CN115057893B - Organic metal iridium complex of sandwich configuration and targeted mitochondria as well as preparation method and application thereof - Google Patents

Organic metal iridium complex of sandwich configuration and targeted mitochondria as well as preparation method and application thereof Download PDF

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CN115057893B
CN115057893B CN202210767038.6A CN202210767038A CN115057893B CN 115057893 B CN115057893 B CN 115057893B CN 202210767038 A CN202210767038 A CN 202210767038A CN 115057893 B CN115057893 B CN 115057893B
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刘金锋
武玉婷
张沛
王丽艳
刘西成
车程川
杨革
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Qufu Normal University
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Abstract

The invention relates to a metal iridium complex, belongs to the field of chemical pharmacy, and in particular relates to a sandwich-configuration organic metal iridium complex for targeting mitochondria, and a preparation method and application thereof. The structural formula of the invention is shown as the formulas (I) - (III):the sandwich-configuration iridium complex provided by the invention can be positioned in mitochondria to induce functional disorder thereof so as to induce apoptosis of cancer cells, has high anticancer activity and good selectivity, and is not easy to generate drug resistance; the series of complexes have good anticancer activity, in vitro anticancer activity is superior to cisplatin, and stability is good, thus providing a new strategy and experimental foundation for development and research of anticancer metal complexes. The preparation method provided by the invention has high synthesis efficiency, and the prepared target complex can accumulate in mitochondria in cells to induce early apoptosis.

Description

Organic metal iridium complex of sandwich configuration and targeted mitochondria as well as preparation method and application thereof
Technical Field
The invention relates to a metal iridium complex, belongs to the field of chemical pharmacy, and in particular relates to a sandwich-configuration organic metal iridium complex for targeting mitochondria, and a preparation method and application thereof.
Background
Malignant tumors seriously affect the health level and life of human beings. Metastasis and drug resistance of cancer are the most troublesome problems faced by clinical tumor treatment. Although research on prevention, diagnosis and treatment of cancer in various countries of the world has put a lot of financial and human resources, the incidence and mortality of cancer have been on the rise year by year. The cisplatin and other platinum antitumor drugs have good treatment effects on various tumors, thereby opening up a new field for researching the anticancer effect of the cisplatin complex. However, at present, cisplatin anticancer drugs have serious toxic and side effects, including nephrotoxicity, gastrointestinal toxicity, ototoxicity and neurotoxicity, have low activity on certain tumor cells, are easy to generate drug resistance, and are not easy to metabolize in vivo.
Iridium (III) (Ir) III ) Complexes are of great interest because of their remarkable antiproliferative capacity and low toxicity. Ir with cyclometalated therein III The complex has the advantages of large emission intensity, long emission life, large Stokes displacement, good light stability and the like, and has good application prospect in the aspects of biological/chemical imaging agents and probes. Mitochondria are important organelles in cells and play an important role in the development and progression of tumors. The integrity of the mitochondrial structure and function influences the development process of tumor cells, and targeting anticancer drugs to mitochondria can effectively improve the therapeutic effect of the drugs and reduce the toxic and side effects on normal tissues. In recent years, as studies on mitochondria continue to be in progress, anti-tumor drugs targeting mitochondria have been receiving increasing attention. At present, better development from chemotherapy is expected in the treatment of tumors, and there is a continuing need to study novel metal anticancer drugs with different mechanisms of action to improve or supplement the performance of existing platinum-based drugs.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides an organic metal iridium complex with anticancer activity.
The invention also provides a preparation method of the organic metal iridium complex with anticancer activity.
The invention also provides application of the organometallic iridium complex in preparing anticancer drugs.
