CN116253718A - Organic compound modified by lonidamine, cyclometallated complex based on organic compound, preparation method and application thereof - Google Patents
Organic compound modified by lonidamine, cyclometallated complex based on organic compound, preparation method and application thereof Download PDFInfo
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- CN116253718A CN116253718A CN202310141520.3A CN202310141520A CN116253718A CN 116253718 A CN116253718 A CN 116253718A CN 202310141520 A CN202310141520 A CN 202310141520A CN 116253718 A CN116253718 A CN 116253718A
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- lonidamine
- organic compound
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- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
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Abstract
The invention discloses a lonidamine modified organic compound, and also discloses a cyclometalated complex based on the organic compound, and a preparation method and application thereof. The organic compound is obtained by carrying out chemical modification on the carboxylic acid group of lonidamine, has good anti-tumor, antibacterial and anti-inflammatory activities, and can solve the problems of poor fat solubility and large dosage existing when lonidamine is used as an anti-tumor drug or an anti-tumor drug component on the one hand and the problems of cisplatin tolerance and adverse side effects generated by tumor cells existing when a simple lonidamine is used as the anti-tumor drug or the anti-tumor drug component on the other hand; the cyclometallated complexes of the invention can also be used as a glycolytic inhibitor or energy metabolism inhibitor to stimulate immune function.
Description
Technical Field
The invention relates to a lonidamine modified organic compound, and also relates to a cyclometal complex based on the organic compound, and a preparation method and application of the cyclometal complex.
Technical Field
In recent years, the potential of metal complexes represented by cisplatin in pharmaceutical chemistry has been explored and expanded throughout the periodic table of elements. However, the clinical application and development of platinum-based anticancer drugs are limited by their resistance and adverse side effects. Under such circumstances, designing complexes containing other transition metals to make up for the deficiency of platinum-based drugs is becoming a continuing effort for scientists. Among them, peter Sadler professor, university of wav, swiss, jul Dyson professor, university of vienna, bernhard Keppler, et al succeeded in attaching a targeting molecule to a transition metal to give a metal complex with high selectivity.
Cancer cells acquire energy and substances mainly by glycolysis, glutamine hydrolysis and fatty acid synthesis, lonidamine, the name of which is ronidazole, is developed by Angelopharm, germany, and is marketed in Italy as an antitumor agent in 1986. Lonidamine is a tumor thermosensitive medicine different from the traditional antitumor medicine, does not influence proliferation of cells, mainly acts on energy metabolism of the cells, inhibits hexokinase activity combined with mitochondria by changing the mitochondrial ultrastructure of the tumor cells, reduces glycolysis of the tumor cells, influences expression of apoptosis related proteins, inhibits oxygen consumption of malignant cells, achieves the purpose of inhibiting and killing the tumor cells, and can be used for treating various tumors such as breast cancer, prostatic cancer, lung cancer, brain tumor and the like, and the characteristics of wide anticancer spectrum, small side effect and the like are increasingly studied and applied. However, lonidamine has the defects of poor fat solubility, low bioavailability, large dosage and the like, and the application of lonidamine as a candidate anticancer drug or an anticancer drug component is limited.
Breast cancer is the second most common malignancy, and Triple Negative Breast Cancer (TNBC) is a highly heterogeneous, recurrent and distal metastatic breast cancer subtype, and current therapies remain very limited due to lack of hormone receptor and HER2 protein expression. In recent years, immunotherapy has proven to be a promising approach to the treatment of TNBC. In 2020, chinese scientists have invented a multi-specific platinum (IV) complex linked to naproxen that inhibits breast cancer proliferation by acting as a PD-L1 inhibitor. Inhibiting glycolysis to block the energy source of tumor cells is an effective strategy to interfere with cell activity and further induce cancer cell death, professor and team, 2022, lv Zhimin studied elevated levels of expression of tumor cells PD-L1 under high levels of glycolytic conditions. Blocking energy metabolism of the triple negative breast cancer cells, and simultaneously stimulating the immune system to carry out immune attack, thereby having important significance for cancer treatment. Up to now, there has been no report on studies of the cyclic metal complex that induce cancer cell death while exerting immune functions by inhibiting glycolysis.
Disclosure of Invention
The invention aims to: the invention aims at providing a lonidamine modified organic compound and also provides a cyclometallation complex based on the organic compound; the organic compound is obtained by carrying out chemical modification on the carboxylic acid group of lonidamine, has good anti-tumor, antibacterial and anti-inflammatory activities, and can solve the problems of poor fat solubility and large dosage existing when lonidamine is used as an anti-tumor drug or an anti-tumor drug component on the one hand and the problems of cisplatin tolerance and adverse side effects generated by tumor cells existing when a simple lonidamine is used as the anti-tumor drug or the anti-tumor drug component on the other hand; the cyclometallated complex can also be used as a glycolysis inhibitor or an energy metabolism inhibitor to stimulate immune function; another object of the present invention is to provide a method for preparing the above cyclic metal complex and its use in preparing an antitumor drug or an antitumor drug component.
