CN111171080A - High-efficiency low-toxicity anticancer compound synthesized by autocatalysis in cells and living bodies and synthesis method thereof - Google Patents
High-efficiency low-toxicity anticancer compound synthesized by autocatalysis in cells and living bodies and synthesis method thereof Download PDFInfo
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- CN111171080A CN111171080A CN202010019962.7A CN202010019962A CN111171080A CN 111171080 A CN111171080 A CN 111171080A CN 202010019962 A CN202010019962 A CN 202010019962A CN 111171080 A CN111171080 A CN 111171080A
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Abstract
The invention discloses a high-efficiency low-toxicity anticancer compound synthesized by autocatalysis in cells and living bodies, which is prepared by chemical synthesis of a metal complex precursor and an organic active molecule precursor outside cells or by biological orthogonal reaction synthesis in cells; the metal complex is a platinum, ruthenium, iridium or osmium metal complex, and the organic active molecules refer to organic small molecules with certain biological activities, such as anti-inflammatory, antibacterial, anti-angiogenesis and anti-cancer biological activities. The organic active molecule precursor is chemically modified organic active molecule, and the organic active molecule is one of rhein, oleanolic acid, ursolic acid, naphthalimide, coumarinic acid, nonanthracenic acid or indomethacin. The invention also discloses a synthesis method of the anticancer compound. The anticancer compound of the invention shows that the anticancer compound has good antitumor effect no matter synthesized in an extracellular reaction or in a cell reaction.
Description
Technical Field
The invention relates to a metal complex based on organic active molecules, and also relates to an autocatalytic synthesis method of the metal complex in cells and living bodies and application of the metal complex in preparation of antitumor drugs or anticancer drug components, belonging to the technical field of biological medicines.
Technical Field
The metal antitumor drug represented by cisplatin is widely used for clinically treating various cancers, and has good treatment effect on various cancers such as ovarian cancer, testicular cancer, bladder cancer, colorectal cancer and the like, wherein the cure rate of patients with testicular cancer is as high as 90%. However, cisplatin does not differentially attack cells, so that the cisplatin can kill tumor cells and cause serious damage to normal cells, and causes great toxic and side effects such as nephrotoxicity, ototoxicity and neurotoxicity to cancer patients, so that the patients suffer great pain. In addition, cisplatin drugs have low activity on some tumor cells (breast cancer, colon cancer and the like) and have primary and acquired drug resistance and the like, and the application of cisplatin drugs in clinical treatment is severely limited by a series of defects.
Disclosure of Invention
The technical problem to be solved by the invention is to provide an anticancer compound which is synthesized by a metal complex precursor and an organic active molecule precursor in a cell, wherein the organic active molecule has multiple biological characteristics of anti-inflammation, antibiosis, anti-angiogenesis, anticancer and the like, on one hand, the organic active molecule and the metal complexes of platinum, aryl ruthenium, iridium, osmium and the like are subjected to specific combination in the cell through a bioorthogonal reaction (the specific combination has the advantage of high reaction efficiency without byproducts), the obtained anticancer compound (metal anticancer drug) not only can keep the advantages of the organic active molecule, but also can adjust the biological activity of the metal drug to achieve the effects of low toxicity and high efficiency, and on the other hand, the anticancer compound can also be prepared based on chemical synthesis.
The technical problem to be solved by the invention is to provide a synthesis method of the anticancer compound, which is simple to operate and mild in reaction conditions.
The technical problem to be solved finally by the invention is to provide the application of the anticancer compound in the aspect of preparing antitumor drugs or anticancer drug components.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
an efficient anticancer compound with low toxicity synthesized by autocatalysis in cell and living body is prepared from the precursor of metal complex and the precursor of organic active molecule through chemical synthesis outside cell or bioorthogonal reaction inside cell; the metal complex is a platinum, ruthenium, iridium or osmium metal complex, the organic active molecule precursor is an organic active molecule subjected to chemical modification, and the organic active molecule is one of rhein, oleanolic acid, ursolic acid, naphthalimide, coumarinic acid, 9-anthracenecarboxylic acid or indometacin.
The organic active molecules refer to organic small molecules with certain biological activities, such as anti-inflammatory, antibacterial, anti-angiogenesis and anti-cancer biological activities.
The metal complex has the following structural general formula:
The synthesis method of the anticancer compound comprises the following steps:
(1) preparation of Metal Complex precursor: dissolving platinum and aryl metal dimer in an organic solvent under the atmosphere of rare gas, adding anion salt into the obtained solution after a chelating ligand coordination reaction, stirring at room temperature, filtering after the reaction, concentrating the filtrate, and putting the filtrate in a refrigerator for recrystallization to obtain a metal complex precursor;
(2) preparation of organic active molecular precursor: placing organic active molecules and a dehydrating agent in an organic solvent to react under the atmosphere of rare gas, removing the solvent after the reaction, washing with water, extracting with trichloromethane, drying, and purifying by column chromatography to obtain an organic active molecule precursor;
(3) and (2) adding the metal complex precursor in the step (1), the organic active molecular precursor in the step (2) and a copper catalyst into an organic solvent, removing the solvent after reaction, and further purifying the crude product by column chromatography to obtain the metal complex.
Wherein, in the step (1), the aryl metal dimer is dichloroaryl ruthenium dimer, dichloroaryl iridium dimer or dichloroaryl osmium dimer.
