Preparation method and application of tridentate clamp type metal iridium complex
By preparing the three-tooth clamp type iridium complex, the problems of resistance and side effects of existing platinum drugs were solved, and efficient and stable anti-tumor effects were achieved, especially the high cytotoxicity to cervical cancer, colon cancer, and lung cancer cells.
Patent Information
- Application Number
- CN202311682972.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-08
- Publication Date
- 2025-07-22
AI Technical Summary
Existing platinum-based anti-tumor drugs have drug resistance and serious side effects. The anti-cancer activity of bidentate iridium (III) complex is rarely reported. Tridentate clamp type iridium (III) complex has potential in chemical stability and cell penetration ability, but its preparation and application have not been fully studied.
The three-toothicone metal iridium complex is prepared by using the cyclization reaction of substituted benzene 1,3-dicarboxylate and 2-aminophenylthiophene, combined with the reaction of hydrated iridium trichloride and L^X ligand, and the trityl clamp type metal iridium complex is preferably used to prepare a catalyst for triphenyl phosphite and tetrabutylamine bromide.
The prepared three-tooth clamp type iridium complex has good light stability, excellent anti-tumor properties, and shows high cytotoxicity to cervical cancer, colon cancer, and lung cancer cells, which is better than the existing cisplatin drugs.
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Figure CN120349355A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of biomedicine, and particularly relates to a preparation method and application of a tridentate pincer-type iridium metal complex. Background Art
[0002] With the successful clinical application of cisplatin as an effective anti-tumor drug, platinum-based drugs have become an emerging field in anti-cancer applications. In recent years, platinum-based anti-cancer drugs such as carboplatin, lobaplatin, and oxaliplatin are still the most widely used anti-cancer drugs. Cisplatin is the first metal anti-tumor drug applied in the market at present, which has opened up new ideas for transition metal complexes as anti-tumor drugs. To this day, cisplatin is still used as a benchmark for evaluating the anti-tumor ability of metal anti-tumor drugs. However, the drug resistance and severe side effects of platinum have hindered the development of platinum. Due to the natural weaknesses of platinum-based drugs (severe toxic and side effects), people have begun to devote themselves to studying the anti-cancer activities of other metal complexes. For example, metal complexes such as Ru, Os, Ir, Re, Au, Pd, and Rh in the same period or the same main group show good anti-tumor activities. Especially, iridium(III) complexes with fewer side effects and different action mechanisms have attracted more and more attention.
[0003] Iridium(III) complexes are considered to be the most promising substitutes for platinum-based drugs. Not only because iridium(III) complexes have rich photophysical properties such as high quantum yield, large Stokes shift, long phosphorescence lifetime, good photostability, and strong cell penetration ability, but also because they have an anti-tumor mechanism different from that of platinum-based drugs, such as destroying mitochondrial activity, inducing cytoplasmic vacuolization, inhibiting protein kinase and enzyme activities, etc. Research shows that iridium(III) complexes can be structurally modified to make them more easily penetrate cell membranes and accumulate in different subcellular organelles, resulting in better anti-tumor activities. However, most of these reported iridium(III) complexes are bidentate-configured iridium metal complexes, and there are few reports on the anti-cancer activities of tridentate pincer-type iridium(III) complexes. This type of iridium(III) complex has advantages such as better chemical stability, longer phosphorescence lifetime, and strong cell penetration ability. Therefore, this type of iridium(III) complex is expected to have great development potential in the field of metal anti-cancer drugs. Summary of the Invention
[0004] One of the purposes of the present invention is to provide a novel tridentate pincer-type iridium complex metal drug with good stability and excellent anti-tumor activity.
[0005] The second purpose of the present invention is to provide a preparation method of the above-mentioned tridentate pincer-type iridium complex.
[0006] The third purpose of the present invention is to provide the application of the above-mentioned tridentate pincer-type iridium complex in anti-tumor aspects.
[0007] One of the technical solutions to achieve one of the purposes of the present invention is: a tridentate pincer-type iridium metal complex, and the general structural formula of this type of complex is as follows:
[0008]
[0009] In the formula, each R independently represents a hydrogen atom, a fluorine atom, a methyl group, a trifluoromethyl group or a tert-butyl group, and L^X represents an N^N-type ligand, which is 2,2-bipyridine, phenanthroline, etc.