The technical scheme adopted by the invention for achieving the purpose is as follows:
the invention provides a sandwich-structured mitochondria-targeted organic metal iridium complex, which has the structural formula shown in formulas (I) - (III):
。
the invention also provides a preparation method of the sandwich-structured targeted mitochondria organometallic iridium complex, which is characterized in that the organometallic iridium dimers D1, D2 and D3 respectively react with ferrocene diphenyl phosphine ligands to obtain target complexes shown in formulas I-III, wherein the specific reaction route is as follows:
。
when the complex provided by the invention is of the formula (I), the complex is prepared by the following method:
(1) Adding 30 mL anhydrous methanol into a microwave digestion tank, carrying out ultrasonic treatment for 5 min, pouring out, drying by a blower, sequentially adding 0.5 g iridium trichloride hydrate and 0.75 mL of 1,2,3,4, 5-pentamethylcyclopentadiene into the digestion tank, adding 20 mL anhydrous methanol into the mixed system, and carrying out ultrasonic treatment for 5 min; blowing nitrogen into the mixed system, putting the mixed system into a microwave digestion instrument for digestion, taking out the mixed system after the digestion is completed, pouring supernatant into a prepared beaker, washing solid in the tank by using ice methanol, and pouring washing liquid into the beaker in the previous step; adding dichloromethane into a tank to dissolve the residual crystals, filtering and removing iridium trichloride which does not participate in the reaction, and spin-drying the solution to obtain a product; spin-drying the solution in a beaker containing a washing solution, washing with ice methanol, dissolving dichloro, filtering iridium trichloride which does not participate in the reaction, adding 8mL n-hexane and 8mL anhydrous diethyl ether into the filtrate, and putting into a refrigerator for crystallization to prepare D1;
(2) 50.0 mg iridium dimer D1, 69.6 mg ferrocene diphenyl phosphine ligand and 81.9 mg ammonium hexafluorophosphonate are placed in a 100 mL chirett bottle, nitrogen is pumped in, 40 mL methanol is injected, 24 h is stirred at 65 ℃, after the spot-plate detection reaction is finished, the solvent is distilled off under reduced pressure, dichloromethane is used for dissolution, filtration is carried out, and acetonitrile/n-hexane/ether diffusion method is adopted for purification, thus obtaining the complex (I).
When the complex provided by the invention is shown as a formula (II), the complex is prepared by the following method:
(1) Anhydrous treatment of tetrahydrofuran with sodium metal wire in advance for standby, adding 4.4 mL (29.5 mmol) 2,3,4, 5-tetramethyl-2-cyclopentenone into a round bottom flask, adding 40 mL of anhydrous tetrahydrofuran treated in advance, adding 12.8 mL and 3M phenylmagnesium bromide with the concentration of 80 mmol into a mixed system under rapid stirring, refluxing the mixture with 3 h, cooling to room temperature after stirring, adding into a beaker containing 60 mL ice water, slowly adding 40 mL concentrated hydrochloric acid into the beaker, and stirring for 0.5 h; extracting with anhydrous diethyl ether to obtain yellow organic layer, drying with anhydrous sodium carbonate, vacuum concentrating to obtain crude product, purifying by column chromatography with petroleum ether as eluent, and selecting the first point as intermediate A; adding 30 mL anhydrous methanol into a microwave digestion tank, carrying out ultrasonic treatment for 5 min, drying, sequentially adding 0.5 g iridium trichloride hydrate and 0.88 g intermediate A into the digestion tank, adding 20 mL anhydrous methanol into a mixed system, and carrying out ultrasonic treatment for 5 min; blowing nitrogen into the mixed system, putting the mixed system into a microwave digestion instrument for digestion, taking out the mixed system after the digestion is completed, pouring supernatant into a prepared beaker, washing solid in the tank by using ice methanol, and pouring washing liquid into the beaker in the previous step; adding dichloromethane into a tank to dissolve the residual crystals, filtering and removing iridium trichloride which does not participate in the reaction, and spin-drying the solution to obtain a product; spin-drying the solution in a beaker containing a washing solution, washing with ice methanol, dissolving dichloro, filtering to remove iridium trichloride which does not participate in the reaction, adding 8ml of n-hexane and 8ml of anhydrous diethyl ether into the filtrate, and putting into a refrigerator for crystallization to obtain D2;
(2) 50.0 mg iridium dimer D2, 60.2 mg ferrocene diphenyl phosphine ligand and 70.9 mg ammonium hexafluorophosphonate are placed in a 100 mL chirett bottle, nitrogen is pumped in, 40 mL methanol is injected, 24 h is stirred at 65 ℃, after the spot-plate detection reaction is finished, the solvent is distilled off under reduced pressure, dichloromethane is used for dissolution, filtration is carried out, and acetonitrile/n-hexane/ether diffusion method is adopted for purification, thus obtaining the complex (II).
