CN117917423A - Preparation method and application of N-heterocyclic carbene mononuclear metal iron complex - Google Patents

Preparation method and application of N-heterocyclic carbene mononuclear metal iron complex Download PDF

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CN117917423A
CN117917423A CN202211294822.6A CN202211294822A CN117917423A CN 117917423 A CN117917423 A CN 117917423A CN 202211294822 A CN202211294822 A CN 202211294822A CN 117917423 A CN117917423 A CN 117917423A
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heterocyclic carbene
mononuclear
iron complex
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沈志凯
于振涛
郭文秀
王小明
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Nanjing University
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Abstract

The invention discloses a preparation method and application of an N-heterocyclic carbene mononuclear metal iron complex, and belongs to the technical field of chemical medicines. The cell biological experiments show that the complexes I1, I2 and I3 prepared by the invention have certain antiproliferative activity on lung cancer cell strains NCI-H460, NCI-H1299 and A549 cells, breast cancer cell strain MDA-MB-231 and liver cancer cell strain HuH-7, in particular to the complex I1, and have obvious antiproliferative effect on the cell strains. The 3N-heterocyclic carbene mononuclear metal iron complexes can be further applied to preparation of antitumor drugs.

Description

Preparation method and application of N-heterocyclic carbene mononuclear metal iron complex
Technical Field
The invention belongs to the technical field of chemical medicines, and particularly relates to a preparation method and application of an N-heterocyclic carbene mononuclear metal iron complex.
Background
Tumors are high morbidity, high mortality diseases worldwide, which have long been a hazard to human health. The traditional tumor treatment method has a major problem: drug resistance is likely to occur. With the rapid development of inorganic chemistry and materials, the development of metal-based drugs attracts the eyes of many researchers. At present, platinum drugs which are widely used clinically have certain toxic and side effects although having therapeutic effects. Therefore, the development of high-efficiency antitumor drugs with low toxic and side effects is an important direction in the field of medicine.
The N-heterocyclic carbene ligand has strong electron donating property, can form a complex with transition metal, and has good stability in air and water, so that the N-heterocyclic carbene ligand has application in various fields in recent years. The N-heterocyclic carbene has simple preparation process, can be prepared from imidazole salt, and has lipophilicity. In addition, N-heterocyclic carbene metal complexes, especially based on group 10 and group 11 transition metals, have potent antibacterial and antitumor activity and are not toxic to normal cells.
The iron element is the transition metal with the highest content on the earth, has various oxidation-reduction states and is low in cost. In addition, iron has biocompatibility such as hemoglobin for transporting and storing oxygen in living body, iron-sulfur protein for catalyzing electrons, iron clusters in nitrogen fixation enzyme, and the like. Therefore, the iron-based metal medicament has the advantages of incomparable low cost, high biocompatibility and the like of other materials, and is one of ideal antitumor medicaments.
Disclosure of Invention
The invention aims to: aiming at the defects of the prior art, the invention provides a preparation method and application of an N-heterocyclic carbene mononuclear metal iron complex for tumor treatment, the N-heterocyclic carbene is combined with iron to form the metal complex, and the prepared complex has low price and biological compatibility; can be further applied to the preparation of antitumor drugs.
The technical scheme is as follows: the aim of the invention is achieved by the following technical scheme:
The invention provides a preparation method of an N-heterocyclic carbene mononuclear iron complex, which comprises the steps of reacting a raw material A with 1-methylimidazole to obtain a crude product, and treating the crude product by hexafluorophosphate to obtain a ligand; and (3) reacting the ligand with ferrous chloride, and treating with hexafluorophosphate after the reaction is finished to obtain the N-heterocyclic carbene mononuclear metallic iron complex I.
Specifically, when the raw material A is dichlorobenzborane, the chemical formula of the N-heterocyclic carbene mononuclear metal iron complex I1 is as follows:
{[phenyl(tris(3-methylimidazol-1-ylidene))borate]2Fe(III)}+，
The structural formula is as follows:
The N-heterocyclic carbene mononuclear metallic iron complex I1 is a stable ferric iron complex, and two N-heterocyclic carbene ligands are combined with one metallic iron.