[0010] Preferably, R is a methyl group or a tert-butyl group and L^X is 2,2-bipyridine; or R is a methyl group or a tert-butyl group and L^X is phenanthroline.
[0011] One of the technical solutions to achieve the second purpose of the present invention is: a preparation method of the above-mentioned tridentate pincer-type iridium complex, including the following steps:
[0012] Step 1, the substituted 1,3-benzenedicarboxylic acid reacts with 2-aminobenzenethiol through a cyclization reaction to obtain a first intermediate;
[0013] Step 2, hydrated iridium trichloride reacts with the first intermediate obtained in Step 1 to obtain a second intermediate;
[0014] Step 3, the L^X-type ligand reacts with the second intermediate obtained in Step 2, and then silver trifluoromethanesulfonate is used to obtain the target product.
[0015] The molar ratio of the substituted 1,3-benzenedicarboxylic acid to the 2-aminobenzenethiol in the above Step 1 is 1:2 to 1:3.
[0016] The cyclization reaction in the above Step 1 is carried out in the presence of a cyclization reagent; the molar ratio of the substituted 1,3-benzenedicarboxylic acid to the cyclization reagent is 1:1 to 1:3.
[0017] The cyclization reagent is trimethyl phosphite, triethyl phosphite or triphenyl phosphite, and preferably triphenyl phosphite.
[0018] The cyclization reaction in the above Step 1 is carried out in the presence of a phase transfer catalyst; the molar ratio of the substituted 1,3-benzenedicarboxylic acid to the phase transfer catalyst is 1:1 to 1:3.
[0019] The phase transfer catalyst is tetrabutylammonium bromide [hereinafter simply referred to as TBAB].
[0020] The reaction temperature in the above Step 1 is 80 to 120 °C, and preferably 100 °C.
[0021] The molar ratio of the hydrated iridium trichloride to the first intermediate in the above Step 2 is 1:2 to 1:3.
[0022] The second step above is carried out in the presence of a mixed solvent; the mixed solvent preferably adopts 2-ethoxyethanol and water with a volume ratio of 1∶1 to 3∶1.
[0023] The reaction temperature of the second step above is 110 - 130 °C, preferably 120 °C.
[0024] In the third step above, the molar ratio of the second intermediate to the L^X auxiliary ligand (2,2-bipyridine or o-phenanthroline) is 1∶2 to 1∶3.
[0025] The reaction of the third step above is carried out in the presence of an organic solvent, and the organic solvent is tetrahydrofuran or toluene; the organic solvent is preferably toluene.
[0026] The reaction of the third step above also requires a dehalogenating reagent for the reaction, and the dehalogenating reagent is silver trifluoromethanesulfonate.
[0027] The technical solution to achieve the third object of the present invention is: the application of the above-mentioned tridentate pincer-type iridium complex in anti-tumor. The anti-tumor activity of cells was tested by the traditional MTT colorimetric method for the inhibitory effects on tumor cells such as cervical cancer cells, colon cancer cells, and lung cancer cells.
[0028] The positive effects of the present invention are as follows: The preparation method of the tridentate pincer-type iridium complex provided by the present invention is simple and efficient in synthesis, and the prepared tridentate pincer-type metal iridium complex has good photo-stability. At the same time, the iridium complex provided by the present invention has excellent anti-tumor properties, has higher cytotoxicity to cervical cancer, colon cancer, and lung cancer, and is superior to the anti-cancer metal drug cisplatin (Pt(NH3)2Cl2) that has been clinically applied at present. Description of the Drawings
[0029] The above and / or additional aspects and advantages of the present invention will become obvious and easy to understand from the description of the embodiments in conjunction with the following drawings, wherein:
[0030] Figure 1 Synthesis routes of the tridentate pincer-type iridium complexes of Examples 1 - 4.
[0031] Figure 2 Fluorescence spectra of the tridentate pincer-type iridium complexes of Examples 1 - 4. Among them, the abscissa is the wavelength, with the unit of nm; the ordinate is the normalized fluorescence intensity, with the unit of a.u.
[0032] Figure 3 Ultraviolet spectra of the tridentate pincer-type iridium complexes of Examples 1 - 4. Among them, the abscissa is the wavelength, with the unit of nm; the ordinate is the ultraviolet absorption intensity, with the unit of a.u.