Further, in the step (1), the structural formula of the intermediate product a is:。
when the complex provided by the invention is of the formula (III), the complex is prepared by the following method:
(1) 11.4 g (48.9 mmol) 4-bromodiphenyl is added into a dry Schlenk bottle, the bottle mouth is sealed by a threaded turning plug, vacuum pumping and nitrogen filling are carried out repeatedly for three times; extracting 110 mL anhydrous tetrahydrofuran which is dried in advance, adding the anhydrous tetrahydrofuran into a Schlenk bottle, and keeping the reaction system at the temperature of-78 ℃ for 1 h under the nitrogen atmosphere; adding 30.6 mL and 1.6M n-butyllithium with the concentration of 32.5 mmol into the reaction system, stirring at a constant temperature for 3 h, adding 8.14 g of 2,3,4, 5-tetramethyl-2-cyclopentenone, and stirring at a low temperature for 1 h; the mixture was stirred at normal temperature for 12. 12 h, the mixture was acidified to ph=4 with dilute hydrochloric acid, 50 mL water was added and stirred for 1. 1 h, the organic layer was separated, the aqueous layer (50 mL ×3) was extracted with anhydrous diethyl ether, the organic layers were combined and dried over anhydrous magnesium sulfate, suction filtered, the precipitate was washed with anhydrous diethyl ether, and the filtrate was collected; concentrating under vacuum to obtain oily liquid, solidifying at room temperature, dissolving solid product with 120 mL n-hexane anhydrous ethanol solution, heating until solid is completely dissolved, rotary evaporating to obtain supersaturated solution, placing in refrigerator overnight, collecting solid, washing solid pure intermediate product B with ice methanol, and vacuum drying; adding 30 mL anhydrous methanol into a microwave digestion tank, carrying out ultrasonic treatment for 5 min, drying, sequentially adding 0.5 g iridium trichloride hydrate and 1.3 g intermediate product B into the digestion tank, adding 20 mL anhydrous methanol into a mixed system, and carrying out ultrasonic treatment for 5 min; blowing nitrogen into the mixed system, putting the mixed system into a microwave digestion instrument for digestion, taking out the mixed system after the digestion is completed, pouring supernatant into a prepared beaker, washing solid in the tank by using ice methanol, and pouring washing liquid into the beaker in the previous step; adding dichloromethane into a tank to dissolve the residual crystals, filtering and removing iridium trichloride which does not participate in the reaction, and spin-drying the solution to obtain a product; the solution in the beaker containing the washing liquid is dried by spin, washed by ice methanol, dissolved by dichloro, iridium trichloride which does not participate in the reaction is filtered, 8ml of normal hexane and 8ml of anhydrous diethyl ether are added into the filtrate, and the filtrate is placed into a refrigerator for crystallization, thus obtaining D3.
(2) 50.0 mg iridium dimer D3, 51.7 mg ferrocene diphenyl phosphine ligand and 60.8 mg ammonium hexafluorophosphonate are placed in a 100 mL Schlenk bottle, nitrogen is pumped in, 40 mL methanol is injected, 24 h is stirred at 65 ℃, after the spot-plate detection reaction is finished, the solvent is distilled off under reduced pressure, a small amount of dichloromethane is used for dissolution, filtration is carried out, and the complex (III) is obtained by purifying by adopting an acetonitrile/n-hexane/ether diffusion method.
Further, the volume ratio of the n-hexane to the absolute ethyl alcohol is 2:1.
further, the structural formula of the intermediate product B is as follows:
。
the invention also provides application of the sandwich-configuration organic metal iridium complex targeting mitochondria in preparation of anticancer drugs.
The invention utilizes the synergistic effect of ferrocene diphenyl phosphine and the metal iridium complex, and the combined metal iridium complex shows more excellent anticancer activity, thereby providing a structural platform for researching novel organic metal anticancer drugs. On the basis of a single compound, the anticancer activity of the target complex is improved through the synergistic effect of the iridium complex. The metallic iridium dimer is changed, and a structural unit with higher activity is screened. The anticancer activity of the target drug is regulated and controlled by selecting a proper ligand, so that the target drug is hopeful to become a novel mitochondrial targeting heteronuclear organic metal anticancer drug.
The beneficial effects of the invention are as follows:
(1) The sandwich-configuration iridium complex provided by the invention can be positioned in mitochondria to induce functional disorder thereof so as to induce apoptosis of cancer cells, has high anticancer activity and good selectivity, and is not easy to generate drug resistance;
(2) The series of complexes have good anticancer activity, in vitro anticancer activity is superior to cisplatin (II, III), and stability is good, thus providing a new strategy and experimental foundation for development and research of anticancer metal complexes.