Wherein in the step (1), the platinum is potassium chloroplatinite, potassium chloroplatinate or cisplatin.
Wherein, in the step (1), the adding molar ratio of the platinum, the aryl metal dimer and the chelating ligand is 1: 2.
Wherein, in the step (3), the adding molar ratio of the metal complex precursor to the organic active molecule precursor is 1: 1.
Wherein, in the step (3), the copper catalyst is cuprous iodide, copper sulfate or copper chloride.
The method for synthesizing the anticancer compound in the cell specifically comprises the following steps: adding the metal complex precursor into a tumor cell culture dish, incubating for 20-30 h in a cell culture box, adding the organic active molecule precursor, continuing to incubate for 20-30 h, washing with PBS, digesting and centrifuging the cells after washing, and collecting; and finally, breaking the cells into fragments by using a cell breaker, filtering the fragments by using a filter membrane, and performing electrospray mass spectrometry to obtain a product of intracellular reaction.
The anticancer compound synthesized in the cell and the chemically synthesized anticancer compound can be applied to the preparation of antitumor drugs or anticancer drug components.
The anticancer compound can be directly synthesized in cells through a bioorthogonal reaction by a metal complex precursor and an organic active molecule precursor. Bioorthogonal reactions are a class of chemical reactions that can be performed in living cells. Such reactions can occur under physiological conditions in the body of an organism, do not interfere with other biochemical reactions occurring simultaneously in the body, and do not damage the organism and the target biomolecules. The anticancer compound of the invention enables organic active molecules to be specifically combined with metal complexes such as platinum, aryl ruthenium, iridium, osmium and the like in cells through biological orthogonal reaction, and the obtained anticancer compound has high antitumor activity.
The reaction mechanism of the chemical synthesis or intracellular synthesis of the anticancer compound is as follows:
Has the advantages that: the anticancer compound synthesized by the metal complex precursor and the organic active molecule precursor has good antitumor effect no matter synthesized in an extracellular reaction or in a cell, and the metal complex precursor and the organic active molecule precursor have little killing performance on the cell, so the anticancer compound has little toxic or side effect on normal tissues; finally, the anticancer compound of the invention has good inhibition effect on the tumor growth of tumor-bearing mice.
Drawings
FIG. 1 shows two precursors of Rhein-alkyne and Ru-N3Mass spectrogram of ruthenium rhein complex as antitumor medicine synthesized in cell;
FIG. 2 shows two precursors of Rhein-alkyne and Ru-N3Mass spectrogram of antitumor drug-ruthenium rhein complex by chemical synthesis;
FIG. 3 shows the tumor changes of five groups of tumor-bearing mice after 21 days of treatment;
FIG. 4 shows the body weight changes of five groups of tumor-bearing mice after 21 days of treatment;
FIG. 5 shows the change of the number of tumor cells in five groups of experiments under a microscope after 21 days of treatment of tumor-bearing mice.
Detailed Description
The technical solutions of the present invention are further described below with reference to the drawings and the specific embodiments, but the scope of the present invention is not limited thereto.
Example 1
Under the protection of argon, 0.5mmol of rhein, 0.5mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 0.5mmol of triethylamine and 0.5mmol of 4-dimethylaminopyridine are dissolved in DMF (N, N-dimethylformamide) and stirred overnight (the reaction temperature is room temperature, the stirring time is 10-24 hours), after the reaction is finished, the DMF is removed by rotary evaporation, washed by water, extracted by trichloromethane, dried, separated and purified by column chromatography to obtain a yellow powdery product, and the yield is 56%.1H NMR(400MHz,DMSO,25℃,TMS)δ11.91(s,1H),9.41(t,J=5.5Hz,1H),8.15(d,J=1.7Hz,1H),7.89-7.80(m,1H),7.79-7.72(m,1H),7.42(dd,J=8.4,1.2Hz,1H),4.10(dd,J=5.5,2.5Hz,1H),3.35(s,5H);13C NMR(100MHz,DMSO,25℃,TMS)δ191.85,181.46,164.18,161.83,161.57,141.26,138.04,134.05,133.67,125.01,122.97,119.92,118.18,118.01,116.47,81.20,73.73,40.52,40.31,40.11,39.90,39.69,39.48,39.27,29.27.ESI-MS[Rhein-alkyne]+: theoretical value: 322.07, Experimental value: 322.33.
under the protection of argon, 0.03mmol of potassium chloroplatinite and 0.03mmol of 4-methyl-2, 2-bipyridine-azide are dissolved in an anhydrous DMF solution and react for 48 hours under the condition of normal temperature and light shielding. After the reaction, the solvent is removed by rotary evaporation, and the precipitate is washed by dichloromethane, acetone and ether respectively to obtain a purer yellow powdery product with the yield of 65 percent, which is named as Pt-N3。1H NMR(400MHz,DMSO)δ8.81(d,J=5.8Hz,2H),8.61(d,J=5.4Hz,2H),7.23(d,J=5.5Hz,1H),7.33(d, J ═ 5.5Hz, 1H), 3.49(s, 2H), 2.64(s, 3H). ESI-MS (+): theoretical value: [ Pt-N ]3]+m/z: 490.00, Experimental value: m/z: 490.15.