[0033] Figure 4Single crystal structure diagram of the tridentate pincer iridium complex of Example 1. Detailed Description of the Invention
[0034] The following is a further detailed description through specific embodiments:
[0035] Example 1
[0036] The structural formula of the tridentate pincer iridium complex [abbreviation: Ir-1] of this example is as follows:
[0037]
[0038] I. Synthesis of the first intermediate 2,2'-(5-(tert-butyl)-1,3-phenylene)bis(benzo[d]thiazole):
[0039] A mixture of 5-tert-butylisophthalic acid (1.00 g, 4.50 mmol), o-aminothiophenol (1.24 g, 9.9 mmol), triphenyl phosphite (2.79 g, 9.00 mmol), and tetrabutylammonium bromide (2.9 g, 9 mmol) was heated to 100 °C in a nitrogen atmosphere and stirred for 2 hours. After the mixture was cooled, 20 ml of methanol was added, and precipitation occurred to obtain 1.30 g of the white solid first intermediate 2,2'-(5-(tert-butyl)-1,3-phenylene)bis(benzo[d]thiazole), with a yield of 72.2%.
[0040] II. Synthesis of the second intermediate iridium-containing chloro-bridged dimer (L)2Ir(μ-Cl)2Ir(L)2:
[0041] 0.30 g of the 2,2'-(5-(tert-butyl)-1,3-phenylene)bis(benzo[d]thiazole) obtained in step I and 0.22 g of IrCl3·3H2O (0.74 mmol) were dissolved in 8 mL of 2-ethoxyethanol and 4 mL of water. Under nitrogen protection, the reaction solution was heated to 120 °C and stirred for 10 h. After the reaction was completed, the reaction solution was cooled to room temperature, then 10 mL of water was added, and filtration was carried out. After vacuum drying, 0.25 g of the red solid powder second intermediate iridium-containing chloro-bridged dimer (L)2Ir(μ-Cl)2Ir(L)2 was obtained, with a yield of 50.8%.
[0042] III. Synthesis of the target product:
[0043] 0.20 g of the second intermediate obtained in Step 2 (150 mmol), 2,2'-bipyridine (0.47 g, 300 mmol) and silver trifluoromethanesulfonate (0.17 g, 675 mmol) were mixed in toluene and heated under reflux for 12 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature. Dichloromethane and water were added to the reaction system for liquid separation, and the organic phase was dried and purified by column chromatography to obtain 30 mg of the target product Ir-1 as an orange-red powder, with a yield of 12.7%. 1H NMR (400 MHz, CDCl3) δ 10.36 (d, J = 5.3 Hz, 1H), 9.26 (d, J = 7.9 Hz, 1H), 8.84 (d, J = 7.6 Hz, 1H), 8.70 (t, J = 7.9 Hz, 1H), 8.22–8.15 (m, 1H), 8.02 (s, 2H), 7.84 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 7.7 Hz, 2H), 7.16 (t, J = 7.1 Hz, 3H), 7.07–7.05 (m, 1H), 6.17 (d, J = 8.4 Hz, 2H), 1.55 (s, 9H). EI-MS: m / z 783.2 (calcd 783.1).
[0044] Example 2
[0045] The structural formula of the tridentate pincer-type iridium complex [abbreviated as Ir-2] in this example is as follows:
[0046]
[0047] Yellow solid Ir-2 (0.25 g, 10.3%). 1H NMR (400 MHz, CDCl3) δ 10.71 (dd, J = 5.0, 1.5 Hz, 1H), 9.28 (dd, J = 8.3, 1.5 Hz, 1H), 8.66 (dd, J = 8.3, 5.0 Hz, 1H), 8.53 (dd, J = 8.3, 1.3 Hz, 1H), 8.46 (d, J = 8.9 Hz, 1H), 8.23 (d, J = 8.9 Hz, 1H), 8.14 (s, 2H), 7.81–7.77 (m, 2H), 7.69 (dd, J = 8.2, 5.5 Hz, 1H), 7.60 (dd, J = 5.5, 1.3 Hz, 1H), 7.29–7.27 (m, 2H), 7.00 (ddd, J = 8.5, 7.3, 1.2 Hz, 2H), 6.04–5.99 (m, 2H), 1.65 (s, 9H). EI-MS: m / z 807.3 (calcd 807.1).
[0048] The preparation method of this tridentate pincer-type iridium complex is basically the same as that of Example 1, and the differences are shown in Table 1.