The technical scheme is as follows: the lonidamine modified organic compound (LND-NH) 2 ) The structural formula is as follows:
the preparation method of the lonidamine modified organic compound specifically comprises the following steps: and (3) dissolving lonidamine, EDCI or DCC, HOBt, TEA and a bridging ligand 4-methyl-4 '-aminomethyl-2, 2' -bipyridine into an organic solvent for reaction in an inert atmosphere, and separating and purifying a crude product generated by the reaction through column chromatography to obtain the lonidamine modified organic compound.
Wherein, the mole ratio of lonidamine to 4-methyl-4 '-aminomethyl-2, 2' -bipyridine is 1:1 to 1.68.
Wherein, the bridged ligand 4-methyl-4 '-aminomethyl-2, 2' -bipyridine has the structural formula:
prepared using the synthetic method reported in literature bioorthognal "Labeling after Recognition" Affording an FRET-Based Luminescent Probe for Detecting and Imaging Caspase-3via Photoluminescence Lifetime Imaging.
Wherein the reaction temperature is-20-0 ℃; the reaction time is 2-48 h.
Wherein the organic solvent is N, N-dimethylformamide or other formamide solvents and acetamide solvents; EDCI (carbodiimide hydrochloride) or DCC (dicyclohexylcarbodiimide) is used as an activating reagent for carboxyl, HOBt (1-hydroxybenzotriazole) is used as a catalyst for condensation reaction, and TEA (triethylamine) acts as a basic catalyst in the system.
The application of the lonidamine modified organic compound in preparing anticancer drugs, anticancer drug components, immune escape inhibition drugs, immune escape inhibition drug components, cell metabolism inhibition drugs, cell metabolism inhibition drug components, immunogenic death induction drugs, immunogenic death induction drug components, autophagy inducer drugs and autophagy inducer drug components.
The cyclometallation complex based on the lonidamine modified organic compound has the following structural general formula:
wherein, when M is Ir or Rh, x=c, y=n; when M is Ru or Os, x=n, y=n.
The cyclometalated complex has higher fat solubility, and can effectively improve the uptake of lonidamine by tumor cells by combining the cyclometalated complex with lonidamine. Meanwhile, the cyclometallated complex has photochemical and photophysical properties and can be used for cell localization.
The synthesis method of the cyclometalated complex with the tail connected with lonidamine specifically comprises the following steps: heating and refluxing the organic ligand modified by lonidamine and the metal precursor in a mixed solvent of dichloromethane and methanol under inert atmosphere, distilling the solvent under reduced pressure, and using NH 4 PF 6 And (3) replacing to obtain a crude product, and separating and purifying the crude product by column chromatography to obtain the cyclometallation complex of the tail lonidamine.
Wherein the molar ratio of lonidamine-modified organic ligand to metal precursor is 1:100.
wherein the temperature of the reflux reaction is 60-80 ℃; the time is 18-20 h.
When M is Ir, rh, ru or Os, the corresponding metal precursors have the structural formulas:
metallic iridium precursor:
prepared using the synthetic procedure reported in literature A New Strategy to Fight Metallodrug Resistance, mitochondronia-Relevant Treatment through Mitophagy to Inhibit Metabolic Adaptations of Cancer Cells.
Metal rhodium precursor:
prepared using the synthetic methods reported in document Mitochondrial targeted rhodium (III) complexes: synthesis, characterized and antitumor mechanism investigation.
Metallic ruthenium precursor:
prepared using the synthetic method reported in literature dysosome-targeted ruthenium (II) polypyridyl complex as photodynamicanticancer agent.
Metal osmium precursor:
prepared using synthetic methods reported in literature physics, spline and biological properties of ruthenium and osmium photosensitizers bearing diversely substituted, 4'-di (styryl) -2,2' -bipyridine ligands.
The cyclometalated complex of the tail-connected lonidamine is applied to the preparation of antitumor drugs or antitumor drug components.
The invention prepares the complex with good anticancer activity, excellent immune escape inhibition, cell metabolism inhibition, autophagy inducibility and good antibacterial and anti-inflammatory activity by carrying out specific group modification on the active ingredient lonidamine with anti-tumor effect and coordinating with cyclometalated dimer. The complex provided by the invention can play a role in inducing autophagy of tumor cells, blocking energy metabolism of the tumor cells and simultaneously stimulating an immune system to perform immune attack.
The beneficial effects are that: the cyclometalated complex has good fat solubility, and can effectively inhibit proliferation of tumor cells, induce generation of ROS and induce autophagy of the tumor cells; meanwhile, after glycolysis can be inhibited, the immune escape of tumor cells can be obviously inhibited; meanwhile, immunogenic death can be induced in tumor cells, and effective anti-tumor immunity is induced, so that the blocking immunotherapy of check points is further enhanced; the cyclometalated complex has outstanding effects in resisting cancer, inhibiting cell metabolism, inhibiting cell immune escape, inducing cell immunogenic death, inducing cell autophagy and the like.