mixing the above prepared 0.5mmol Rhein-alkyne, 0.5mmol Pt-N3Respectively dropwise adding the mixture into 5mL of anhydrous DMF, stirring for reacting for 72h, adding 50mL of dichloromethane solution, precipitating yellow precipitates, washing the precipitates with ethanol, acetone and diethyl ether for three times, and performing centrifugal separation to obtain a pure yellow product, wherein the yield is 54%.1H NMR (400MHz, DMSO) δ 11.33(d, J ═ 11.9Hz, 2H), 9.64(t, J ═ 6.8Hz, 1H), 8.90(d, J ═ 6.2Hz, 1H), 8.78(d, J ═ 6.0Hz, 1H), 8.69(s, 1H), 8.60(s, 1H), 8.41(d, J ═ 9.4Hz, 1H), 8.22(s, 1H), 7.90(dd, J ═ 12.8Hz, 5.9Hz, 2H), 7.69(d, J ═ 7.1Hz, 1H), 7.67(d, J ═ 5.3Hz, 1H), 7.52(d, J ═ 6.9Hz, 2H), 6.22-5.95(m, 2H), 4.56(t, 56.56, t, 2H), 7.79 (d, J ═ 6.9Hz, 2H). ESI-MS: theoretical value [ Pt-Rhein]+: 811.07, Experimental value: m/z: 811.23.
example 2
0.03mmol of dichloro (p-methylisopropylphenyl) ruthenium (II) dimer and 0.06mmol of 4-methyl-2, 2-bipyridine-azide (prepared in reference: Xun, Z.Q.et al.J.Mater.chem.A, 2015, 3, 12965-12971) were dissolved in methanol under argon and reacted at 65 ℃ for 24 h; after the reaction, adding 20 times of equivalent weight of ammonium hexafluorophosphate, stirring for 0.5-24 h at room temperature, finally adding diethyl ether for precipitation to obtain a pure yellow powdery product, wherein the yield is 43 percent and the name is Ru-N3。1H NMR(400 MHz,CD3OD, 25 ℃, TMS) δ 9.43(d, J ═ 5.9Hz, 1H), 9.29(d, J ═ 5.8Hz, 1H), 8.45(d, J ═ 19.1Hz, 2H), 7.68(ddd, J ═ 44.9, 5.9, 1.4Hz, 2H), 6.15-6.05(m, 2H), 5.88-5.76(m, 2H), 4.83(s, 2H), 2.65(m, 4H), 2.28(s, 3H), 1.06(dd, J ═ 6.9, 1.0Hz, 6H), ESI-MS (+): theoretical value: [ Ru-N ]3-PF6]+: theoretical value: m/z: 496.08, experimental value: m/z 496.25.
0.05mmol of Rhein-alkyne prepared in example 1, 0.05mmol of Ru-N3Dissolving 0.01mmol of copper sulfate and 0.01mmol of sodium ascorbate in DMF, stirring and reacting for 24h, removing solvent after reaction, and performing column chromatography separation to obtain yellow product with yield of 43%.1H NMR(400MHz,DMSO)δ9.54(s,1H),9.46(dd,J=24.7,5.9Hz,1H),9.34(dd,J=23.9,5.8Hz,1H),8.55(s,1H),8.46(d,J=6.8Hz,1H),8.30(s,1H),8.18(s,1H),7.84(dd,J=14.0,5.9Hz,2H),7.76(d,J=7.3Hz,1H),7.64(dd,J=13.6,5.8Hz,1H),7.45(dd,J=22.5,6.4Hz,2H),6.19(dd,J=12.8,6.1Hz,2H),6.12(t,J=5.7Hz,1H),5.96(dd,J=16.7,8.4Hz,2H),5.88(s,2H),4.60(d,J=5.3Hz,2H),2.58(d,J=3.9Hz,4H),2.15(s,2H),2.09(s,4H),0.94(t,J=6.5Hz,5H)。ESI-MS[Ru-Rhein]+: theoretical value: 817.15, Experimental value: 817.33.
the invention verifies two precursors of Rhein-alkyne and Ru-N by electrospray mass spectrometry3Can directly synthesize the anti-tumor drug-Rhein ruthenium complex Ru-Rhein-cell in cells. The specific method comprises the following steps: the final concentration of 100 mu M of ruthenium azide complex Ru-N3Adding the mixture into a tumor cell culture dish, incubating the mixture in a cell culture box for 24 hours, adding Rhein-alkyne to a final concentration of 100 mu M, continuously incubating the mixture for 24 hours, washing the mixture for 3 times by PBS, digesting and centrifuging the cells, and collecting the cells; finally, the cells are broken into fragments by a cell breaker, the fragments are filtered by a filter membrane, and then the electrospray mass spectrometry is carried out, so as to obtain a product of the intracellular reaction, wherein the mass spectrogram of the product synthesized in the cells is shown in figure 1, the mass spectrogram of the product synthesized by the chemistry in the example 2 is shown in figure 2, and the comparison between the figure 1 and the figure 2 shows that the two precursors of Rhein-alkyne and Ru-N3Can directly synthesize the antitumor drug ruthenium Rhein complex Ru-Rhein-cell in cells. As can be seen from Table 1 in the specification, the expression of the chemically synthesized ruthenium Rhein complex Ru-Rhein-Chem and the intracellularly synthesized ruthenium Rhein complex Ru-Rhein-cell on several tumor cells is much higher than the antitumor activities of two prodrugsAnd the activity on tumor cells is equivalent to that of cisplatin; meanwhile, the activity of the ruthenium complex to normal cells, namely human embryonic lung fibroblasts (HLF), is poor, which shows that the ruthenium complex based on the organic active molecule rhein has high selectivity to cancer cells. The above results demonstrate that the metal anticancer drug synthesized in the cell can reduce the side effects of the drug by reducing the administration dose.