The molar ratio of the dichlorobenzoborane to the 1-methylimidazole is 1: (3-3.3).
In order to improve the reaction efficiency and ensure that the reaction is completely carried out, the molar ratio of the ferrous chloride to the ligand is 1: (2-2.4).
A preferred embodiment of the preparation method of the invention is as follows: dissolving dichlorobenzene borane and 1-methylimidazole in toluene, adding trifluoromethyl sulfonate, and reacting at 70-80 ℃ for 12-24 hours under the protective atmosphere. The obtained product is recrystallized and then treated by tetrabutylammonium bromide or tetrabutylammonium chloride to obtain a crude product. The crude product was treated with hexafluorophosphate to give the ligand.
The ligand reacts with ferrous chloride in super-dry DMF under protective atmosphere with potassium tert-butoxide. Reacting for 6-18 hours in an atmosphere containing oxygen to obtain solid. And then hexafluorophosphate is used for treatment to obtain a final product complex I1.
The invention utilizes the iron atom of the fixed center of the N-heterocyclic carbene ligand L1, one octahedral iron center in the molecular structure is surrounded by two tridentate ligands, and a phenyl group exists on the boron atom of the ligand, so that the huge ligand can stably coordinate the unsaturated iron center. Strong electron donating N-heterocyclic carbene ligands are also beneficial in stabilizing the entire molecule. The good stability of the medicine is a precondition for biological treatment, and the N-heterocyclic carbene mononuclear metal iron complex is easy to synthesize and separate, and has the potential of large-scale and accurate synthesis.
Specifically, when the raw material A is 2, 6-dibromopyridine, the chemical formula of the N-heterocyclic carbene mononuclear metal iron complex I2 is as follows:
{[2,6-bis(3-methylimidazolium-1yl)pyridine]2Fe}2+，
The structural formula is as follows:
A preferred embodiment of the preparation method of the invention is as follows: and (3) reacting 2, 6-dibromopyridine with 1-methylimidazole to obtain a crude product, treating the crude product by hexafluorophosphate to obtain a ligand, combining the ligand with ferrous chloride, adding potassium tert-butoxide, reacting under an acidic condition, and treating by hexafluorophosphate to obtain the N-heterocyclic carbene Fe (II) complex I2.
Specifically, when the raw material A is 2, 6-dibromopyridine-4 carboxylic acid, the chemical formula of the N-heterocyclic carbene mononuclear metal iron complex I3 is as follows:
{[2,6-bis(3-methylimidazolium-1-yl)pyridine-4-carboxylicacid]2Fe}2+。
The structural formula is as follows:
a preferred embodiment of the preparation method of the invention is as follows: and (3) reacting 2, 6-dibromopyridine-4 carboxylic acid with 1-methylimidazole to obtain a crude product, treating the crude product by hexafluorophosphate to obtain a ligand, combining the ligand with ferrous chloride, adding potassium tert-butoxide, reacting under an acidic condition, and treating by hexafluorophosphate to obtain the N-heterocyclic carbene Fe (II) complex I3.
The invention also provides application of the N-heterocyclic carbene mononuclear metal iron complex in preparation of antitumor drugs.
The medicine comprises an N-heterocyclic carbene mononuclear metal iron complex and pharmaceutically acceptable auxiliary materials.
The auxiliary materials comprise one or more of an emulsifying agent, an adhesive, a diluent, a wetting agent, an antioxidant, a lubricant, a solubilizer, a preservative or a disintegrating agent.
The emulsifier is at least one selected from span, tween, pectin, glycerin fatty acid ester, sodium alginate, agar, gelatin or silicon dioxide.
The binder is at least one selected from hydroxypropyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, starch slurry, povidone or ethyl cellulose.
The diluent is at least one selected from celluloses, starches, saccharides or inorganic salts.
The wetting agent is selected from at least one of water or ethanol.
The antioxidant is at least one selected from sulfite, bisulfite, gallic acid and lipid thereof.
The lubricant is at least one selected from talcum powder, magnesium stearate, polyethylene glycol and micropowder silica gel.
The solubilizer is at least one of Tween or polyoxyethylene fatty alcohol ether.
