CN111925398B - FTO (fluorine-doped tin oxide) small-molecule inhibitor palladium complex and synthesis method thereof - Google Patents
FTO (fluorine-doped tin oxide) small-molecule inhibitor palladium complex and synthesis method thereof Download PDFInfo
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 title claims abstract description 122
- 229910052763 palladium Inorganic materials 0.000 title claims abstract description 57
- 238000001308 synthesis method Methods 0.000 title claims abstract description 16
- 239000003112 inhibitor Substances 0.000 title claims abstract description 11
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/006—Palladium compounds
- C07F15/0066—Palladium compounds without a metal-carbon linkage
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention discloses an FTO decimal fractionThe palladium complex of the sub-inhibitor and the synthesis method thereof are that the thiosemicarbazide is dissolved in anhydrous CH3OH, adding 2-pyridine formaldehyde, refluxing, filtering, volatilizing filtrate at room temperature to precipitate crystals, and adding anhydrous CH3OH washing to obtain a ligand; taking ligand and PdCl2Adding anhydrous CH into a round-bottom flask3Dissolving OH, carrying out reflux reaction, filtering while the solution is hot, volatilizing the filtrate at room temperature, separating out solids, and recrystallizing by using absolute ethyl alcohol to obtain palladium complex crystals. The invention further performs various tumor cell proliferation inhibition activity experiments on the synthesized palladium complex, performs FTO protein activity test experiments and determines the interaction between the palladium complex and the FTO protein, thereby proving that the palladium complex can be used as an alternative of FTO protein small-molecule inhibitors. The synthesis method is simple to operate and convenient to implement.
Description
Technical Field
The invention relates to an FTO (fluorine-doped tin oxide) micromolecule inhibitor, in particular to a palladium complex taking 2-pyridinecarboxaldehyde thiosemicarbazone as a ligand and a synthesis method thereof, and the influence of the palladium complex on the activity of FTO protein is verified.
Background
The FTO (fat mass and obesity associated) gene, also known as the obesity gene, is the most established obesity susceptibility gene that has been confirmed by studies to date. Recent researches find that the obesity gene FTO is also closely related to cancers, and can cause various cancers, so that a potential target is provided for developing effective targeted therapeutic drugs. In 2011, FTO was identified as a demethylase that regulates RNA methylation modification. This finding reveals that the modification process of m6A in cells is dynamically reversible, and raises the hot tide of research on m6A modification and protein biology regulation, and gradually forms a new direction of epigenetics research with m6A modification as the core content. Later, it was discovered that FTO gene is one of the important oncogenes in cancer development such as leukemia, breast cancer, glioblastoma. FTO plays a crucial role in the development and progression of cancer, it regulates cancer stem cells and immune escape. In other words, FTO promotes growth, self-renewal, metastasis and immune escape of cancer cells.
Thiosemicarbazones are chelating agents with remarkable anti-tumor activity, at present, many researches mainly study on metal complexes such as thiosemicarbazone copper and platinum, the research on anti-tumor thiosemicarbazone palladium complexes is less, and particularly, the synthesis of palladium complexes with FTO protein inhibition activity is rarely reported.
Disclosure of Invention
The invention aims to provide an FTO small-molecule inhibitor palladium complex and a synthesis method thereof, wherein the palladium complex is synthesized by taking 2-pyridylaldehyde thiosemicarbazone as a ligand, and experiments prove that the palladium complex has obvious FTO activity inhibition effect and good activity on mouse breast cancer cells.
The technical scheme for realizing the purpose of the invention is as follows:
an FTO small molecule inhibitor palladium complex, the structural formula of which is shown as the following formula C1-C5:
the synthesis route of the palladium complex shown by the formula C1-C5 is as follows:
the synthesis method of the palladium complex shown as the formula C1-C4 comprises the following steps:
(1) dissolving thiosemicarbazide in anhydrous CH3Adding 2-pyridylaldehyde into OH, condensing and refluxing at 65 ℃, filtering, volatilizing the filtrate at room temperature to separate out crystals, and washing with anhydrous methanol to obtain a ligand;
(2) taking ligand and PdCl2In a flask, anhydrous CH is added3Dissolving OH, condensing and refluxing at 80 ℃, filtering while hot, volatilizing the filtrate at room temperature, separating out solids, and recrystallizing with absolute ethyl alcohol to obtain palladium complex crystals.