The Pt-Rhein-cell, the Os-Rhein-cell, the Ru-Olea-cell, the Ir-Rhein-cell, the Ru-Coum-cell and the Ru-Indo-cell of the embodiments 1 and 3-7 can be synthesized into the metal anticancer drug in the cell by the same method of the embodiment 2.
Example 3
Under the protection of argon, 0.05mmol of dichloro (p-methylisopropyl phenyl) osmium (II) dimer and 0.1mmol of 4-methyl-2, 2-bipyridyl-azide are dissolved in methanol to react for 48 hours at 70 ℃, after the reaction, 20 times of equivalent of ammonium hexafluorophosphate is added, the mixture is stirred for 0.5 to 24 hours at room temperature, and finally, diethyl ether is added to precipitate to obtain a pure yellow powdery product, wherein the yield is 32 percent and the product is named as Os-N3。1H NMR(400MHz,CD3OD, 25 ℃, TMS) δ 9.21(d, J ═ 5.9Hz, 1H), 9.02(d, J ═ 5.8Hz, 1H), 8.33(d, J ═ 19.1Hz, 2H), 7.52(ddd, J ═ 44.9, 5.9, 1.4Hz, 2H), 6.31-6.15(m, 2H), 5.74-5.59(m, 2H), 4.81(s, 2H), 2.58(m, 4H), 2.23(s, 3H), 1.11(dd, J ═ 6.9, 1.0Hz, 6H), ESI-MS (+): theoretical value: [ Os-N ]3-PF6]+: theoretical value: m/z: 586.14, Experimental value: m/z 586.35.
0.06mmol of Rhein-alkyne prepared in example 1, 0.06mmol of Os-N3And 0.012mmol cuprous iodide are dissolved in DMF and stirred for reaction for 12h, the solvent is removed after the reaction is finished, and the yellow product is obtained by column chromatography separation, and the yield is 32%.1H NMR(400MHz,MeOD)δ9.36(d,J=5.9Hz,1H),9.22(d,J=5.9Hz,1H),8.48(d,J=19.1Hz,2H),7.86-7.68(m,4H),7.58(d,J=5.8Hz,1H),7.49(d,J=5.6Hz,1H),7.39-7.32(m,1H),6.29(dd,J=9.5,5.9Hz,2H),6.06-5.91(m,4H),4.72(s,2H),2.69(s,3H),2.47(dt,J=13.6,6.8Hz,1H),2.34-2.28(m,3H),0.96(t,J=7.7Hz,6H)。ESI-MS[Os-Rhein]+ theoretical value: 907.44, Experimental value: 907.40.
example 4
Under the protection of argon, dissolving 0.2mmol of oleanolic acid, 0.2mmol of dicyclohexylcarbodiimide and 0.2mmol of 4-dimethylaminopyridine in DMF, and stirring for 48 h; after the reaction is finished, DMF is removed by rotary evaporation, washed by water, extracted by trichloromethane, dried, separated and purified by column chromatography to obtain white powder, and the yield is 30%.1H NMR(400MHz,DMSO)δ7.67(t,J=5.6Hz,1H),5.21(t,J=3.2Hz,1H),4.29(dd,J=5.1,2.3Hz,1H),3.84(ddd,J=17.2,5.7,2.4Hz,1H),3.72(ddd,J=17.2,5.3,2.4Hz,1H),3.00(dd,J=10.1,4.9Hz,1H),2.96(t,J=2.4Hz,1H),2.79(dd,J=13.7,4.0Hz,1H),1.10-1.95(m),0.94-0.83(m,21H)。ESI-MS[Olea-alkyne]+: theoretical value: 493.39, Experimental value: 493.23.