The preservative is at least one selected from benzoic acid and salts thereof, sorbic acid and salts thereof or parabens.
The disintegrating agent is at least one selected from starch, sodium carboxymethyl starch, crosslinked povidone, low-substituted hydroxypropyl cellulose and crosslinked polyvinylpyrrolidone.
The medicine is in the form of tablet, granule, capsule, oral liquid, injection, pill, ointment or patch.
The administration route of the medicine is oral administration, enema administration or injection administration.
The tumor is lung cancer, breast cancer, or liver cancer.
The technology not mentioned in the present invention refers to the prior art.
The beneficial effects are that:
(1) According to the invention, a cell biological experiment is carried out on 3N-heterocyclic carbene mononuclear metal iron complexes by an MTT (thiazole blue) colorimetric method. The half inhibitory concentration (IC 50) values of the 3 complexes on lung cancer cell lines NCI-H460, NCI-H1299 and A549 cells, breast cancer cell line MDA-MB-231 and liver cancer cell line HuH-7 were calculated respectively. The results show that the 3N-heterocyclic carbene mononuclear metallic iron complexes have good antiproliferative activity on the tumor cell lines. In particular to the complex I1, the IC 50 of the cell strains is smaller than 15 mu M, and the complex I1 has obvious antiproliferative effect. Therefore, the 3N-heterocyclic carbene mononuclear metal iron complexes can be further applied to the preparation of antitumor drugs.
(2) The 3N-heterocyclic carbene mononuclear metal iron complexes are iron-based metal complexes, do not contain noble metal elements, have low price, and have biocompatibility because the iron elements widely exist in organisms (such as hemoglobin for conveying and storing oxygen in human bodies, nitrogen fixation enzymes in plants and the like); the preparation method provided by the invention is safe, environment-friendly, simple in flow, low in cost and easy to obtain raw materials, and is beneficial to large-scale production.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of the ligand in example 1;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of N-heterocyclic carbene mononuclear metallic iron complex I1 in example 1;
FIG. 3 is a graph showing the change in cell activity at various concentrations of the N-heterocyclic carbene mononuclear metallic iron complex I1 of example 1.
Detailed Description
The technical scheme of the present invention is described in detail below through specific examples, but the scope of the present invention is not limited to the examples.
EXAMPLE 1N preparation of a heterocyclic carbene mononuclear metallic iron Complex I1
(1) Dichlorobenzoborane (1.0 g,6.30 mmol) and 1-methylimidazole (1.61 g,19.7 mmol) were dissolved in 15mL of toluene, and after stirring for 15min, 20mL of toluene solution (containing 3.20g,14.5mmol of trifluoromethylsulfonate) was added. Under the protection atmosphere (such as N 2), heating to 80 ℃ for reaction for 24 hours. Cooled to room temperature, filtered to give a white solid, dissolved in 10mL of dichloromethane and recrystallized at-30 ℃. After filtration, phB (MeImH) 3(OTf)2 was obtained. PhB (MeImH) 3(OTf)2 (0.780 g,1.25 mmol) was dissolved in 5mL acetone and 2mL acetone solution (containing 0.82 g,2.55mmol tetrabutylammonium bromide) was added with stirring to give a white solid precipitate, which was filtered, washed and dried to give the crude product. The crude product was dissolved in 5mL of water, 10mL of ammonium hexafluorophosphate aqueous solution (2.55 mmol) was added with stirring, and the white solid was collected as ligand L1 with a collection rate of 83.4%. The ligand L1 was subjected to nuclear magnetic resonance hydrogen spectrum characterization, and the results are shown in FIG. 1.
1H NMR(500MHz,CD3CN)：δ8.05(s,3H)，7.42-7.48(m,6H)，7.15(m,2H)，7.11(m,3H)，3.81(s,9H)。
(2) The ligand (200 mg,0.321 mmol) and FeCl 2 (20 mg,0.160 mmol) were dissolved in 3mL of super-dry DMF and reacted under stirring for 30min under protective atmosphere, followed by the addition of potassium tert-butoxide (195 mg,1.5 mmol). Stir in air at room temperature for 12 hours. Filtering after the reaction to obtain a red filtrate, adding 50mL of saturated potassium hexafluorophosphate aqueous solution to precipitate a red solid, filtering, washing and drying to obtain a solid product, dissolving with 5mL of acetonitrile, slowly diffusing diethyl ether into the solution to precipitate a single crystal, wherein the obtained single crystal is the N-heterocyclic carbene mononuclear metal iron complex I1, and the collection rate is 64.8%. The nuclear magnetic hydrogen spectrum of the complex I1 is characterized, and the result is shown in figure 2.