(3) The preparation method provided by the invention has high synthesis efficiency, and the prepared target complex can accumulate in mitochondria in cells to induce early apoptosis.
Drawings
FIG. 1 is a graph showing the characterization of the complex (I) prepared in example 1.
FIG. 2 is a graph showing the characterization of the complex (II) prepared in example 2.
FIG. 3 is a graph showing the characterization of the complex (III) prepared in example 1.
FIG. 4 is a diagram of a tissue targeting test according to the present invention.
FIG. 5 is a graph of apoptosis assays according to the present invention.
Detailed Description
The invention is further illustrated with respect to the following examples of representative compounds, which are not intended to limit the invention.
The starting compounds used in the synthesis of the compounds are commercial products or can be prepared from known synthetic methods, the preparation of all organic compound starting materials is available from the literature and these methods are fundamental and obvious to synthetic chemists. Accordingly, the following description of the synthetic methods may be considered to be detailed and specific.
Example 1
(1) Adding 30 mL anhydrous methanol into a microwave digestion tank, carrying out ultrasonic treatment for 5 min, pouring out, drying by a blower, sequentially adding 0.5 g iridium trichloride hydrate and 0.75 m of 1,2,3,4, 5-pentamethylcyclopentadiene into the digestion tank, adding 20 m anhydrous methanol into the mixed system, and carrying out ultrasonic treatment for 5 min. And (3) nitrogen is blown into the mixed system, microwave digestion is carried out, after the digestion is finished, the mixed system is taken out, the supernatant is poured into a prepared beaker, the solid in the tank is washed by ice methanol, and the washing liquid is poured into the beaker in the previous step. Adding dichloromethane into a tank to dissolve the residual crystals, filtering and removing iridium trichloride which does not participate in the reaction, and spin-drying the solution to obtain the product. The solution in a beaker containing the washing liquid is dried by spin, washed by ice methanol, dissolved by dichloro, and iridium trichloride which does not participate in the reaction is filtered, 8ml of normal hexane and 8ml of anhydrous diethyl ether are added into the filtrate, and the filtrate is placed into a refrigerator for crystallization to prepare D1;
(2) 50.0 mg iridium dimer D1, 69.6 mg ferrocene diphenyl phosphine ligand and 81.9 mg ammonium hexafluorophosphonate are placed in a 100 mL chirett bottle, nitrogen is pumped in, 40 mL methanol is injected, stirring is carried out at 65 ℃ for 24 h, after the spot-plate detection reaction is finished, the solvent is distilled off under reduced pressure, dichloromethane is used for dissolution, filtration is carried out, and acetonitrile/n-hexane/ether diffusion method is adopted for purification to obtain a complex (I) 75.0 mg (yield 65.1%).
The characterization spectrum is shown in fig. 1: 1 H NMR (500 MHz, CDCl 3 ) δ 7.65 (d,J= 96.3 Hz, 14H), 7.42 – 7.22 (m, 6H), 5.10 (s, 2H), 4.61 – 3.92 (m, 6H), 1.98 (s, 3H), 1.51 (s, 6H), 1.21(s, 6H).