The mol ratio of the thiosemicarbazide to the 2-pyridylaldehyde in the step (1) is 1: 1; the solvent is preferably used in an amount capable of dissolving the raw materials participating in the reaction.
The ligand in the step (2) and PdCl2In a molar ratio of 1: 1; the solvent is preferably used in an amount capable of dissolving the raw materials participating in the reaction.
The synthesis method of the palladium complex shown as the formula C5 comprises the following steps:
dissolving thiosemicarbazide in anhydrous CH3OH, adding 2-pyridylaldehyde and PdCl2In a flask, carrying out condensation reflux reaction at 80 ℃, filtering while the solution is hot, volatilizing the filtrate at room temperature, and separating out transparent yellow crystals to obtain a palladium complex C5;
the mol ratio of the thiosemicarbazide to the 2-pyridylaldehyde to the PdCl2 is 1:1: 1;
the solvent is preferably used in an amount capable of dissolving the raw materials participating in the reaction.
The method comprises the steps of carrying out condensation reaction on 2-pyridylaldehyde and thiosemicarbazide to obtain a ligand; the ligand is further reacted with PdCl2The palladium complex is obtained after the reaction. The invention also provides a cell activity experiment of the C1-C5 palladium complex on MCF-7 and MDA-MB-231 tumor cells, and the result shows that the palladium complex has stronger activity inhibition on MDA-MB-231 tumor cells, but has very low toxicity to normal cells and is far lower than that of cisplatin.
The invention further performs FTO protein activity test experiments on the synthesized C1-C5 palladium complex and determines the interaction between the palladium complex and the FTO protein, thereby proving that the palladium complex has good inhibition effect on the FTO protein, can effectively act on tumors, and can be used as an alternative of FTO protein small molecule inhibitors. The synthesis method is simple to operate and convenient to implement.
Drawings
FIG. 1 is a single crystal structural diagram of a C1 palladium complex synthesized in example 1;
FIG. 2 is a single crystal structural diagram of a C2 palladium complex synthesized in example 2;
FIG. 3 is a single crystal structural diagram of a C3 palladium complex synthesized in example 3;
FIG. 4 is a single crystal structural diagram of a C4 palladium complex synthesized in example 4;
FIG. 5 is a single crystal structural diagram of a C5 palladium complex synthesized in example 5;
FIG. 6 is a graph showing the results of an experiment for inhibiting the in vitro activity of FTO protein using palladium complex C1-C5.
Detailed Description
The present disclosure will be better understood from the following detailed description taken in conjunction with the accompanying drawings, which are set forth below, but are not intended to limit the present disclosure to the following embodiments.