1H NMR(500MHz,CD3CN)：δ14.77(s,2H),10.41(s,2H),9.76(s,1H),4.91(s,8H),2.15(s,22H),1.60(s,2H).
ESI–HRMS:[I1-(PF6)]+m/z＝718.3039。
Example 2 preparation of N-heterocyclic carbene mononuclear metallic iron Complex I1
(1) Dichlorobenzoborane (1.0 g,6.30 mmol) and 1-methylimidazole (1.66 g,20.35 mmol) were dissolved in 15mL of toluene, and after stirring for 15min, 20mL of toluene solution (containing 3.20g,14.5mmol of trifluoromethylsulfonate) was added. Under the protection atmosphere (such as N 2), heating to 80 ℃ for reaction for 24 hours. Cooled to room temperature, filtered to give a white solid, dissolved in 10mL of dichloromethane and recrystallized at-30 ℃. After filtration, phB (MeImH) 3(OTf)2 was obtained. PhB (MeImH) 3(OTf)2 (0.780 g,1.25 mmol) was dissolved in 5mL acetone and 2mL acetone solution (containing 0.82 g,2.55mmol tetrabutylammonium bromide) was added with stirring to give a white solid precipitate, which was filtered, washed and dried to give the crude product. The crude product was dissolved in 5mL of water, 10mL of ammonium hexafluorophosphate aqueous solution (2.55 mmol) was added with stirring, and a white solid was collected as ligand L1 with a collection rate of 79.1%. Nuclear magnetic hydrogen spectrum characterization was performed on ligand L1:
1H NMR(500MHz,CD3CN)：δ8.06(s,3H)，7.42-7.48(m,6H)，7.16(m,2H)，7.13(m,3H)，3.82(s,9H)。
(2) The ligand (220 mg,0.353 mmol) and FeCl 2 (20 mg,0.160 mmol) were dissolved in 3mL of super-dry DMF and the reaction was stirred under protective atmosphere for 30 minutes, after which potassium tert-butoxide (195 mg,1.5 mmol) was added. Stir in air at room temperature for 12 hours. Filtering after the reaction to obtain a red filtrate, adding 50mL of saturated potassium hexafluorophosphate aqueous solution to precipitate a red solid, filtering, washing and drying to obtain a solid product, dissolving with 5mL of acetonitrile, slowly diffusing diethyl ether into the solution to precipitate a single crystal, wherein the obtained single crystal is the N-heterocyclic carbene mononuclear metal iron complex I1, and the collection rate is 58.7%. Nuclear magnetic hydrogen spectrum characterization was performed on complex I1:
1H NMR(500MHz,CD3CN)：δ14.78(s,2H),10.42(s,2H),9.78(s,1H),4.91(s,8H),2.14(s,22H),1.60(s,2H).