Drawings
FIG. 1 is a map of the localization of cyclometallated iridium complex LND-Ir in MDA-MB-231 cells;
FIG. 2 is a laser confocal fluorescence imaging and flow cytometry of cyclometallated iridium complex LND-Ir in MDA-MB-231 cells to promote intracellular reactive oxygen species generation: FIG. 2a is a confocal fluorescence imaging, and FIG. 2b is a cell flow chart at different concentrations;
FIG. 3 is a confocal fluorescence imaging of cyclometallated iridium complex LND-Ir in MDA-MB-231 cells to induce autophagosomes;
FIG. 4 is an immunoblot protein diagram of cyclometallated iridium complex LND-Ir inducing HK II protein and Akt protein in MDA-MB-231 cells;
FIG. 5 is a confocal fluorescence imaging of cyclometallated iridium complex LND-Ir in MDA-MB-231 cells for PD-L1;
FIG. 6 is a graph showing ICD induction of cyclometallated iridium complex LND-Ir in MDA-MB-231 cells: FIG. 6a is a CRT confocal fluorescence imaging, and FIG. 6b is an immunoblot protein of intracellular induction of HMGB1 protein.
Detailed Description
The technical scheme of the invention is further described below with reference to specific embodiments.
Example 1
The invention relates to a preparation method of cyclometallated iridium (III) complex (LND-Ir), which specifically comprises the following steps:
(1) Preparation of lonidamine-modified bipyridine ligands: lonidamine (160.58 mg,0.5 mmol) and EDCI (9.59 g,50 mmol) are weighed into a two-necked flask under argon atmosphere, vacuum is pumped, argon is introduced, anhydrous DMF (2 mL) and TEA (100 mu L) are added into the flask under ice bath condition and stirred for 60min, then DMF solution (50 mu L) containing HOBt (113.50 mg,0.84 mmol) is added into the flask, and after stirring for 60min, the ice bath is removed and the temperature is restored to room temperature; to this was added a solution (50. Mu.L) of 4-methyl-4 '-aminomethyl-2, 2' -bipyridine (167.10 mg,0.84 mmol) in DMF and reacted for 48h; after the reaction was completed, 20mL of distilled water was added, extraction was performed with methylene chloride (3×30 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation, and the crude product was further purified by flash chromatography to give a beige solid with a yield of 70%. 1 H NMR(400MHz,DMSO-d6)δ9.16(t,J＝6.3Hz,1H),8.60(d,J＝5.0Hz,1H),8.48(d,J＝4.9Hz,1H),8.37(d,J＝1.5Hz,1H),8.22(d,J＝8.0Hz,2H),7.78(d,J＝8.6Hz,1H),7.71(d,J＝2.1Hz,1H),7.52–7.46(m,1H),7.41–7.29(m,3H),7.26(dd,J＝4.9,1.6Hz,1H),6.83(d,J＝8.4Hz,1H),5.86(s,2H),4.59(d,J＝6.2Hz,2H),2.40(s,3H).
(2) Dissolving the lonidamine modified bipyridine ligand (25.1 mg,0.05 mmol) synthesized in the step (1) and cyclometalated iridium dimer (5.36 g,5 mmol) in a mixed solvent of anhydrous dichloromethane and anhydrous methanol (the volume ratio of the anhydrous dichloromethane to the anhydrous methanol is 1:2) under the protection of argon, and heating, refluxing and stirring for 18h at 80 ℃; after the reaction, the solvent is distilled off under reduced pressure and saturated NH is added 4 PF 6 After stirring for 5h, the solid was collected by centrifugation, and the crude product was further purified by column chromatography to give LND-Ir as a yellow solid in 75% yield. 1 H NMR(400MHz,DMSO-d6)δ9.08(t,J＝6.1Hz,1H),8.83(d,J＝1.6Hz,1H),8.72(d,J＝1.6Hz,1H),8.25(t,J＝8.3Hz,2H),8.19(d,J＝8.2Hz,1H),7.97–7.86(m,5H),7.78(dd,J＝7.1,4.4Hz,2H),7.72(d,J＝2.2Hz,1H),7.69(d,J＝5.7Hz,1H),7.63(d,J＝5.8Hz,2H),7.58(dd,J＝5.7,1.8Hz,1H),7.53(dd,J＝5.7,1.6Hz,1H),7.49(ddd,J＝8.4,6.8,1.2Hz,1H),7.36–7.33(m,1H),7.30(d,J＝7.4Hz,1H),7.16(dddd,J＝7.3,5.7,4.3,1.4Hz,2H),7.00(dtd,J＝9.2,7.5,1.3Hz,2H),6.88(qd,J＝7.6,1.4Hz,2H),6.79(d,J＝8.4Hz,1H),6.18(d,J＝7.6Hz,2H),5.84(s,2H),2.53(s,3H).ESI-MS(positive mode,m/z):calcd.1002.21,found 1002.3。
Example 2
The invention relates to a preparation method of a cyclometallated rhodium (III) complex (LND-Rh), which specifically comprises the following steps:
the lonidamine modified bipyridine ligand (25.1 mg,0.05 mmol) synthesized in the step (1) of example and the cyclometallated rhodium dimer (4.5 g,5 mmol) are dissolved in a mixed solvent of anhydrous dichloromethane and anhydrous methanol (the volume ratio of the anhydrous dichloromethane to the anhydrous methanol is 1:2) under the protection of argon, and the mixed solvent is heated and refluxed and stirred for 18 hours at 80 ℃; after the reaction, the solvent is distilled off under reduced pressure and saturated NH is added 4 PF 6 After stirring for 8h, the solid was collected by centrifugation and the crude product was further purified by column chromatography to give LND-Rh as a yellow solid in 80% yield. 1 H NMR(400MHz,DMSO-d6)δ10.08(t,J＝6.1Hz,1H),9.83(d,J＝1.6Hz,1H),9.72(d,J＝1.6Hz,1H),9.25(t,J＝8.3Hz,2H),9.19(d,J＝8.2Hz,1H),8.97–7.86(m,5H),8.78(dd,J＝7.1,4.4Hz,2H),8.72(d,J＝2.2Hz,1H),8.69(d,J＝5.7Hz,1H),8.63(d,J＝5.8Hz,2H),8.58(dd,J＝5.7,1.8Hz,1H),8.53(dd,J＝5.7,1.6Hz,1H),8.49(ddd,J＝8.4,6.8,1.2Hz,1H),8.36–8.33(m,1H),8.30(d,J＝7.4Hz,1H),8.16(dddd,J＝7.3,5.7,4.3,1.4Hz,2H),8.00(dtd,J＝9.2,7.5,1.3Hz,2H),7.88(qd,J＝7.6,1.4Hz,2H),7.79(d,J＝8.4Hz,1H),7.18(d,J＝7.6Hz,2H),6.84(s,2H),2.53(s,3H).ESI-MS(positive mode,m/z):calcd.912.21,found 912.3。
Example 3
The invention discloses a preparation method of a cyclometallic ruthenium (II) complex (LND-Ru), which comprises the following steps:
the lonidamine modified bipyridine ligand (25.1 mg,0.05 mmol) synthesized in the step (1) of the example and the metallic ruthenium precursor (2.42 g,5 mmol) are dissolved in a mixed solvent of anhydrous dichloromethane and anhydrous methanol (the volume ratio of the anhydrous dichloromethane to the anhydrous methanol is 1:2) under the protection of argon, and the mixture is heated and refluxed and stirred for 18 hours at 80 ℃; after the reaction, the solvent is distilled off under reduced pressure and saturated NH is added 4 PF 6 After stirring for 8h, the solid was collected by centrifugation, and the crude product was further purified by column chromatography to give LND-Ru as a yellow solid in 78% yield. 1 H NMR(400MHz,DMSO-d6)δ9.18(t,J＝6.1Hz,1H),8.93(d,J＝1.6Hz,1H),8.82(d,J＝1.6Hz,1H),8.35(t,J＝8.3Hz,2H),8.29(d,J＝8.2Hz,1H),8.07–7.96(m,5H),7.88(dd,J＝7.1,4.4Hz,2H),7.82(d,J＝2.2Hz,1H),7.79(d,J＝5.7Hz,1H),7.73(d,J＝5.8Hz,2H),7.68(dd,J＝5.7,1.8Hz,1H),7.63(dd,J＝5.7,1.6Hz,1H),7.59(ddd,J＝8.4,6.8,1.2Hz,1H),7.46–7.43(m,1H),7.40(d,J＝7.4Hz,1H),7.26(dddd,J＝7.3,5.7,4.3,1.4Hz,2H),7.10(dtd,J＝9.2,7.5,1.3Hz,2H),6.98(qd,J＝7.6,1.4Hz,2H),6.89(d,J＝8.4Hz,1H),6.28(d,J＝7.6Hz,2H),5.94(s,2H),2.63(s,3H).ESI-MS(positive mode,m/z):calcd.457.5,found 457.7。
Example 4
The invention relates to a preparation method of a cyclometallated osmium (II) complex (LND-Os), which specifically comprises the following steps:
the lonidamine-modified bipyridine ligand (25.1 mg,0.05 mmol) synthesized in step (1) of example 1 and osmium metal precursor (2.87 g,5 mmol) were dissolved in a mixed solvent of anhydrous dichloromethane and anhydrous methanol under an argon-protected atmosphereIn (in the mixed solvent, the volume ratio of the anhydrous dichloromethane to the anhydrous methanol is 1:2), heating, refluxing and stirring for 18h at 80 ℃; after the reaction, the solvent is distilled off under reduced pressure and saturated NH is added 4 PF 6 After stirring for 8 hours, the solid was collected by centrifugation, and the crude product was further purified by column chromatography to give LND-Ir as a yellow solid in 60% yield. 1 H NMR(400MHz,DMSO-d6)δ9.08(t,J＝8.1Hz,1H),10.83(d,J＝1.6Hz,1H),10.72(d,J＝1.6Hz,1H),10.25(t,J＝8.3Hz,2H),10.19(d,J＝8.2Hz,1H),9.97–9.86(m,5H),9.78(dd,J＝7.1,4.4Hz,2H),9.72(d,J＝2.2Hz,1H),9.69(d,J＝5.7Hz,1H),9.63(d,J＝5.8Hz,2H),9.58(dd,J＝5.7,1.8Hz,1H),9.53(dd,J＝5.7,1.6Hz,1H),9.49(ddd,J＝8.4,6.8,1.2Hz,1H),9.36–9.33(m,1H),9.30(d,J＝7.4Hz,1H),9.16(dddd,J＝7.3,5.7,4.3,1.4Hz,2H),9.00(dtd,J＝9.2,7.5,1.3Hz,2H),8.88(qd,J＝7.6,1.4Hz,2H),8.79(d,J＝8.4Hz,1H),8.18(d,J＝7.6Hz,2H),7.84(s,2H),4.53(s,3H).ESI-MS(positive mode,m/z):calcd.502.5,found 502.5。
Comparative example 1
The structural formula of the metal complex without lonidamine modification is as follows:
wherein m=ir or Rh, x=c, y=n; m=ru or Os, x=n, y=n.