[0049] Example 3
[0050] The structural formula of the tridentate pincer iridium complex [abbreviation Ir-3] in this example is as follows:
[0051]
[0052] Yellow solid Ir-3 (0.23 g, 11.7%). 1H NMR (400 MHz, CDCl3) δ 10.44–10.39 (m, 1H), 9.33 (d, J = 8.3 Hz, 1H), 8.90 (d, J = 8.1 Hz, 1H), 8.76 (td, J = 8.0, 1.7 Hz, 1H), 8.26 (ddd, J = 7.6, 5.4, 1.1 Hz, 1H), 7.91 (d, J = 0.8 Hz, 2H), 7.87 (dd, J = 7.9, 1.6 Hz, 1H), 7.83 (dd, J = 8.0, 1.0 Hz, 2H), 7.39 (ddd, J = 8.2, 7.3, 1.0 Hz, 2H), 7.27 (d, J = 1.6 Hz, 1H), 7.20 (ddd, J = 8.5, 7.3, 1.2 Hz, 2H), 7.10 (ddd, J = 7.4, 5.8, 1.4 Hz, 1H), 6.22 (d, J = 8.4 Hz, 2H), 2.75 (s, 3H). EI-MS: m / z 741.3 (calcd 741.1).
[0053] The preparation method of this tridentate pincer iridium complex is basically the same as that of Example 1, and the differences are shown in Table 1.
[0054] Example 4
[0055] The structural formula of the tridentate pincer iridium complex [abbreviation Ir-4] in this example is as follows:
[0056]
[0057] Yellow solid Ir-4 (0.35 g, 14.21%). 1H NMR (400 MHz, CDCl3) δ 10.71 (dd, J = 5.1, 1.4 Hz, 1H), 9.28 (dd, J = 8.3, 1.4 Hz, 1H), 8.67 (dd, J = 8.3, 5.0 Hz, 1H), 8.52–8.48 (m, 1H), 8.46 (d, J = 8.9 Hz, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.97 (s, 2H), 7.78 (d, J = 8.1 Hz, 2H), 7.69–7.63 (m, 2H), 7.29 (d, J = 7.7 Hz, 2H), 6.99 (ddd, J = 8.4, 7.3, 1.2 Hz, 2H), 6.02 (d, J = 8.5 Hz, 2H), 2.79 (s, 3H). EI-MS: m / z 765.3 (calcd 765.1).
[0058] The preparation method of this tridentate pincer-type iridium complex is basically the same as that of Example 1, and the differences are shown in Table 1 below.
[0059] Table 1 is as follows:
[0060]
[0061]
[0062] Photophysical properties of the tridentate pincer-type iridium complex:
[0063] The fluorescence emission spectra of the tridentate pincer-type iridium complexes of Examples 1-4 were measured in dichloromethane solution at room temperature, as Figure 2 shown. The UV-visible absorption spectra of the tridentate pincer-type iridium complexes of Examples 1-4 were measured in dichloromethane solution at room temperature, as Figure 3 shown.
[0064] Cytotoxicity test of the tridentate pincer-type (III) iridium complex:
[0065] Experimental procedure: The cytotoxicity was determined by the MTT method. When the cells were cultured to logarithmic growth, the cells were digested into single-cell suspensions with trypsin, and the cell concentration was adjusted to 8×104 / ml using a cell counting chamber. The cells were inoculated in a 96-well plate, with 100 μL added to each well. After the cells adhered, different concentrations of iridium complexes diluted with the culture medium were added respectively, and then cultured in an incubator for 48 hours. Then, 20 μL of MTT was added to each well. After culturing in the incubator for four hours, the culture medium was discarded, 100 μL of DMSO was added to each well, and shaken for about 5 minutes. The OD value at 570 nm was measured using an enzyme-linked immunosorbent assay (ELISA) reader. Finally, the IC50 value was calculated through data processing. The IC50 results of the complexes described in Examples 1-4 against cervical cancer cells (HeLa cells), colon cancer cells (RKO cells), and lung cancer cells (A549 cells) are shown in Table 1. The in vitro toxicity of the four implemented tridentate pincer-type iridium complexes Ir-1-Ir-4 against HeLa, PKO, and A549 cells indicates that this type of iridium complex has good in vitro cytotoxicity, and the overall in vitro toxicity is better than that of cisplatin. It is a class of highly efficient metal anti-tumor drugs.