Example 3 preparation of N-heterocyclic carbene mononuclear metallic iron Complex I1
(1) Dichlorobenzoborane (1.0 g,6.30 mmol) and 1-methylimidazole (1.70 g,20.79 mmol) were dissolved in 15mL of toluene and stirred for 15min before 20mL of toluene solution (containing 3.20g,14.5mmol of trifluoromethylsulfonate) was added. Under the protection atmosphere (such as N 2), heating to 80 ℃ for reaction for 24 hours. Cooled to room temperature, filtered to give a white solid, dissolved in 10mL of dichloromethane and recrystallized at-30 ℃. After filtration, phB (MeImH) 3(OTf)2 was obtained. PhB (MeImH) 3(OTf)2 (0.780 g,1.25 mmol) was dissolved in 5mL acetone and 2mL acetone solution (containing 0.82 g,2.55mmol tetrabutylammonium bromide) was added with stirring to give a white solid precipitate, which was filtered, washed and dried to give the crude product. The crude product was dissolved in 5mL of water, 10mL of ammonium hexafluorophosphate aqueous solution (2.55 mmol) was added with stirring, and a white solid was collected as ligand L1 at a collection rate of 81.8%. Nuclear magnetic hydrogen spectrum characterization was performed on ligand L1:
1H NMR(500MHz,CD3CN)：δ8.04(s,3H)，7.42-7.48(m,6H)，7.13(m,2H)，7.10(m,3H)，3.78(s,9H)。
(2) The ligand (240 mg,0.385 mmol) and FeCl 2 (20 mg,0.160 mmol) were dissolved in 3mL of super-dry DMF and the reaction was stirred under protective atmosphere for 30 minutes, after which potassium tert-butoxide (195 mg,1.5 mmol) was added. Stir in air at room temperature for 12 hours. Filtering after the reaction to obtain a red filtrate, adding 50mL of saturated potassium hexafluorophosphate aqueous solution to precipitate a red solid, filtering, washing and drying to obtain a solid product, dissolving with 5mL of acetonitrile, slowly diffusing diethyl ether into the solution to precipitate a single crystal, wherein the obtained single crystal is the N-heterocyclic carbene mononuclear metallic iron complex I1, and the collection rate is 60.7%. Nuclear magnetic hydrogen spectrum characterization was performed on complex I1:
1H NMR(500MHz,CD3CN)：δ14.77(s,2H),10.40(s,2H),9.74(s,1H),4.90(s,8H),2.15(s,22H),1.60(s,2H).
Example 4 preparation of N-heterocyclic carbene mononuclear metallic iron Complex I2
(1) 2, 6-Dibromopyridine (6.4 g,26.7 mmol) was added to 1-methylimidazole (8.6 mL,106.9 mmol), reacted at 150℃for 3 hours, cooled to room temperature, and then filtered to give a solid which was washed with 10mL of methylene chloride and 10mL of diethyl ether in this order 3 times. The washed solid was dissolved in 5mL of deionized water, 50mL of saturated aqueous potassium hexafluorophosphate solution was added, and the precipitated solid was ligand L2 with a collection rate of 75.8%. Nuclear magnetic hydrogen spectrum characterization was performed on ligand L2:
1H NMR(500MHz,CD3CN)：δ10.61(s,1H),8.80(s,1H),8.60(t,J＝8.1Hz,1H),8.24(d,J＝8.1Hz,1H),8.0(m,1H),4.04(s,2H).
(2) Ligand L2 (200 mg,0.46 mmol) and FeCl 2 (29 mg, 0.231mmol) were dissolved in 3mL of super-dry DMF, stirred for 30 min, potassium tert-butoxide (195 mg,1.5 mmol) was added, stirred for 10 min at room temperature, adjusted to pH 2 with dilute nitric acid and the reaction was continued for 12 h. After completion of the reaction, the mixture was filtered, and 50mL of a saturated aqueous potassium hexafluorophosphate solution was added to the solution. Filtering to obtain a solid product, dissolving the solid product with 5mL of acetonitrile, slowly diffusing diethyl ether into the solution, and obtaining a separated monocrystal, namely the N-heterocyclic carbene mononuclear metal iron complex I2, wherein the collection rate is 61.8%. Nuclear magnetic hydrogen spectrum characterization was performed on complex I2:
1H NMR(500MHz,CD3CN)：δ8.30(s,4H)，8.15(s,4H)，7.01(s,4H)，2.49(s,14H)。
ESI–HRMS:[I2-(PF6)]+m/z＝679.1325。
example 5 preparation of N-heterocyclic carbene mononuclear metallic iron Complex I3