example 2
Anhydrous tetrahydrofuran was prepared by adding 4.4. 4.4 mL (29.5 mmol) 2,3,4, 5-tetramethyl-2-cyclopentenone to a round bottom flask in advance with sodium wire, adding 40 mL of the anhydrous tetrahydrofuran which had been treated in advance, adding 12.8. 12.8 mL (80 mmol) 3M phenylmagnesium bromide to the mixture with rapid stirring (rapid addition, prevention of needle clogging), and after adding phenylmagnesium bromide, the mixture turned from colorless to pale yellow and a large amount of gas was evolved. The mixture was refluxed 3 h, cooled to room temperature after stirring, added to a beaker containing 60 mL ice water, slowly added 40 mL concentrated hydrochloric acid to the beaker, and stirred 0.5 h. Extracting with anhydrous diethyl ether (50 mL ×2) to obtain yellow organic layer, drying with anhydrous sodium carbonate, vacuum concentrating to obtain crude product, purifying by column chromatography with petroleum ether as eluent, and collecting the first pointLabeled as intermediate a. Adding 30 mL anhydrous methanol into a microwave digestion tank, carrying out ultrasonic treatment for 5 min, pouring out, drying by a blower, taking 0.5 g iridium trichloride hydrate and 0.88 g intermediate product A, sequentially adding into the digestion tank, adding 20 mL anhydrous methanol into a mixed system, and carrying out ultrasonic treatment for 5 min. Nitrogen is blown into the mixed system for microwave digestion, after the digestion is completed, the mixed system is taken out, the supernatant is poured into a prepared beaker, and the mixed system is cannedThe medium solids were washed with ice methanol and the wash was poured into the previous beaker. Adding dichloromethane into a tank to dissolve the residual crystals, filtering and removing iridium trichloride which does not participate in the reaction, and spin-drying the solution to obtain the product. Spin-drying the solution in a beaker containing a washing solution, washing with ice methanol, dissolving dichloro, filtering to remove iridium trichloride which does not participate in the reaction, adding 8ml of n-hexane and 8ml of anhydrous diethyl ether into the filtrate, and putting into a refrigerator for crystallization to obtain D2;
(2) 50.0 mg iridium dimer D2, 60.2 mg ferrocene diphenyl phosphine ligand and 70.9 mg ammonium hexafluorophosphonate are placed in a 100 mL chirett bottle, nitrogen is pumped in, 40 mL methanol is injected, stirring is carried out at 65 ℃ for 24 h, after the spot-plate detection reaction is finished, the solvent is distilled off under reduced pressure, dichloromethane is used for dissolution, filtration is carried out, and the complex (II) 64.5 mg (yield 60.6%) is obtained by purifying by adopting an acetonitrile/n-hexane/ether diffusion method.
The characterization spectrum is shown in fig. 2: 1 H NMR (500 MHz, CDCl 3 ) δ 7.44 (dd,J= 210.6, 69.5 Hz, 25H), 5.10 (s, 2H), 4.64 – 3.87 (m, 6H), 1.39 (d,J= 129.5 Hz, 12H).
example 3
(1) To the dried Schlenk flask was added 11.4. 11.4 g (48.9 mmol) of 4-bromobiphenyl, and the flask mouth was sealed with a screw-type flip-top plug, and the vacuum-pumping and nitrogen-filling operations were repeated three times. 110 mL anhydrous tetrahydrofuran which is dried in advance is extracted and added into a Schlenk bottle, a balloon filled with nitrogen in advance is inserted into a rubber plug, and the reaction system is kept at the temperature of-78 ℃ for 1 h. To the reaction system, 30.6 mL (32.5 mmol) of 1.6M n-butyllithium was added while maintaining the temperature under stirring for 3 h, 8.14 g (58.9 mmol) of 2,3,4, 5-tetramethyl-2-cyclopentenone was added while the reaction system turned yellow and stirring for 1 h at a low temperature was maintained. The mixture was stirred at ambient temperature for 12 h and the solution turned orange, and the mixture was poured into a 500 mL beaker and acidified with dilute hydrochloric acid to ph=4. 50 mL water was added and stirred for 1 h, the organic layer was separated, the aqueous layer (50 mL ×3) was extracted with anhydrous diethyl ether, and after combining several layers, dried over anhydrous magnesium sulfate, suction filtered, and the precipitate was washed with anhydrous diethyl ether, and the filtrate was collected. Concentrated in vacuo to an oily liquid which solidified at room temperature with 120 mL n-hexane: absolute ethanol = 2:1 (v/v) solution dissolution solidsHeating to dissolve solid completely, rotary evaporating to obtain supersaturated solution, placing in refrigerator overnight, collecting solid, and washing the solid with ice methanolThe method comprises the steps of carrying out a first treatment on the surface of the Labeled as intermediate C. And (5) vacuum drying. Adding 30. 30 mL anhydrous methanol into a microwave digestion tank, carrying out ultrasonic treatment for 5 min, pouring out, drying by a blower, sequentially adding 0.5 g iridium trichloride hydrate and 1.3 g intermediate C into the digestion tank, adding 20. 20 mL anhydrous methanol into the mixed system, and carrying out ultrasonic treatment for 5 min. And (3) nitrogen is blown into the mixed system to be digested, the mixed system is taken out after the digestion is completed, the supernatant is poured into a prepared beaker, the solid in the tank is washed by ice methanol, and the washing liquid is poured into the beaker in the previous step. Adding dichloromethane into a tank to dissolve the residual crystals, filtering and removing iridium trichloride which does not participate in the reaction, and spin-drying the solution to obtain the product. The solution in the beaker containing the washing liquid is dried by spin, washed by ice methanol, dissolved by dichloro, iridium trichloride which does not participate in the reaction is filtered, 8ml of normal hexane and 8ml of anhydrous diethyl ether are added into the filtrate, and the filtrate is placed into a refrigerator for crystallization, thus obtaining D3.
