m, 24H, ArH), δ2.10 (, 3H, CH3COO - ). Elemental anal.For RuC 34 H 43 N3O6P2 (%), calculated: C, 54.24; H, 5.76; N, 5.58; found: C, 54.36; H, 5.85; N, 5.66.

[0108] Experiment 1: Breast cancer cell toxicity experiment

[0109] Test subjects: breast cancer cells MCF-7, triple-negative breast cancer cells MDA-MB-231

[0110] Test method:

[0111] 1. Antitumor activity experiment

[0112] Cell culture

[0113] Human breast tumor MCF-7 and MDA-MB-231 cells were cultured in a culture medium containing 1.5 g / l NaHCO3, 10% FBS, insulin (10 mg / l) and penicillin / streptomycin (100 U / ml and 100 μg / ml). All cell culture processes were carried out in an incubator at 37°C containing 5% CO2 and 95% air.

[0114] 1.2. Cytotoxicity (survival rate) test

[0115] The antitumor activity of the indicated compounds against human breast tumor cell lines MCF-7 and MDA-MB-231 was evaluated by determining the tumor cell survival rate induced by the indicated compounds.

[0116] Preparation of drug: The compounds obtained in Examples 1 to 7 and 8-1 to 8-3 are used as test drugs, and appropriate amounts of each are taken to prepare 1.0×10 -3 mol / L DMSO solution; take an appropriate amount of cisplatin and dissolve it in physiological saline to make 5×10 -3 mol / L solution. The cells were seeded into a 96-well plate so that each well contained 1×10 4 Cells were cultured overnight at 37°C in a 5% CO2 incubator. After 24 hours, the culture medium was replaced with a series of fresh culture medium containing different concentrations of the test drug or cisplatin as a control.

[0117] Cultivate in a 37°C, 5% CO2 incubator for 48 hours, add 10 μl CCK-8 reagent (CellCounting Kit) to each well, continue incubation at 37°C for 1 hour, and then record the absorbance (OD) at 450nm using a Victor V spectrophotometer. Correct the results with the blank culture medium as the benchmark, and perform 6 replicates of each test drug concentration to obtain the average value. This is used as the experimental group.

[0118] That is, the experimental groups were wells containing cells, culture medium, and CCK-8 reagent added later.

[0119] The following two comparison groups were also set up:

[0120] Comparative group 1: No drugs were added to the cells in the wells, i.e., compared with the “experimental group”, the test drugs were eliminated, with the purpose of determining the absorbance OD value caused by the natural proliferation of cells in the absence of drugs;

[0121] Comparative group 2, the wells contained no cells but culture medium and CCK-8 reagent added later; that is, compared with the "experimental group", cells were eliminated in order to determine the background absorbance OD value caused by the composition of culture medium, CCK-8 and culture well materials;

[0122] The cytotoxicity was calculated using the following formula:

[0123] Cytotoxicity = [(A c -A s ) / (A c -A b )]×100%,

[0124] A c Refers to the OD value of cells in the wells of control group 1 (without test drug); A s Refers to the OD value in the wells of the experimental group (containing culture medium, CCK-8, cells and a certain concentration of test drug); A b is the OD value in the wells of control group 2 (containing culture medium, CCK-8 and test drug). The IC value of the test drug was obtained based on the cytotoxicity curves at different concentrations of the test drug. 50 value.

[0125] Table 1 shows the half-lethal concentration of each test compound for human tumor cell lines MCF-7 and MDA-MB-231, and the migration inhibition rate).

[0126] Table 1. Toxicity of di-hydrate-tri-ammonia-triphenylphosphine ruthenium salt compounds to breast cancer

[0127]

[0128]

[0129] The half-lethal concentration of each compound on breast cancer cells in Table 1 above shows that, compared with the control drug cisplatin, the di-hydrate-tri-ammonia-triphenylphosphine ruthenium salt compound prepared by the present invention has a much stronger killing ability on breast cancer cells MCF-7 and MDA-MB-231 than the widely used clinical drug cisplatin, and is a potential substitute for cisplatin. The toxicity of the compounds of the present invention to breast cancer cells is generally similar, so when selecting lead compounds, more consideration can be given to candidates with less toxicity to healthy cells.

[0130] Experiment 2: Inhibition of breast cancer cell migration

[0131] Test subjects: breast cancer cells MCF-7, triple-negative breast cancer cells MDA-MB-231

[0132] Test method:

[0133] According to literature reports, the effect of test drugs on tumor cell migration can be measured by cell scratch assay. Tumor cells were seeded into 24-well plates, cultured in a 37°C incubator to about 80-90% cell coverage, and washed with serum-free medium. The test drug was added to a final concentration of 2.5 μM, and the cell layer was scratched with a sterile pipette tip and gently washed with 1× PBS. The cell scratch profile was photographed at the same location immediately (0 hours) and 24 hours later, and the width of the scratch (W) was measured. The migration rate was calculated as follows:

[0134] (W 0h -W 24h ) / W 0h × 100%. The results are shown in Table 2 below.