(1) 2, 6-Dibromopyridine-4 carboxylic acid (0.35 g,1.24 mmol) was added to 1-methylimidazole (1 mL,12.4 mmol), reacted at 150℃for 3 hours, cooled to room temperature, and filtered to give a solid, which was washed 3 times with 5mL of diethyl ether. Then dissolving in 5mL of methanol, slowly adding diethyl ether until a large amount of white powder is separated out, dissolving the solid obtained after filtration by using 5mL of deionized water, adding 50mL of saturated potassium hexafluorophosphate aqueous solution, and obtaining the separated solid which is ligand L3, wherein the collection rate is 74.6%. Nuclear magnetic hydrogen spectrum characterization was performed on ligand L3:
1H NMR(500MHz,DMSO-d6)：δ10.55(s,2H)，8.88(s,2H)，8.48(s,2H)，8.05(s,2H)，4.02(s,6H)。
(2) Ligand L3 (200 mg,0.35 mmol) and FeCl 2 (22 mg,0.175 mmol) were dissolved in 3mL of super-dry DMF, stirred for 30 min, potassium tert-butoxide (195 mg,1.5 mmol) was added, stirred for 10 min at room temperature, adjusted to pH 2 with dilute nitric acid and the reaction was continued for 12 h. After completion of the reaction, the mixture was filtered, and 50mL of a saturated aqueous potassium hexafluorophosphate solution was added to the solution. Filtering to obtain a solid product, dissolving the solid product with 5mL of acetonitrile, slowly diffusing diethyl ether into the solution, and obtaining a separated monocrystal, namely the N-heterocyclic carbene mononuclear metal iron complex I3, wherein the collection rate is 58.7%. Nuclear magnetic hydrogen spectrum characterization was performed on complex I3:
1H NMR(500MHz,CD3CN)：δ8.30(s,4H)，8.15(s,4H)，7.01(s,4H)，2.49(s,14H)。
ESI–HRMS:[I3-(2PF6)]+m/z＝311.0746。
example 6 determination of antitumor Activity
In this experiment, 3 kinds of complexes prepared in example 1, example 4 and example 5 were subjected to a cell biology experiment by MTT (thiazole blue) colorimetry.
Materials: human lung cancer cell NCI-H460, human lung cancer cell NCI-H1299, human lung cancer cell A549, human breast cancer cell MDA-MB-231, human liver cancer cell Huh-7 (purchased from Shanghai cell biology institute of Chinese academy of sciences), and identified correctly by STR
The testing method comprises the following steps: human lung cancer cells (NCI-H460) were washed, digested, centrifuged (800 rpm,5 min) with 1ml of 10% FBS, and then cultured in 10% FBS-containing medium (DMEM medium, available from Punuocele) by inoculating 2.0X10 3 cells in a six-well plate circular well having a growth area of 9.5cm 2 per well, and culturing until adherence. The concentration of the complex was set at 100.0000, 50.0000, 25.0000, 12.5000,6.2500,3.1250,1.5625 μm (diluted with 10% fbs, total 7 groups), and each group was tested 3 times repeatedly and averaged. The blank wells contained medium alone and were incubated at 37℃for 48h with 5% CO 2 using DMEM medium containing 2% FBS as a reference (containing human lung cancer cells, medium, no drug). The MTT kit (available from Menlan) stored at-20℃was removed and warmed up (37 ℃) and 10. Mu.L of MTT solution (5 mg/ml) was added to each well for further incubation for 4 hours. After the completion, the liquid remained in the wells and the precipitate was removed by suction, and 150. Mu. LDMSO was added for coloring. The absorbance (OD value, YT-1101 type microplate reader) was measured at 570nm wavelength, and the IC 50 value was obtained by analytical processing.
The antiproliferative activity of 3N-heterocyclic carbene mononuclear metallic iron complexes on other cell lines (human lung cancer cell NCI-H1299, human lung cancer cell A549, human breast cancer cell MDA-MB-231, human liver cancer cell Huh-7) was tested according to the method, and the results are shown in Table 1:
TABLE 1 IC 50 values of three complexes for different cell lines
Note that: in the table/indicating that the item was not tested.
As can be seen from Table 1, the N-heterocyclic carbene mononuclear metallic iron complexes I2 and I3 according to the invention have a certain antiproliferative activity on all the above-mentioned cell lines, but the effect is not obvious. The antiproliferative effect of complex I1 is significantly better than that of complex I2 and complex I3. The IC 50 value of the complex I1 on the cell lines is below 15 mu M, and especially has obvious effect on human lung cancer cells NCI-H460, NCI-H1299 and human breast cancer cells MDA-MB-231, the IC 50 value is below 10 mu M, and the antiproliferative effect is excellent.