0.1mmol of Olea-alkyne and 0.1mmol of Ru-N prepared in example 230.02mmol of copper sulfate and 0.02mmol of sodium ascorbate are dissolved in DMF and stirred for 4 hours at normal temperature, the solvent is removed after the reaction is finished, and a yellow product is obtained by column chromatography separation, wherein the yield is 25%. 1H NMR (400MHz, MeOD) δ 9.41(d, J ═ 5.9Hz, 1H), 9.33(s, 1H), 9.32(s, 1H), 9.29(d, J ═ 5.9Hz, 1H), 9.21(s, 1H), 9.20(s, 1H), 7.63(d, J ═ 5.9Hz, 1H), 7.58(d, J ═ 5.9Hz, 2H), 7.49(d, J ═ 5.9Hz, 1H), 7.43(s, 2H), 6.08(dd, J ═ 9.5, 6.7Hz, 2H), 5.98(d, J ═ 2.0Hz, 2H), 5.97(s, 2H), 3.02(s, 1H), 2.88(d, J ═ 0.63, 1H), 3.8 (H), 3.47H, 26H), 3.8H, 26H. ESI-MS (+): [ Ru-OA-Cl-]+Theoretical value: m/z: 989.40, Experimental value: m/z: 989.45。
Example 5
Under the protection of argon, 0.03mmol of dichloro (pentamethylcyclopentadienyl) iridium (III) dimer and 0.06mmol of 4-methyl-2, 2-bipyridyl-azide are dissolved in a methanol solution and react for 24 hours at the temperature of 65 ℃; after the reaction, adding 10 times of equivalent weight of ammonium hexafluorophosphate, stirring for 0.5-24 h at room temperature, and finally adding diethyl ether to precipitate to obtain a pure yellow powdery product, wherein the yield is 70%, and the name of the product is Ir-N3。1H NMR (400MHz, DMSO) δ 8.95(d, J ═ 5.8Hz, 1H), 8.82(d, J ═ 5.8Hz, 1H), 8.72(s, 2H), 7.80(d, J ═ 5.4Hz, 1H), 7.71(d, J ═ 5.5Hz, 1H), 4.95(s, 2H), 2.64(s, 3H), 1.65(s, 15H). ESI-MS (+): theoretical value: [ Ir-N ]3-PF6]+m/z: 603.17, Experimental value: m/z: 603.25.
0.5mmol of Rhein-alkyne prepared in example 1, 0.5mmol of Ir-N3Dissolving the product and 0.1mmol cuprous iodide in DMF, stirring to react for 48 hr, removing solvent, and column chromatographic separation to obtain yellow product with yield of 32%.1H NMR (400MHz, DMSO) δ 11.92(d, J ═ 12.3Hz, 2H), 9.56(t, J ═ 5.3Hz, 1H), 8.95(d, J ═ 5.9Hz, 1H), 8.82(d, J ═ 5.8Hz, 1H), 8.69(s, 1H), 8.59(s, 1H), 8.31(d, J ═ 11.0Hz, 1H), 8.19(s, 1H), 7.85(dd, J ═ 14.0, 5.9Hz, 2H), 7.77(d, J ═ 7.2Hz, 1H), 7.67(d, J ═ 5.3Hz, 1H), 7.44(d, J ═ 7.6, 2H), 6.03-5.89(m, 2H), 4.63(t, 8.81, 8.3 Hz, 1H), 1H, 7.61 (d, J ═ 7.6.6, 2H), 6.61H). MS (ESI): theoretical value: [ Ir-Rhein-PF6]+The experimental value is as follows: m/z: 1001.33.
example 6
Under the protection of argon, 0.2mmol of coumarin acid and 0.2mmol of O-benzotriazole-N, N, N', N' -tetramethyluronium tetrafluoroborate (TBTU), 0.2mmol 1-hydroxybenzotriazole (HOBt) and 0.2mmol propargylamine were dissolved in anhydrous DMF and stirred for 48 h; after the reaction is finished, DMF is removed by rotary evaporation, washed by water, extracted by trichloromethane, dried, separated and purified by column chromatography to obtain white powder with the yield of 88 percent.1H NMR(400MHz,DMSO)δ(ppm):8.95(s,1H),8.88(s,1H),7.99(dd,J=7.8,1.5Hz,1H),7.76(ddd,J=7,7.4,1.6Hz,1H),7.54-7.40(m,2H),4.13(dd,J=5.6,2.5Hz,2H),3.17(t,J=2.5Hz,1H)。
0.05mmol of Coum-alkyne and 0.05mmol of Ru-N prepared in example 23Dissolving the mixture and 0.01mmol of copper chloride and 0.01mmol of sodium ascorbate in DMF, stirring and reacting for 8h, removing the solvent after the reaction is finished, and performing column chromatography separation to obtain a yellow product Ru-Coum with the yield of 27.6%.1H NMR (400MHz, MeOD) delta (ppm): 9.34(d, J ═ 5.9Hz, 1H), 9.20(d, J ═ 5.9Hz, 1H), 8.89(s, 1H), 8.40(s, 1H), 8.36(s, 1H), 8.15(s, 1H), 7.86(dd, J ═ 8.0, 1.5Hz, 1H), 7.77(dd, J ═ 7.4, 1.6Hz, 1H), 7.56(d, J ═ 4.8Hz, 1H), 7.46(ddd, J ═ 6.8, 5.1, 2.0Hz, 3H), 5.96(dd, J ═ 5.8, 2.2Hz, 2H), 5.93(s, 1H), 5.82(d, J ═ 6.3Hz, 2H), 4.77(s, 2H), 2.81 (s, 1H), 5.82(d, J ═ 6.3, 2H), 2H, 2(s, 1H), 5.47 (t, 6.6, 6.47 (s, 1H), 3H), 5.47 (s, 6, 3H), 5.47 (t, 1H), 3H, 2H), 3H, 2H: 723.14, [ Ru-Coum-PF6]+The experimental value is as follows: m/z: 723.21.
example 7
Under the protection of argon, 0.5mmol of indometacin, 0.5mmol of O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU), 0.5mmol of 1-hydroxybenzotriazole (HOBt) and 0.5mmol of propargylamine are dissolved in 10mLN, N-dimethylformamide and stirred overnight, after the reaction is finished, DMF is removed by rotary evaporation, water is used for washing, chloroform is used for extraction, drying, column chromatography separation and purification are carried out, and a white powdery product is obtained, wherein the yield is 40%.1H NMR(400MHz,CDCl3)δ7.72-7.68(m,2H),7.54-7.49(m,2H),6.89(dd,J=10.4,3.5Hz,2H),6.73(dd,J=9.0,2.5Hz,1H),5.80(s,1H),4.04(dd,J=5.5,2.5Hz,2H),3.85(s,3H),3.69(s,2H),2.42(s,3H),2.19(t,J=2.5Hz,1H).