[0135] Table 2. Effect of di-hydrate-tri-ammonia-triphenylphosphine ruthenium salt compounds on the inhibition of breast cancer migration

[0136]

[0137]

[0138] It can be seen that the compound of the present invention has a good inhibitory effect on the migration of breast cancer cells, and the inhibitory ability on triple-negative breast cancer cells MDA-MB-231 is better than that on estrogen receptor-positive strain MCF-7 tumor cells. However, the traditional anti-tumor cisplatin has no such activity or has a very low activity. In comparison, 2-mercaptonicotinic acid silver di-hydrate-tri-ammonia-triphenylphosphine ruthenium has better anti-tumor activity.

[0139] Experiment 3: The breast tumor cells MCF-7 and MDA-MB-231 were replaced with normal breast epithelial cells MCF-10A. The experiment was carried out according to the method described in Experiment 1, breast cancer cell toxicity experiment. The results are listed in Table 3 below.

[0140] Table 3. Toxic effects of di-hydrate-tri-ammonia-triphenylphosphine ruthenium salt compounds on healthy breast cells

[0141]

[0142]

[0143] Finally, it should be noted that the above are only some embodiments of the present invention. Obviously, the present invention is not limited to the above implementation, and there are many variations. All variations that can be directly derived or associated with the content disclosed by a person skilled in the art should be considered as the protection scope of the present invention.

Claims

1. A class of antitumor compounds characterized by The general structural formula is: Wherein: M is P(Ph)3, 1,1-bis(diphenylphosphine)methylene, 1,2-bis(diphenylphosphine)vinyl, 1,2-bis(diphenylphosphine)phenyl; R is any of the following: CH3COO - 、F - , Cl - Br - ,I - 、NO2 - ; Or the general structural formula is: Wherein: M is P(Ph)3, 1,1-bis(diphenylphosphine)methylene, 1,2-bis(diphenylphosphine)vinyl, 1,2-bis(diphenylphosphine)phenyl; R is [Ag(Hmna)2(mna)4] 4- 。 2. The method for preparing the antitumor compound according to claim 1, characterized in that The steps include: 1) Mixing a tris(triphenylphosphine)ruthenium dichloride raw material with acetic acid and reacting at 60-150° C. for 3-8 hours to obtain an intermediate product; The tris(triphenylphosphine)ruthenium dichloride raw material is tris(triphenylphosphine)ruthenium dichloride or tris(triphenylphosphine) derivative ruthenium dichloride; For every 0.050mmol of tris(triphenylphosphine)ruthenium dichloride raw material, add 30±10ml of acetic acid; 2) adding ethanol to dissolve the intermediate product, adding ammonia water, and continuing the reaction at room temperature for 7±0.5 hours; thereby obtaining an antitumor compound; The molar ratio of the intermediate product to ammonia is 1:3-5, and the volume ratio of water to ethanol is 1:1-5; 3) mixing the product obtained in step 2) with ammonium salt NH4R in a molar ratio of 1:1 to 3 and reacting at 20 to 50° C. for 3 to 10 hours, drying the reaction product to obtain a dihydrate-triammine-triphenylphosphine ruthenium salt compound as an antitumor compound; When the tris(triphenylphosphine)ruthenium dichloride raw material is tris(triphenylphosphine)ruthenium dichloride, The general formula of the product obtained in step 2) and step 3) is: Step 2) The R of the obtained product is CH3COO - ; Step 3) R of the obtained product is any of the following: F - , Cl - Br - ,I - 、NO2 - 、[Ag(Hmna)2(mna)4] 4- .

3. The method for preparing the antitumor compound according to claim 2, characterized in that: The tris(triphenylphosphine)ruthenium dichloride raw material is tris(triphenylphosphine derivative)ruthenium dichloride; When the tris(triphenylphosphine derivative) ruthenium dichloride is tris{(1,1-bis(diphenylphosphine)methylene ruthenium dichloride, the intermediate product obtained in step 1) is diacetate{(1,1-bis(diphenylphosphine)methylene ruthenium complex, and the product obtained in step 2) is acetate dihydrate-triammine-1,1-bis(diphenylphosphine)methylene phosphine ruthenium; When the tris(triphenylphosphine derivative) ruthenium dichloride is tris[1,2-bis(diphenylphosphine)vinyl]ruthenium dichloride, the intermediate product obtained in step 1) is diacetate[1,2-bis(diphenylphosphine)vinyl]ruthenium complex, and the product obtained in step 2) is acetate dihydrate-triammine-1,2-bis(diphenylphosphine)vinylphosphine ruthenium; When tris(triphenylphosphine derivative) ruthenium dichloride is tris[1,2-bis(diphenylphosphine)phenyl]ruthenium dichloride, the intermediate product obtained in step 1) is diacetate[1,2-bis(diphenylphosphine)phenyl]ruthenium complex, and the product obtained in step 2) is acetate dihydrate-triammine-1,2-bis(diphenylphosphine)phenyl]ruthenium.

4. Use of the antitumor compound according to claim 1 in the preparation of a drug for inhibiting breast tumor cells.

5. The use according to claim 4, characterized in that: Used to inhibit the proliferation and metastasis of breast malignant tumor cells.

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