The invention further illustrates the antiproliferative effect of the N-heterocyclic carbene mononuclear metallic iron complex I1 through a change chart (see figure 3) of the cell activity of the N-heterocyclic carbene mononuclear metallic iron complex I1 at different concentrations. As can be seen from FIG. 3, the N-heterocyclic carbene mononuclear metallic iron complex I1 has antiproliferative effects on all the cell lines, especially on human lung cancer cells NCI-H460 cells, and the cell activity is reduced to nearly 0% when the complex concentration reaches more than 25 mu M. For human lung cancer cells NCI-H1299 and human breast cancer cells MDA-MB-231, the cell activity also decreases to nearly 0% when the complex concentration reaches more than 50 mu M. The effect on human lung cancer cells A549 and human liver cancer cells Huh-7 is slightly poorer, but is below 50 percent.
The invention carries out cell biological experiments on 3N-heterocyclic carbene mononuclear metal iron complexes by an MTT (thiazole blue) colorimetric method. The results show that the 3N-heterocyclic carbene mononuclear metallic iron complexes have good antiproliferative activity on the tumor cell lines. In particular to the complex I1, the IC 50 of the cell strains is smaller than 15 mu M, and the complex I1 has obvious antiproliferative effect. Therefore, the 3N-heterocyclic carbene mononuclear metal iron complexes can be further applied to the preparation of antitumor drugs.
As described above, although the present invention has been shown and described with reference to certain preferred embodiments, it is not to be construed as limiting the invention itself. Various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (10)

1. A preparation method of an N-heterocyclic carbene mononuclear metallic iron complex is characterized by comprising the following steps: reacting the raw material A with 1-methylimidazole to obtain a crude product, and treating the crude product by hexafluorophosphate to obtain a ligand; and (3) reacting the ligand with ferrous chloride, and treating with hexafluorophosphate after the reaction is finished to obtain the N-heterocyclic carbene mononuclear metallic iron complex I.
2. The preparation method according to claim 1, wherein the raw material A is dichlorobenzoborane, and the N-heterocyclic carbene mononuclear metal iron complex I1 has a chemical formula:
{[phenyl(tris(3-methylimidazol-1-ylidene))borate]2Fe(III)}+，
The structural formula is as follows:
3. The preparation method according to claim 2, wherein the molar ratio of dichlorobenzoborane to 1-methylimidazole is 1: (3-3.3).
4. The method of claim 2, wherein the molar ratio of ferrous chloride to ligand is 1: (2-2.4).
5. The preparation method according to claim 1, wherein the raw material A is 2, 6-dibromopyridine, and the N-heterocyclic carbene mononuclear metallic iron complex I2 has a chemical formula:
{[2,6-bis(3-methylimidazolium-1yl)pyridine]2Fe}2+，
The structural formula is as follows:
6. The preparation method according to claim 1, wherein the raw material A is 2, 6-dibromopyridine-4-carboxylic acid, and the N-heterocyclic carbene mononuclear metal iron complex I3 has a chemical formula:
{[2,6-bis(3-methylimidazolium-1-yl)pyridine-4-carboxylic acid]2Fe}2+。
The structural formula is as follows:
the application of N-heterocyclic carbene mononuclear metal iron complex in preparing antitumor drugs.
8. The use according to claim 7, wherein the medicament comprises an N-heterocyclic carbene mononuclear metal iron complex and a pharmaceutically acceptable excipient.
9. The use according to claim 8, wherein the auxiliary material comprises one or more of an emulsifier, a binder, a diluent, a wetting agent, an antioxidant, a lubricant, a solubilizer, a preservative or a disintegrant.
10. The use according to claim 8, wherein the medicament is in the form of a tablet, granule, capsule, oral liquid, injection, pill, ointment or patch.
CN202211294822.6A 2022-10-21 2022-10-21 Preparation method and application of N-heterocyclic carbene mononuclear metal iron complex Pending CN117917423A (en)

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