0.02mmol of Indo-alkyne and 0.02mmol of Ru-N prepared in example 2 were added3Dissolving 0.005mmol of copper sulfate and 0.01mmol of sodium ascorbate in DMF, stirring and reacting for 18h, removing the solvent after the reaction is finished, and performing column chromatography separation to obtain a yellow product Ru-Indo with the yield of 26%.1H NMR (400MHz, MeOD) δ 9.37(d, J ═ 5.9Hz, 1H), 9.28(d, J ═ 5.8Hz, 1H), 8.27(d, J ═ 10.1Hz, 2H), 7.99(s, 1H), 7.73-7.69(m, 2H), 7.62-7.57(m, 3H), 7.42(d, J ═ 5.9Hz, 1H), 6.95(d, J ═ 2.5Hz, 1H), 6.90(d, J ═ 9.0Hz, 1H), 6.63(dd, J ═ 9.0, 2.5Hz, 1H), 6.07(dd, J ═ 11.9, 5.9Hz, 2H), 5.89(s, 2H), 5.84(t, J ═ 9, 2.5, 2H), 5.89(s, 2H), 5.84(t, 6.5, 2.5, 1H), 2.65(s, 3.5H), 3.5H, 3.65 (s, 3.5H), 3.5H, 3H, 3.5H, 3H: 890.19, [ Ru-Indo-PF6]+The experimental value is as follows: m/z: 890.05.
the metal anticancer medicine of the invention is applied to the treatment of tumor cells.
The method comprises the following steps: MTT colorimetric method for determining in vitro anticancer activity of human cancer cell lines such as breast cancer (MCF-7), ovarian cancer (A2780), non-small cell lung cancer (A549), etc., and toxic and side effects of normal cell human embryonic lung fibroblast (HLF). MCF-7, A2780, A549 and HLF cells were placed in DMEM medium with 10% fetal bovine serum and 1% penicillin-streptomycin solution at 37 ℃ with 5% CO2Culturing in a cell culture box. Cells were seeded into 96-well cell culture plates at an initial density of 5000 cells/well, the medium was removed after 24 hours of culture, three sets of parallel comparative experiments were set up, five concentrations of the sample to be tested, and incubation continued for 48 h. Then 15. mu.L of 5mg/mL MTT was added to each well, followed by incubation in a 37 ℃ incubator for 4h followed by 150. mu.L DMSO, shaking until the purple crystals were completely dissolved, and reading the absorbance at 490nm on a microplate reader (model Tecan Infinite M1000 Pro).
The anticancer activity of the rhein platinum complex prepared in example 1 is shown in table 1.
Table 1 shows complexes Pt-Rhein-cell, Pt-Rhein-chem, azido platinum complex (Pt-N) prepared inside and outside cells3) IC of Rhein-alkyne and cisplatina0Value of (. mu.M)
The results show that the platinum complex Pt-Rhein-chem synthesized chemically and the platinum complex Pt-Rhein-cell synthesized in cells have the antitumor activity far higher than that of two prodrugs on several tumor cells, and the activity on the tumor cells is equivalent to that of cisplatin. The above results demonstrate that a platinum complex based on an organic active molecule synthesized in cells can reduce the side effects of the drug by reducing the administration dose.
The anticancer activity of the rhein ruthenium complex prepared in example 2 is shown in table 2.
Table 2 shows complexes Ru-Rhein-cell, Ru-Rhein-chem and ruthenium azide complexes (Ru-N) prepared inside and outside cells3) IC of Rhein-alkyne and cisplatina0Value of (. mu.M)
The results show that the organic active molecule precursor Rhein-alkyne shows moderate antiproliferative activity on several cells, and the metal complex precursor Ru-N3Has little activity on several cells (IC)50More than 100 mu M), and the ruthenium complex Ru-Rhein-chem which is chemically synthesized has high anti-tumor activity on a plurality of tumor cells, the activity of the ruthenium complex Ru-Rhein-chem is equivalent to that of cis-platinum, and the activity of the ruthenium complex Ru-Rhein-chem on normal cells and human embryonic lung fibroblast (HLF) is poor, which shows that the ruthenium complex based on the organic active molecule Rhein has high selectivity on cancer cells. Similarly, the intracellular synthesized metal complex Ru-Rhein-cell also shows the anti-tumor activity equivalent to that of cisplatin on a plurality of tumor cells and has the anti-tumor activity on normal cellsThe cytotoxicity is very low. Therefore, the ruthenium metal complex synthesized in cells based on organic active molecules helps to reduce the side effects of the drug.
The anticancer activity of the osmium rheinate complex prepared in example 3 is shown in table 3.