MTT colorimetric method for analyzing cyclometallation complex LND-M, LND of tail-connected lonidamine and cyclometallation complex M-NH of no lonidamine 2 Anti-tumor cell proliferation effects of cisplatin CDDP. MTT (thiazole blue) is a tetrazolium salt which is reduced by succinate dehydrogenase in the mitochondria of living cells to form a blue-violet product, formazan (the product is soluble in DMSO) and has an absorption peak at 570nm, so A can be used 570 nm To analyze the proliferation of cells.
The specific experimental steps are as follows:
(1) Firstly, resuscitating a tube of tumor cells, culturing with fresh culture solution (DMEM culture medium+10% fetal calf serum+1% penicillin and streptomycin), and carrying out passage for 2 times for use;
(2) When the cells reached the logarithmic phase, they were inoculated into 96-well plates (100. Mu.L of culture medium per well) at a cell density of 5000 cells/well, followed by placing in an incubator (37 ℃,5% CO) 2 ) Culturing in medium;
(3) After the cells are attached, 100 mu L of compound LND-Ir with different concentration gradients, LND with different concentration gradients and compound Ir-NH with different concentration gradients are respectively added into each hole 2 And fresh culture solution containing cisplatin CDDP with different concentration gradients are placed in an incubator immediately for continuous incubation;
(4) After 48 hours of incubation, 2. Mu.L MTT (5 mg/mL) was added to each well and incubation was continued for 4 hours at 37℃in an incubator, the supernatant was aspirated, 150. Mu.L dimethyl sulfoxide (DMSO) was added to each well, and A was detected using an ELISA 570nm Calculating the cell proliferation inhibition ratio and obtaining IC 50 Value (drug concentration corresponding to inhibition equal to 50%).
Cytotoxicity of the complex LND-Ir prepared in example 1 on human lung cancer cell A549, human breast cancer cell MCF-7, human triple negative breast cancer cell MDA-MB-231 and normal liver cell LO 2:
table 1 shows the compounds LND (lonidamine), ir-NH 2 (Metal Ir complex without lonidamine attached to the tail), LND-NH 2 MTT test results of (lonidamine-modified organic ligand) LND-Ir and cisplatin CDDP
The results show that: lonidamine itself has little cytotoxicity to cancer cells and normal cell lines, IC 50 Organic compounds LND-NH modified by lonidamine specific groups with values of more than 100 mu M 2 Has certain activity to cancer cells, and is not connected with a cyclometalated complex Ir-NH of lonidamine 2 Has certain toxicity to cancer cells and normal cell lines, but has smaller toxicity. The cytotoxicity of the cyclometallation complex LND-Ir connected with lonidamine is obviously improved, especially the activity of the cyclometallation complex LND-Ir on the triple-negative breast cancer cells is best, and compared with the activity of cisplatin on the triple-negative breast cancer (about 32.4 mu M), the activity of the LND-Ir (1.9 mu M) is improved by nearly 17 times.
Cytotoxicity of the complex LND-Rh prepared in example 2 on human lung cancer cell A549, human breast cancer cell MCF-7, human triple negative breast cancer cell MDA-MB-231 and normal liver cell LO 2:
table 2 shows the compounds LND, rh-NH 2 MTT test results of LND-Rh and cisplatin CDDP
The results show that: cyclometallation complex Rh-NH without lonidamine linkage 2 Has certain toxicity to cancer cells and normal cell lines, but has smaller toxicity. The cyclometallation complex LND-Rh cytotoxicity after connecting lonidamine is obviously improved, especially the activity of the cyclometallation complex LND-Rh on the triple-negative breast cancer cells is best, and compared with the activity of cisplatin on the triple-negative breast cancer (about 32.4 mu M), the activity of the LND-Rh (4.9 mu M) is improved by nearly 7 times.