(2) 50.0 mg iridium dimer D3, 51.7 mg ferrocene diphenylphosphine ligand and 60.8 mg ammonium hexafluorophosphonate are placed in a 100 mL Schlenk bottle, nitrogen is pumped in, 40 mL methanol is injected, 24 h is stirred at 65 ℃, after the spot-plate detection reaction is finished, the solvent is distilled off under reduced pressure, a small amount of dichloromethane is used for dissolution, filtration is carried out, and the complex (III) 66.9 mg (yield 68%) is obtained by purifying by using an acetonitrile/n-hexane/ether diffusion method.
The characterization spectrum is shown in fig. 3: 1 H NMR (500 MHz, CDCl 3 ) δ 7.89 – 6.99 (m, 29H), 5.11 (s, 2H), 4.48 – 3.97 (m, 6H), 1.59 (s, 6H), 1.23 (s, 6H).
effect example 1
Proliferation inhibition activity experiment of organometallic iridium complex with anticancer activity on tumor cell lines:
(1) Preparation of test compound: dissolving a target compound in dimethyl sulfoxide (DMSO) to prepare a stock solution with a certain concentration, further diluting the stock solution by using a cell culture solution until the working concentration is reached, and culturing 24 h;
(2) Cell growth inhibition assay (MTT method):
1) 5000 cancer cells (A549 and HeLa) are taken to prepare cell suspension, and inoculated into a 96-well culture plate;
2) Pre-culturing cells with a drug-free medium, 5% CO 2 Incubating 24 h with 310 and K, adding the prepared compound to be tested, and culturing 24 h;
3) Added to each hole by 15μThe MTT solution of L5 mg/mL was further cultured for 4: 4 h to form purple crystalline material formazan;
4) Terminating the culture, carefully washing off the culture solution in the wells, and adding 100 to each wellμL DMSO fully dissolves formazan sediment, and after the mixture is uniformly mixed by an oscillator, the optical density value of each hole is measured by using an enzyme-labeling instrument with the wavelength of 570 nm;
5) Each experiment was repeated three times, IC 50 Mean ± SEM.
The inhibition rates of the target complex and cisplatin on the growth of human alveolar basal epithelial cancer cells (a 549) and cervical cancer cells (HeLa) are shown in table 1.
TABLE 1
As can be seen from Table 1, the metal complexes all showed some anticancer activity, and the activity of some complexes was far higher than that of commercial cisplatin, especially for A549 cells, and the activity of the complexes (II and III) was significantly higher than that of cisplatin.
Effect example 2
The confocal laser microscope can conveniently detect the target of the target complex III after entering the A549 cells. Lyso Tracker Red DND-99 (LTRD) and Mito Tracker Deep Red (MTDR) are respectively used as fluorescent probes of lysosomes and mitochondria. A549 cells were incubated with target complex (9.1 μM) at 37 ℃ for 1 h, then LTRD (100 nM) and MTDR (50 nM) were added for 30 min staining, and the cell plates were washed 3 times with phosphate-balanced physiological saline (PBS) buffer, and observed with a laser confocal microscope. The excitation wavelength of the target complex is 405 nm, and the collection wavelength is 420-500 nm; the excitation wavelength of the LTRD is 630+/-30 nm, and the collection wavelength is 493-630 nm; MTDR was excited at 644 nm with an emission wavelength of 690±30 nm. The test is shown in fig. 4, where the pearson co-localization coefficient of complex III in mitochondria is 0.77 and the co-localization coefficient in lysosomes is 0.13, confirming that the target complex is primarily targeted to mitochondria.
Effect example 3
Apoptosis is a form of programmed cell death, where a series of cells self-destruct in the absence of an inflammatory response. This is the response of the cell to environmental physiological, pathological stimulus signals, environmental conditions or palliative damage, controlled by cellular genes in response to the death process. Research shows that Ir III The complex has apoptosis inducing and antitumor activities. Flow cytometry was used to investigate whether III could induce apoptosis. A549 cells were isolated using III (0.5, 1.0 and 2.0 x IC 50 ) After 24 hours of treatment, annexin V-FITC/PI staining, FIG. 5 shows a dose-dependent increase in the percentage of early apoptotic cells.