Table 3 shows complexes Os-Rhein-cell, Os-Rhein-chem, azido osmium complex (Os-N) prepared inside and outside cells3) IC of Rhein-alkyne and cisplatin50Value of (. mu.M)
The results show that the chemically synthesized osmium complex Os-Rhein-chem shows much higher anti-tumor activity to several tumor cells than two prodrugs, and is slightly lower than cisplatin. The activity of the osmium complex Os-Rhein-cell synthesized in the cell on several tumor cells is equivalent to that of the Os-Rhein-chem synthesized chemically. Therefore, it is proved again that the metal complex based on the organic active molecule synthesized in the cell is expected to reduce the side effect of the drug by reducing the administration dosage, thereby realizing higher drug use and research value.
The anticancer activity of the ruthenium oleanolic acid complex prepared in example 4 is shown in table 4.
Table 4 shows complexes Ru-Olea-cell, Ru-Olea-chem and ruthenium azide complexes (Ru-N) prepared inside and outside cells3) IC of Oleanolic acid alkyne (Olea-alkyne) and cisplatin (cissplatin)50Value of (. mu.M)
The results show that the organic active molecule precursor Olea-alkyne shows moderate antiproliferative activity on several cells, and the metal complex precursor Ru-N3Has little activity on several cells (IC)50More than 100 mu M), the chemically synthesized ruthenium complex Ru-Olea-Chem shows higher anti-tumor activity to a plurality of tumor cells, the activity is slightly lower than that of cis-platinum but far higher than that of organic active molecules and metal complex precursors, and the activity is the sameThe ruthenium complex Ru-Rhein-cell synthesized in the cell also shows high anti-tumor activity to a plurality of tumor cells, and proves that the organic active molecular metal complex synthesized in the cell is helpful for reducing the side effect of the drug, thereby realizing higher drug use and research value.
The anticancer activity of the iridium rheinate complex prepared in example 5 is shown in table 5.
Table 5 shows complexes Ir-Rhein-cell, Ir-Rhein-chem, ruthenium azide complexes (Ir-N) prepared inside and outside cells3) IC of Rhein-alkyne and cisplatin50Value of (. mu.M)
The results show that the organic active molecule precursor Rhein-alkyne shows moderate antiproliferative activity on several cells, and the metal complex precursor Ir-N3Has little activity on several cells (IC)50More than 100 mu M), and the anti-tumor activity of the iridium complex Ir-Rhein-Chem which is chemically synthesized on a plurality of tumor cells is obviously improved. Similarly, the activity of the metal complex Ir-Rhein-cell synthesized in the cell to a plurality of tumor cells is obviously improved, and the antitumor activity equivalent to that of Ir-Rhein-Chem is shown. Therefore, the feasibility of autocatalytic synthesis of antitumor drugs in cells is proved.
The anticancer activity of the coumarin acid ruthenium complex prepared in example 6 is shown in table 6.
Table 6 shows the complexes Ru-Coum-cell, Ru-Coum-chem, osmium azide complex (Ru-N) prepared inside and outside cells3) iC of coumarinic alkyne (Coum-alkyne) and cisplatin (cissplatin)a0Value of (. mu.M)
The results show that the ruthenium complex Ru-Coum-chem which is chemically synthesized shows much higher antitumor activity to several tumor cells than two prodrugs, and is slightly lower than cisplatin. The activity of the ruthenium complex Ru-Coum-cell synthesized in the cell on several tumor cells is equivalent to that of chemically synthesized Ru-Coum-chem. This again demonstrates the feasibility of autocatalytic synthesis of antitumor drugs in cells.
The anticancer activity of the indomethacin ruthenium complex prepared in example 7 is shown in table 7.
Table 7 shows complexes Ru-Indo-cell, Ru-Indo-chem and ruthenium azide complexes (Ru-N) prepared inside and outside cells3) IC of indomethacin alkyne (Indo-alkyne) and cisplatin (cissplatin)50Value of (. mu.M)
The results show that the organic active molecule precursor Indo-alkyne and the metal complex precursor Ru-N3Has little activity on several cells (IC)50Greater than 100 μ M), the chemically synthesized ruthenium complex Ru-Indo-chem shows higher anti-tumor activity to several tumor cells, which is slightly lower than cisplatin but far higher than the activity of organic active molecules and metal complex precursors. Similarly, the antitumor activity of the ruthenium complex Ru-Indo-cell synthesized in the cell on several tumor cells is obviously improved, and the feasibility of synthesizing antitumor drugs by autocatalysis in the cell is proved again.
The metal anticancer drug is applied to the tumor inhibition of tumor-bearing mice.
The method comprises the following steps: and (3) selecting a female Balb/c nude mouse with the weight of 20-25g, inoculating the lung cancer cell A549, and establishing an A549 lung cancer cell tumor-bearing nude mouse animal model. The tumor volume of the tumor-bearing nude mice reaches 50mm3At this time, after obtaining tumor-bearing nude mice, the mice were randomly divided into 5 groups of 6 mice each. Under different conditions, Rhein-alkyne and Ru-N are respectively used3Ru-Rhein-Chem (prepared in example 2), Ru-Rhein-cell (prepared in example 2) and physiological saline were injected intratumorally. The dose of the injection complex was 8mg/1kg of mouse body weight. Dosing once every two days, using vernier caliper at the same timeRecord the size of the tumor (formula: volume ═ length × width)2X 0.5) and nude mouse body weight. After the treatment, the mice were sacrificed, and the tumors and the main organs of the mice, such as heart, liver, spleen, lung, kidney, intestinal tract, spleen, etc., were removed and fixed with formalin. The removed organs were subjected to hematoxylin and eosin (H), respectively&E) And TUNEL apoptosis staining and analysis of mouse anti-tumor effect.