[0066] The anti-tumor activity data of the tridentate pincer-type iridium complexes of Examples 1 to 4 are as follows:
[0067]
[0068] The above are only the embodiments of the present invention. Specific structures and common knowledge such as characteristics known in the art are not described in detail here. Those of ordinary skill in the art know all the common general technical knowledge in the technical field to which the invention belongs before the application date or the priority date, can know all the existing technologies in this field, and have the ability to apply the conventional experimental means before this date. Those of ordinary skill in the art can, under the inspiration given in this application, combine their own abilities to improve and implement this solution. Some typical well-known structures or well-known methods should not become an obstacle for those of ordinary skill in the art to implement this application. It should be noted that for those skilled in the art, without departing from the structure of the present invention, several modifications and improvements can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the implementation effect of the present invention and the practicality of the patent. The protection scope required by this application should be based on the content of its claims, and the specific implementation manners described in the specification can be used to explain the content of the claims.
Claims
1. A tridentate pincer-type iridium metal complex, characterized in that The general structural formula is as follows: In the formula, each R independently represents a hydrogen atom, a fluorine atom, a methyl group, a trifluoromethyl group or a tert-butyl group, and L^X represents an N^N type ligand, such as 2,2-bipyridine or phenanthroline.
2. The tridentate pincer-type iridium metal complex according to claim 1, characterized in that: R is a methyl group or a tert-butyl group and L^X is 2,2-bipyridine; or R is a methyl group or a tert-butyl group and L^X is phenanthroline.
3. A preparation method of a tridentate pincer-type iridium metal complex, characterized in that: A method for preparing a tridentate pincer-type iridium metal complex based on Claim 1 and Claim 2 includes the following steps: Step 1, a substituted 1,3-benzenedicarboxylic acid reacts with 2-aminobenzenethiol through a cyclization reaction to obtain a first intermediate; Step 2, hydrated iridium trichloride reacts with the first intermediate obtained in Step 1 to obtain a second intermediate; Step 3, an L^X type ligand reacts with the second intermediate obtained in Step 2, and then silver trifluoromethanesulfonate is used to obtain the target product.
4. The preparation method of the tridentate clamp-type iridium metal complex according to claim 3, wherein: In the cyclization reaction in Step 1, the molar ratio of the substituted 3-benzenedicarboxylic acid to the 2-aminobenzenethiol is 1:2 to 1:3; the cyclization reaction in Step 1 is carried out in the presence of a cyclization reagent; the molar ratio of the substituted 1,3-benzenedicarboxylic acid to the cyclization reagent is 1:1 to 1:3; the cyclization reaction in Step 1 is carried out in the presence of a phase transfer catalyst; the molar ratio of the substituted 1,3-benzenedicarboxylic acid to the phase transfer catalyst is 1:1 to 1:3; the reaction temperature in Step 1 is 80 to 120 °C.
5. The preparation method of the tridentate pincer-type metal iridium complex according to claim 3, characterized in that: In Step 2, the molar ratio of the hydrated iridium trichloride to the first intermediate is 1:2 to 1:3; Step 2 is carried out in the presence of a mixed solvent; the mixed solvent preferably has a volume ratio of 1:1 to 3:1; the reaction temperature in Step 2 is 110 to 130 °C.
6. The preparation method of the tridentate clamp-type metal iridium complex according to claim 3, characterized in that: In Step 3, the molar ratio of the second intermediate to the L^X auxiliary ligand is 1:2 to 1:3; the reaction in Step 3 is carried out in the presence of an organic solvent, and the organic solvent is tetrahydrofuran or toluene; the reaction in Step 3 also requires a dehalogenating reagent for the reaction.
7. Application of a tridentate pincer-type iridium metal complex, characterized in that: The application of the tridentate pincer-type iridium metal complex based on Claim 1 and Claim 2, and the tridentate pincer-type iridium complex is applied to anti-tumor aspects.
8. Use of the tridentate pincer-type iridium metal complex according to claim 7, characterized in that: As a metal anti-tumor drug, this type of tridentate pincer-type iridium complex has tested the anti-tumor activities of a series of cells by using the classical MTT method, including cervical cancer cells (HeLa cells), colon cancer cells (RKO cells) and lung cancer cells (A549 cells), and the test results all show good results.