Cytotoxicity of the complex LND-Ru prepared in example 3 on human lung cancer cell A549, human breast cancer cell MCF-7, human triple negative breast cancer cell MDA-MB-231 and normal liver cell LO 2:
table 3 shows the compounds LND, ru-NH 2 MTT test results of LND-Ru and cisplatin CDDP
The results show that: cyclic metal complexes Ru-NH without lonidamine attached 2 Has certain toxicity to cancer cells and normal cell lines, but has smaller toxicity. The cytotoxicity of the cyclometalated complex LND-Ru after connecting lonidamine is obviously improved, especially the activity of the cyclometalated complex LND-Ru on the triple negative breast cancer cells is best, and compared with the activity of cisplatin on the triple negative breast cancer (about 32.4 mu M), the activity of the LND-Ru (2.9 mu M) is improved by nearly 11 times.
Cytotoxicity of the complexes LND-Os prepared in example 4 on human lung cancer cell A549, human breast cancer cell MCF-7, and human triple negative breast cancer cell MDA-MB-231, and normal liver cell LO 2:
table 4 shows the compounds LND, os-NH 2 MTT test results of LND-Os and cisplatin CDDP
The results show that: cyclic metal complex Os-NH without lonidamine linkage 2 Has certain toxicity to cancer cells and normal cell lines, but has smaller toxicity. The cytotoxicity of the cyclometallation complex LND-Os after connecting lonidamine is obviously improved, especially the activity of the cyclometallation complex LND-Os on the triple negative breast cancer cells is best, and compared with the activity of cisplatin on the triple negative breast cancer (about 32.4 mu M), the activity of the LND-Os (3.9 mu M) is improved by nearly 8 times.
Example 5
Positioning of cyclometallated iridium complex LND-Ir prepared in example 1 in cells.
The method comprises the following steps: MDA-MB-231 cells were inoculated into 35mm Corning laser confocal dishes, when the cell density grew to 70%, after LND-Ir treatment with a concentration of 2. Mu.M was added for 8 hours, the medium was aspirated, washed twice with PBS, 500. Mu.L of the prepared mitochondrial green fluorescent probe was added, incubated in a 37℃incubator for 30 minutes, the probe was aspirated, washed twice with PBS, and fresh pre-warmed serum-free medium was replaced, followed immediately by observation with a confocal microscope.
Example 1 intracellular localization of cyclometallated iridium complex LND-Ir is shown in fig. 1, and the results indicate that: the cyclometallated iridium complex LND-Ir can be taken up by MDA-MB-231 cells in a large amount through cell membranes in a short time, and is mainly distributed in mitochondria, and the co-localization coefficient is 0.85.
Example 6
Application of cyclometallated iridium complex LND-Ir prepared in example 1 to inducing intracellular reactive oxygen species production:
method 1: confocal microscopy detects ROS within cancer cells. MDA-MB-231 cells were inoculated into 35mm Corning laser confocal dishes, and when the cell density grew to 70%, LND-Ir and Ir-NH were added at a concentration of 4. Mu.M, respectively 2 After 24H of treatment, the cells were then treated with a solution containing 10mM H 2 Serum-free culture of DCFH-DA was stained for 30min at 37℃in the absence of light, immediately followed by confocal microscopy, excitation at 488nm and emission at 530.+ -. 20nm.
Method 2: flow cytometry detects ROS within tumor cells. MDA-MB-231 cells were added with LND-Ir at concentrations of 2, 4 and 6. Mu.M and Ir-NH at concentrations of 6. Mu.M, respectively 2 After 24h of treatment, the mixture is treated with a solution containing 10mM H 2 Serum-free culture of DCFH-DA was based on staining at 37℃for 30min in the absence of light, centrifuging to discard the supernatant, washing three times with serum-free medium to remove H that did not enter the cells 2 DCFH-DA; measuring green fluorescence intensity by a flow cytometer within the second half hour of collecting the cells; the excitation wavelength was 488nm and the emission wavelength was 530.+ -.20 nm. The average fluorescence intensity of green light was analyzed using FlowJo 7.6 (Tree Star, OR, USA) software.
Example 1 results of cyclometallated iridium complex LND-Ir on inducing intracellular reactive oxygen species are shown in FIG. 2, which shows that both flow cytometry and confocal results show a significant increase in green fluorescence after LND-Ir treatment compared to control, indicating that the complex LND-Ir is effective in inducing an increase in intracellular reactive oxygen species.
Example 7
Application of cyclometallated iridium complex LND-Ir prepared in example 1 to induction of autophagy of MDA-MB-231 cells:
the method comprises the following steps: MDA-MB-231 cells were inoculated into 35mm Corning laser confocal dishes, and when the cell density grew to 70%, LND-Ir and Ir-NH were added at a concentration of 4. Mu.M, respectively 2 After 24h treatment, cells were fixed with 4% Paraformaldehyde (PFA) by washing 2 times with PBS to remove the solidsThe cells were fixed and washed 3 times with PBS. After blocking treatment with 0.2% triton x-100 and 1.5% bsa, LC3 primary antibody dilutions were added and incubated for 1 hour; the primary antibody was removed, washed 3 times with PBS and incubated with FITC-conjugated secondary antibody for 1 hour in the dark; the secondary antibody was removed, washed 3 times with PBS and nuclei stained with DAPI for 5 min; the dye was removed and washed 3 times with PBS and the cells were imaged under confocal microscopy with excitation wavelength of 488nm and emission wavelength of 530.+ -. 20nm.