Claims (7)

1. The organic metal iridium complex of the targeted mitochondria in sandwich configuration is characterized by having a structural formula shown in formulas I-III:
。
2. the preparation method of the sandwich-configuration targeted mitochondria organometallic iridium complex as claimed in claim 1, wherein the target complex shown in the formulas I-III is obtained by reacting metallic iridium dimers D1, D2 and D3 with ferrocene diphenyl phosphine ligands, and the specific reaction route is as follows:
。
3. the preparation method according to claim 2, wherein when the complex is of formula I, it is prepared by the following method:
(1) Adding 30 mL anhydrous methanol into a microwave digestion tank, carrying out ultrasonic treatment for 5 min, pouring out, drying by a blower, sequentially adding 0.5 g iridium trichloride hydrate and 0.75 mL of 1,2,3,4, 5-pentamethylcyclopentadiene into the digestion tank, adding 20 mL anhydrous methanol into the mixed system, and carrying out ultrasonic treatment for 5 min; blowing nitrogen into the mixed system, putting the mixed system into a microwave digestion instrument for digestion, taking out the mixed system after the digestion is completed, pouring supernatant into a prepared beaker, washing solid in the tank by using ice methanol, and pouring washing liquid into the beaker in the previous step; adding dichloromethane into a tank to dissolve the residual crystals, filtering and removing iridium trichloride which does not participate in the reaction, and spin-drying the solution to obtain a product; spin-drying the solution in a beaker containing a washing solution, washing with ice methanol, dissolving dichloro, filtering iridium trichloride which does not participate in the reaction, adding 8mL n-hexane and 8mL anhydrous diethyl ether into the filtrate, and putting into a refrigerator for crystallization to prepare D1;
(2) 50.0 mg iridium dimer D1, 69.6 mg ferrocene diphenyl phosphine ligand and 81.9 mg ammonium hexafluorophosphonate are placed in a 100 mL chirett bottle, nitrogen is pumped in, 40 mL methanol is injected, 24 h is stirred at 65 ℃, after the spot-plate detection reaction is finished, the solvent is distilled off under reduced pressure, dichloromethane is used for dissolution, filtration is carried out, and acetonitrile/n-hexane/ether diffusion method is adopted for purification, so that the complex shown in the formula I is obtained.
4. The method of claim 2, wherein when the complex is of formula II, it is prepared by:
(1) Anhydrous treatment of tetrahydrofuran with sodium metal wire in advance for standby, adding 4.4 mL (29.5 mmol) 2,3,4, 5-tetramethyl-2-cyclopentenone into a round bottom flask, adding 40 mL of anhydrous tetrahydrofuran treated in advance, adding 12.8 mL and 3M phenylmagnesium bromide with the concentration of 80 mmol into a mixed system under rapid stirring, refluxing the mixture with 3 h, cooling to room temperature after stirring, adding into a beaker containing 60 mL ice water, slowly adding 40 mL concentrated hydrochloric acid into the beaker, and stirring for 0.5 h; extracting with anhydrous diethyl ether to obtain yellow organic layer, drying with anhydrous sodium carbonate, vacuum concentrating to obtain crude product, purifying by column chromatography with petroleum ether as eluent, and selecting the first point as intermediate A; adding 30 mL anhydrous methanol into a microwave digestion tank, carrying out ultrasonic treatment for 5 min, drying, sequentially adding 0.5 g iridium trichloride hydrate and 0.88 g intermediate A into the digestion tank, adding 20 mL anhydrous methanol into a mixed system, and carrying out ultrasonic treatment for 5 min; blowing nitrogen into the mixed system, putting the mixed system into a microwave digestion instrument for digestion, taking out the mixed system after the digestion is completed, pouring supernatant into a prepared beaker, washing solid in the tank by using ice methanol, and pouring washing liquid into the beaker in the previous step; adding dichloromethane into a tank to dissolve the residual crystals, filtering and removing iridium trichloride which does not participate in the reaction, and spin-drying the solution to obtain a product; spin-drying the solution in a beaker containing a washing solution, washing with ice methanol, dissolving dichloro, filtering to remove iridium trichloride which does not participate in the reaction, adding 8ml of n-hexane and 8ml of anhydrous diethyl ether into the filtrate, and putting into a refrigerator for crystallization to obtain D2;
the structural formula of the intermediate product A is as follows:；
(2) 50.0 mg iridium dimer D2, 60.2 mg ferrocene diphenyl phosphine ligand and 70.9 mg ammonium hexafluorophosphonate are placed in a 100 mL chirett bottle, nitrogen is pumped in, 40 mL methanol is injected, stirring is carried out at 65 ℃ for 24 h, after the spot-plate detection reaction is finished, the solvent is distilled off under reduced pressure, dichloromethane is used for dissolution, filtration is carried out, and acetonitrile/n-hexane/ether diffusion method is adopted for purification, thus obtaining the complex shown in the formula II.