FIG. 3 represents the discovery of two prodrugs Rhein-alkyne and Ru-N21 days after tumor-bearing mice were treated3And the tumor of the mice treated by the normal saline is gradually increased, and the tumor of the mice treated by the Ru-Rhein-Chem and the Ru-Rhein-cell synthesized inside and outside the cells is obviously reduced, which shows that the metal anti-cancer drugs synthesized inside and outside the cells have obvious tumor inhibition effect on the tumor-bearing mice. Figure 4 shows that there was no significant reduction in body weight in mice before and after treatment, and also demonstrates that the drug toxicity was minimal and that there was essentially no harm to the mice. FIG. 5 shows the number of tumor cells observed under a microscope, and shows that two prodrugs Rhein-alkyne and Ru-N3And the number of the mouse tumor cells treated by the normal saline is increased or decreased, and the number of the mouse tumor cells treated by Ru-Rhein-Chem and Ru-Rhein-cell synthesized inside and outside the cells is obviously reduced.
Experiments show that the effect of the metal anticancer drugs prepared in the examples 1 and 3-7 on the tumor inhibition of tumor-bearing mice is equivalent to that of the metal anticancer drug prepared in the example 2.
Claims (10)
1. The high-efficiency low-toxicity anticancer compound synthesized by autocatalysis in cells and living bodies is characterized in that: prepared by chemical synthesis of a metal complex precursor and an organic active molecule precursor outside cells or by bio-orthogonal reaction synthesis inside cells; the metal complex is a platinum, ruthenium, iridium or osmium metal complex, the organic active molecule precursor is an organic active molecule subjected to chemical modification, and the organic active molecule is one of rhein, oleanolic acid, ursolic acid, naphthalimide, coumarinic acid, 9-anthracenecarboxylic acid or indometacin.
2. The cell and in vivo autocatalytically synthesized highly potent and low toxic anticancer compound of claim 1, wherein the anticancer compound has the following general structural formula:
3. The method for synthesizing highly potent and low toxic anticancer compounds according to claim 1, which is synthesized by autocatalysis in vivo, comprising the following steps:
(1) preparation of Metal Complex precursor: dissolving platinum and aryl metal dimer in an organic solvent under the atmosphere of rare gas, adding anion salt into the obtained solution after a chelating ligand coordination reaction, stirring at room temperature, filtering after the reaction, concentrating the filtrate, and putting the filtrate in a refrigerator for recrystallization to obtain a metal complex precursor;
(2) preparation of organic active molecular precursor: under the atmosphere of rare gas, placing organic active molecules and a dehydrating agent in an organic solvent for condensation reaction, removing the solvent after reaction, and purifying a crude product by column chromatography to obtain an organic active molecule precursor;
(3) and (2) adding the metal complex precursor in the step (1), the organic active molecule precursor in the step (2) and a copper catalyst into an organic solvent, removing the solvent after reaction, and further purifying the crude product by column chromatography to obtain the metal complex.
4. The method of claim 3 for synthesizing highly potent and low toxic anticancer compounds by autocatalytic synthesis in cells and vivo, wherein: in the step (1), the aryl metal dimer is a dichloroaryl ruthenium dimer, a dichloroaryl iridium dimer or a dichloroaryl osmium dimer.
5. The method of claim 3 for synthesizing highly potent and low toxic anticancer compounds by autocatalytic synthesis in cells and vivo, wherein: in the step (1), the platinum is potassium chloroplatinite, potassium chloroplatinate or cisplatin.
6. The method of claim 3 for synthesizing highly potent and low toxic anticancer compounds by autocatalytic synthesis in cells and vivo, wherein: in the step (1), the mole ratio of the platinum to the aryl metal dimer to the chelating ligand is 1: 1-1: 2.
7. The method of claim 3 for synthesizing highly potent and low toxic anticancer compounds by autocatalytic synthesis in cells and vivo, wherein: in the step (3), the addition molar ratio of the metal complex precursor to the organic active molecule precursor is 1: 1.
8. The method of claim 3 for synthesizing highly potent and low toxic anticancer compounds by autocatalytic synthesis in cells and vivo, wherein: in the step (3), the copper catalyst is cuprous iodide, copper sulfate or copper chloride.
9. The cell of claim 1 and a method for synthesizing a highly potent and low toxic anticancer compound in vivo by autocatalytic synthesis, comprising: adding the metal complex precursor into a tumor cell culture dish, incubating for 20-30 h in a cell culture box, adding the organic active molecule precursor, continuing to incubate for 20-30 h, washing with PBS, digesting and centrifuging the cells after washing, and collecting; and finally, breaking the cells into fragments by using a cell breaker, filtering the fragments by using a filter membrane, and performing electrospray mass spectrometry to obtain a product of intracellular reaction.
10. Use of the cell of any one of claims 1 or 9 and the highly potent and low toxic anticancer compound autocatalytically synthesized in vivo for the preparation of an antitumor drug or an anticancer drug component.
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