Example 1 laser confocal images of cyclometallated iridium complex LND-Ir induced autophagy of cells are shown in FIG. 3, and the results indicate that after 4. Mu.M LND-Ir is used for incubation of MDA-MB-231 cells for 24 hours, autophagy corpuscles are produced, indicating that LND-Ir can induce MDA-MB-231 cells to die by autophagy.
Example 8
Application of cyclometallated iridium complex LND-Ir prepared in example 1 in inhibiting glycolysis in MDA-MB-231 cells:
the method comprises the following steps: autophagic protein content changes were detected using Western Blotting (WB). Adding pre-prepared LND-Ir (2, 4, 6 μM) containing complex, lonidamine (6 μM) and Ir-NH into 100mm culture dish with MDA-MB-231 cells growing on the wall 2 (6 mu M) cell culture solution, after the drug treatment for 24 hours, centrifugally collecting cells, washing with PBS to remove serum in the residual culture solution, adding PMSF-containing strong RIPA lysate of Biyun Tian for 20min whole cell lysis, and ensuring a low-temperature environment at 4 ℃ in the whole process to ensure protein invariance. Centrifuging at 13400rpm for 20min under low temperature condition, and sucking supernatant obtained by centrifugation to obtain cell whole protein sample required by experiment; determining the protein concentration in the protein sample using a BCA protein content assay kit; and detecting the expression content of different proteins in the sample by SDS-PAGE gel electrophoresis. After the gel is prepared, adding protein samples with the same volume into each hole for gel electrophoresis experiments, and immediately stopping electrophoresis after proper separation; the target protein was transferred onto PVDF membrane using a wet method, and after the completion, the membrane was blocked in 5% nonfat milk powder for 2 hours. Diluting the primary antibody with skimmed milk powder according to the corresponding ratio according to the usage instructions of the antibody, and placing the sealed membrane on the primary antibody incubatorIncubation is carried out in the incubation liquid at room temperature for a period of time so that the incubation liquid can be specifically combined with the target protein. After completion, the cells were washed with PBST (5X 6 min/time). The washed membrane was incubated in a pre-formulated secondary antibody incubation for a period of time to bind to the primary antibody, again washed with PBST. An equal volume of ECL developer is prepared, covered on a PVDF film, and photographed by a chemiluminescent imaging system after 2min of treatment.
Example 1 results of experiments on MDA-MB-231 cells induced glycolysis-related protein HK II by LND-Ir complex are shown in FIG. 4, and the results indicate that: compared with a control group which is not treated with the drug, after the cells are treated by the complex LND-Ir, the expression of the glycolysis-related proteins HK II and Akt is obviously down-regulated, which indicates that the complex LND-Ir can inhibit the expression of the cell HK II and Akt proteins so as to inhibit the glycolysis capacity of the cell.
Example 9
Application of cyclometallated iridium complex LND-Ir prepared in example 1 in MDA-MB-231 cells for inhibiting immune escape:
the method comprises the following steps: MDA-MB-231 cells were inoculated into 35mm Corning laser confocal dishes, and when the cell density grew to 70%, LND-Ir and Ir-NH were added at a concentration of 4. Mu.M, respectively 2 After 24 hours of treatment, the cells were fixed with 4% Paraformaldehyde (PFA) by washing 2 times with PBS, the fixing solution was removed, and the cells were washed 3 times with PBS. After blocking treatment with 0.2% Triton X-100 and 1.5% BSA, PD-L1 primary anti-dilution was added and incubated for 1 hour. The primary antibody was removed, washed 3 times with PBS and incubated with FITC-conjugated secondary antibody for 1 hour in the dark. The secondary antibody was removed, washed 3 times with PBS and nuclei stained with DAPI for 5 min. Removing dye, washing with PBS for 3 times, and performing cell imaging under confocal microscope, wherein excitation wavelength is 488nm, and emission wavelength is 530+ -20 nm
Example 1 a laser confocal image of cyclometallated iridium complex LND-Ir to suppress cellular immune escape is shown in figure 5. The results show that after MDA-MB-231 cells are incubated with 4 mu M LND-Ir for 24 hours, the expression of the programmed death ligand PD-L1 is inhibited, which indicates that the LND-Ir can inhibit the immune escape of the MDA-MB-231 cells.