5. The method of claim 2, wherein when the complex is of formula III, it is prepared by:
(1) 11.4 g (48.9 mmol) 4-bromodiphenyl is added into a dry Schlenk bottle, the bottle mouth is sealed by a threaded turning plug, vacuum pumping and nitrogen filling are carried out repeatedly for three times; extracting 110 mL anhydrous tetrahydrofuran which is dried in advance, adding the anhydrous tetrahydrofuran into a Schlenk bottle, and keeping the reaction system at the temperature of-78 ℃ for 1 h under the nitrogen atmosphere; adding 30.6 mL and 1.6M n-butyllithium with the concentration of 32.5 mmol into the reaction system, stirring at a constant temperature for 3 h, adding 8.14 g of 2,3,4, 5-tetramethyl-2-cyclopentenone, and stirring at a low temperature for 1 h; the mixture was stirred at normal temperature for 12. 12 h, the mixture was acidified to ph=4 with dilute hydrochloric acid, 50 mL water was added and stirred for 1. 1 h, the organic layer was separated, the aqueous layer (50 mL ×3) was extracted with anhydrous diethyl ether, the organic layers were combined and dried over anhydrous magnesium sulfate, suction filtered, the precipitate was washed with anhydrous diethyl ether, and the filtrate was collected; concentrating under vacuum to obtain oily liquid, solidifying at room temperature, dissolving solid product with 120 mL n-hexane anhydrous ethanol solution, heating until solid is completely dissolved, rotary evaporating to obtain supersaturated solution, placing in refrigerator overnight, collecting solid, washing solid pure intermediate product B with ice methanol, and vacuum drying; adding 30 mL anhydrous methanol into a microwave digestion tank, carrying out ultrasonic treatment for 5 min, drying, sequentially adding 0.5 g iridium trichloride hydrate and 1.3 g intermediate product B into the digestion tank, adding 20 mL anhydrous methanol into a mixed system, and carrying out ultrasonic treatment for 5 min; blowing nitrogen into the mixed system, putting the mixed system into a microwave digestion instrument for digestion, taking out the mixed system after the digestion is completed, pouring supernatant into a prepared beaker, washing solid in the tank by using ice methanol, and pouring washing liquid into the beaker in the previous step; adding dichloromethane into a tank to dissolve the residual crystals, filtering and removing iridium trichloride which does not participate in the reaction, and spin-drying the solution to obtain a product; spin-drying the solution in a beaker containing a washing solution, washing with ice methanol, dissolving dichloro, filtering to remove iridium trichloride which does not participate in the reaction, adding 8ml of n-hexane and 8ml of anhydrous diethyl ether into the filtrate, and putting into a refrigerator for crystallization to obtain D3;
the structural formula of the intermediate product B is as follows:；
(2) 50.0 mg iridium dimer D3, 51.7 mg ferrocene diphenyl phosphine ligand and 60.8 mg ammonium hexafluorophosphonate are placed in a 100 mL Schlenk bottle, nitrogen is pumped in, 40 mL methanol is injected, 24 h is stirred at 65 ℃, after the spot-plate detection reaction is finished, the solvent is distilled off under reduced pressure, a small amount of dichloromethane is used for dissolution, filtration is carried out, and the complex shown in a formula III is obtained by purifying by adopting an acetonitrile/n-hexane/ether diffusion method.
6. The method according to claim 5, wherein the volume ratio of n-hexane to absolute ethanol is 2:1.
7. use of a mitochondria-targeting organometallic iridium complex in sandwich configuration according to claim 1 for the preparation of anticancer drugs.
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