Example 10
Application of cyclometallated iridium complex LND-Ir prepared in example 1 in inducing ICD in MDA-MB-231 cells:
method 1: MDA-MB-231 cells were inoculated into 35mm Corning laser confocal dishes, and when the cell density grew to 70%, LND-Ir and Ir-NH were added at a concentration of 4. Mu.M, respectively 2 After 24h treatment, cells were fixed with 4% Paraformaldehyde (PFA) by washing 2 times with PBS, the fixing solution was removed, and cells were washed 3 times with PBS. After blocking treatment with 0.2% Triton X-100 and 1.5% BSA, CRT primary antibody dilutions were added and incubated for 1 hour. The primary antibody was removed, washed 3 times with PBS and incubated with FITC-conjugated secondary antibody for 1 hour in the dark. The secondary antibody was removed, washed 3 times with PBS and nuclei stained with DAPI for 5 min. Removing dye, washing with PBS for 3 times, and performing cell imaging under confocal microscope, wherein excitation wavelength is 488nm, and emission wavelength is 530+ -20 nm
Method 2: protein immunoblotting (WB) was used to detect changes in ICD-related protein HMGB1 content. Adding pre-prepared LND-Ir (2, 4, 6 μM) containing complex, lonidamine (6 μM) and Ir-NH into 100mm culture dish with MDA-MB-231 cells growing on the wall 2 (6 mu M) cell culture solution, after the drug treatment for 24 hours, centrifugally collecting cells, washing with PBS to remove serum in the residual culture solution, adding PMSF-containing strong RIPA lysate of Biyun Tian for 20min whole cell lysis, and ensuring a low-temperature environment at 4 ℃ in the whole process to ensure protein invariance. Centrifuging at 13400rpm for 20min under low temperature condition, and sucking supernatant obtained by centrifugation to obtain cell whole protein sample required by experiment; determining the protein concentration in the protein sample using a BCA protein content assay kit; and detecting the expression content of different proteins in the sample by SDS-PAGE gel electrophoresis. After the gel is prepared, adding protein samples with the same volume into each hole for gel electrophoresis experiments, and immediately stopping electrophoresis after proper separation; the target protein was transferred onto PVDF membrane using a wet method, and after the completion, the membrane was blocked in 5% nonfat milk powder for 2 hours. Diluting the primary antibody with skimmed milk powder according to the corresponding proportion according to the instruction of the antibody, and placing the sealed membrane in a primary antibody incubation liquid for incubation for a period of time at room temperature so as to enable the membrane to be specifically combined with the target protein. After completion, the cells were washed with PBST (5X 6 min/time)). The washed membrane was incubated in a pre-formulated secondary antibody incubation for a period of time to bind to the primary antibody, again washed with PBST. An equal volume of ECL developer is prepared, covered on a PVDF film, and photographed by a chemiluminescent imaging system after 2min of treatment.
Example 1 cyclometallated iridium complex LND-Ir pair induced cell immunogenic death ICD results are shown in figure 6. The results show that compared with the control group, the cell CRT is exposed after the LND-Ir treatment, the HMGB1 protein expression is down-regulated, and the LND-Ir can induce the MDA-MB-231 cell to be immunogenic and dead.
Claims (10)
1. A lonidamine-modified organic compound, which is characterized by the following structural formula:
2. the method for preparing the lonidamine-modified organic compound according to claim 1, which is characterized by comprising the following steps: and (3) dissolving lonidamine, EDCI or DCC, HOBt, TEA and a bridging ligand 4-methyl-4 '-aminomethyl-2, 2' -bipyridine into an organic solvent for reaction in an inert atmosphere, and separating and purifying a crude product generated by the reaction through column chromatography to obtain the lonidamine modified organic compound.
3. A process for the preparation of lonidamine-modified organic compounds according to claim 2, characterized in that: the molar ratio of lonidamine to 4-methyl-4 '-aminomethyl-2, 2' -bipyridine is 1:1 to 1.68.
4. A process for the preparation of lonidamine-modified organic compounds according to claim 2, characterized in that: the reaction temperature is between 20 ℃ below zero and 0 ℃; the reaction time is 2-48 h.
5. Use of a lonidamine-modified organic compound of claim 1 for the preparation of an anticancer drug, an anticancer drug component, an immune escape suppression drug component, a cell metabolism suppression drug component, an immunogenic death induction drug component, an autophagy inducer drug, and an autophagy inducer drug component.
6. The cyclometallated complex based on an organic compound according to any one of claims 1 to 5, characterized in that it has the general structural formula:
wherein, when M is Ir or Rh, x=c, y=n; when M is Ru or Os, x=n, y=n.
7. The method for producing a cyclometallated complex according to claim 6, comprising the steps of: heating and refluxing the organic ligand modified by lonidamine and the metal precursor in a mixed solvent of dichloromethane and methanol under inert atmosphere, distilling the solvent under reduced pressure, and using NH 4 PF 6 The crude product is obtained by displacement, and the cyclic metal complex of the tail lonidamine is obtained by separating and purifying the crude product through column chromatography;
wherein, the structural formula of the metal precursor is respectively:
metallic iridium precursor:
metal rhodium precursor:
metallic ruthenium precursor:
metal osmium precursor:
8. the method for producing a cyclometallated complex according to claim 7 wherein: the molar ratio of lonidamine-modified organic ligand to metal precursor is 1:100.
9. the method for producing a cyclometallated complex according to claim 7 wherein: the temperature of the heating reflux reaction is 60-80 ℃; the time is 18-20 h.
10. Use of the cyclometallated complex of claim 7 for the preparation of an antitumor drug or an antitumor drug component.
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