Example 1:
the specific synthesis method of the C1 palladium complex comprises the following steps:
(1) dissolving 3mmol of thiosemicarbazide in 25ml of anhydrous methanol, adding 3mmol of 2-pyridylaldehyde, condensing and refluxing for 4h at 65 ℃, filtering, volatilizing the filtrate at room temperature to separate out transparent colorless crystals, and washing for 2-3 times by using 10ml of anhydrous methanol to obtain ligand L1(0.4435g, 82.1 percent, transparent white crystals);
Yield:0.4435g，82.1％,C7H8N4S：C,46.65；H,4.47；N,31.09；S,17.79.Found：C,46.58；H,4.37；N,31.19；S,17.89.IR,cm-1:3426(s,amide),3269(s,NH),3168(m,aromatic hydrogen),1614(s),1538(s),1468(s,aromatic),1297(m,C＝N),1108(s,thioamide),877(m,C-H),776(m,C＝S),624(m)；
(2) 0.1mmol of ligand L1 and 0.1mmol of PdCl were weighed out2Adding 20ml of anhydrous methanol into a 50ml flask for dissolving, then carrying out condensation reflux at 80 ℃ for 4h, filtering while the solution is hot, standing the filtrate at room temperature, slowly volatilizing, separating out yellow solid, and recrystallizing by using anhydrous ethanol to obtain palladium complex C1(0.02546g,79.6 percent, yellow crystals), wherein the crystal structure and data are stored in the application number of Cambridge crystal data center (CCDC database): no. 2019138; acquiring diffraction data by using a single crystal diffractometer, and analyzing the crystal structure of the palladium complex C1 by using OLEX 2 software, as shown in FIG. 1;
Yield:0.02546g，79.6％,C7H7ClN4PdS：C,26.18；H,2.20；Cl,11.04；N,17.45；Pd,33.14；S,9.99.Found：C,26.31；H,2.17；Cl,10.94；N,17.24；Pd,33.35；S,9.95.IR,cm-1:3437(s,amide),3067(m,aromatic hydrogen),1501(s),1437(s),1319(s,aromatic),1253(m,C＝N),1158(s,thioamide),755(m,C-H),691(m,C＝S),613(m)。
example 2:
the specific synthesis method of the C2 palladium complex comprises the following steps:
(1) dissolving 3mmol of 4-methyl-3-thiosemicarbazide in 25ml of anhydrous methanol, adding 3mmol of 2-pyridylaldehyde, condensing and refluxing for 4h at 65 ℃, filtering, volatilizing the filtrate at room temperature, separating out transparent colorless crystals, and washing for 2-3 times by using 10ml of anhydrous methanol to obtain a ligand L2(0.4605, 79.1 percent, transparent white crystals);
Yield:0.4605g，79.1％，C8H10N4S：C,49.46；H,5.19；N,28.84；S,16.51.Found：C,49.51；H,5.21；N,28.73；S,16.41.IR,cm-1:3288(s,amide),3138(s,NH),3045(m,aromatic hydrogen),1551(s),1527(s),1459(s,aromatic),1264(m,C＝N),1038(s,thioamide),885(m,C-H),779(m,C＝S),675(m)；
(2) 0.1mmol of ligand L2 and 0.1mmol of PdCl were weighed out2Adding 20ml of anhydrous methanol into a 50ml flask for dissolving, then carrying out condensation reflux at 80 ℃ for 4h, filtering while the solution is hot, standing the filtrate at room temperature, slowly volatilizing, separating out yellow solid, and recrystallizing with anhydrous ethanol to obtain palladium complex C2(0.02785g,83.4 percent, yellow crystals), wherein the crystal structure and data are stored in the application number of Cambridge crystal data center (CCDC database): no. 2019136; acquiring diffraction data by using a single crystal diffractometer, and analyzing the crystal structure of the palladium complex C2 by using OLEX 2 software, as shown in FIG. 2;
Yield:0.02785g，83.4％，C8H9ClN4PdS：C,28.67；H,2.71；Cl,10.58；N,16.72；Pd,31.76；S,9.57.Found：C,28.71；H,2.73；Cl,10.51；N,16.74；Pd,31.73；S,9.58.IR,cm-1:3425(s,amide),3287(s,NH),3143(m,aromatic hydrogen),1642(s),1529(s),1431(s,aromatic),1246(m,C＝N),1152(s,thioamide),881(m,C-H),776(m,C＝S),618(m)。
example 3:
the specific synthesis method of the C3 palladium complex comprises the following steps:
(1) dissolving 3mmol of 4, 4-dimethyl-3-thiosemicarbazide in 25ml of anhydrous methanol, adding 3mmol of 2-pyridylaldehyde, condensing and refluxing for 4h at 65 ℃, filtering, volatilizing the filtrate at room temperature to separate out transparent colorless crystals, and washing for 2-3 times by using 10ml of anhydrous methanol to obtain ligand L3(0.5194g, 83.2% of yellow crystals);
Yield:0.5194g，83.2％，C9H12N4S：C,51.90；H,5.81；N,26.90；S,15.39.Found：C,51.88；H,5.91；N,26.95；S,15.49.IR,cm-1:3436(s,amide),3257(s,NH),2974(m,aromatic hydrogen),1585(s),1525(s),1356(s,aromatic),1266(m,C＝N),1079(s,thioamide),899(m,C-H),781(m,C＝S),634(m)；
(2) 0.1mmol of ligand L3 and 0.1mmol of PdCl were weighed out2Adding 20ml of anhydrous methanol into a 50ml flask for dissolving, then carrying out condensation reflux at 80 ℃ for 4h, filtering while the solution is hot, standing the filtrate at room temperature, slowly volatilizing, separating out yellow solid, and recrystallizing with anhydrous ethanol to obtain Pd complex C3(0.02957g,85.0 percent, yellow crystals), wherein the crystal structure and data are stored in the application number of Cambridge crystal data center (CCDC database): no. 2019137; acquiring diffraction data by using a single crystal diffractometer, and analyzing the crystal structure of the palladium complex C3 by using OLEX 2 software, as shown in FIG. 3;
Yield:0.02957g，85.0％，C9H11ClN4SPd：C,29.91；H,3.07；Cl,9.81；N,15.50；S,8.87；Sn,32.84.Found：C,29.92；H,3.06；Cl,9.83；N,15.48；S,8.87；Sn,32.84.IR,cm-1:3445(s,amide),2922(m,aromatic hydrogen),1509(s),1381(s),1314(s,aromatic),1248(m,C＝N),1124(s,thioamide),910(m,C-H),772(m,C＝S),597(m)。
example 4:
the specific synthesis method of the C4 palladium complex comprises the following steps:
(1) dissolving 3mmol of 4-phenylthiosemicarbazide in 25ml of anhydrous methanol, adding 3mmol of 2-pyridylaldehyde, condensing and refluxing for 4h at 65 ℃, filtering, volatilizing the filtrate at room temperature to separate out transparent colorless crystals, and washing for 2-3 times by using 10ml of anhydrous methanol to obtain a ligand L4(0.6384g, 83.1 percent, transparent white crystals);
Yield:0.6384g，83.1％，C13H12N4S：C,60.91；H,4.72；N,21.86；S,12.51.Found：C,60.93；H,4.79；N,21.76；S,12.59.IR,cm-1:3453(s,amide),3308(s,NH),2951(m,aromatic hydrogen),1596(s),1550(s),1327(s,aromatic),1256(m,C＝N),1190(s,thioamide),923(m,C-H),753(m,C＝S),692(m)；
(2) 0.1mmol of ligand L4 and 0.1mmol of PdCl were weighed out2Adding 20ml of anhydrous methanol into a 50ml flask for dissolving, then carrying out condensation reflux at 80 ℃ for 4h, filtering while the solution is hot, standing the filtrate at room temperature, slowly volatilizing, separating out yellow solid, and recrystallizing with anhydrous ethanol to obtain palladium complex C4(0.03231g,81.6 percent, yellow crystals), wherein the crystal structure and data are stored in the application number of Cambridge crystal data center (CCDC database): no. 2019125; acquiring diffraction data by using a single crystal diffractometer, and analyzing the crystal structure of the palladium complex C4 by using OLEX 2 software, as shown in FIG. 4;
Yield：0.03231g，81.6％，C13H11ClN4SPd：C,38.13；H,2.71；Cl,8.66；Sn,28.99；N,13.68；S,7.83.Found：C,38.12；H,2.72；Cl,8.69；Sn,28.99；N,13.65；S,7.83.IR,cm-1:3447(s,amide),3317(s,NH),3261(m,aromatic hydrogen),1600(s),1536(s),1487(s,aromatic),1317(m,C＝N),1122(s,thioamide),895(m,C-H),755(m,C＝S),692(m)。
example 5:
the specific synthesis method of the C5 palladium complex comprises the following steps:
dissolving 1mmol of thiosemicarbazide in 25ml of anhydrous CH3OH, adding 1mmol of 2-pyridylaldehyde and 1mmol of PdCl2In a flask, the mixture is condensed and refluxed for 4 hours at 80 ℃, filtered while hot, and the filtrate is volatilized at room temperature to precipitate transparent yellow crystals, so that palladium complex C5(0.0261g, 78.4%, yellow crystals) is obtained, and the crystal structure and data of the palladium complex C5 are stored in a Cambridge crystal data center (CCDC database) application number: no. 2019135; obtaining diffraction data by single crystal diffractometer, and analyzing palladium coordination by using OLEX 2 softwareCrystal structure of C5, as shown in FIG. 5;
Yield:0.03261g，78.4％，C14H19Cl1N4PdS：C,40.30；H,4.59；Cl,8.50；N,13.43；Pd,25.50；S,7.68.Found：C,40.11；H,4.77；Cl,8.12；N,13.73；Pd,25.42；S,7.76.IR,cm-1:3436(s,amide),2928(m,aromatic hydrogen),1635(s),1540(s),1486(s,aromatic),1387(m,C＝N),1128(s,thioamide),897(m,C-H),760(m,C＝S),696(m)。
the palladium complexes of examples 1 to 5 were synthesized with the corresponding ligands and PdCl2In a sealed glass bottle, acetone and anhydrous CH are added dropwise according to the ratio of 1:13Dissolving OH, sealing in vacuum, and standing in a drying oven at 80 ℃ to obtain the palladium complex.
To illustrate the palladium complexes of the present invention using 2-pyridinecarboxaldehyde thiosemicarbazone as a ligand, the applicant conducted in vitro tumor cell proliferation inhibition activity experiments on the palladium complexes C1-C5 prepared in examples 1-5:
1. experimental methods and materials
(1) Cell lines and cell cultures
The activity of human breast cancer cell strain (MCF-7), human cervical cancer cell strain (Hela) and human normal mammary gland liver cell (HBL-100) are selected for activity study in the experiment. All cell lines were cultured in DMEM medium containing 10% calf serum and 100U/mL streptomycin at 37 ℃ with 5% CO by volume2Culturing in an incubator.
(2) Preparation of test Compounds
The purity of the used test drug is more than or equal to 95 percent, the DMSO stock solution is diluted by physiological buffer solution to be prepared into 5mmol/L final solution, wherein the concentration of the cosolvent DMSO is less than or equal to 1 percent, and the degree of inhibition of the compound on the growth of various tumor cells under the concentration is tested.
(3) Cell growth inhibition assay (MTT method)
(I) Taking tumor cells in a logarithmic growth phase, digesting the tumor cells by trypsin, preparing a cell suspension with the concentration of 5000/mL by using a culture solution containing 10% calf serum, inoculating 180 mu L of the cell suspension into a 96-well culture plate, and enabling the concentration of cells to be detected to be 1000-10000/well (the marginal wells are filled with sterile PBS);
(II)5％CO2incubating for 24h at 37 ℃ until a cell monolayer is paved on the bottom of the hole, adding 20 mu L of medicine with a certain concentration gradient into each hole, and arranging 5 compound holes in each concentration gradient;
(III)5％CO2incubating at 37 ℃ for 48h until the observation is carried out under an inverted microscope;
(IV) adding 10 mu L of MTT solution (5mg/mL PBS, namely 0.5% MTT) into each well, and continuing to culture for 4-6 h;
(V) terminating the culture, carefully removing the culture medium in the wells, adding 100. mu.L of DMSO into each well to sufficiently dissolve the formazan precipitate, uniformly mixing the precipitate with an oscillator, and measuring the optical density of each well with a microplate reader at a wavelength of 570nm and a reference wavelength of 450 nm;
(VI) determining the number of viable cells based on the measured optical density (OD value), the greater the OD value, the more active the cells. Using the formula:
tumor cell growth inhibition (%) [ (1-mean OD of experimental group)/(mean OD of control group) ] ×%;
IC50and (3) determination: by using the method, each compound is required to be provided with a concentration gradient which comprises a plurality of (generally 5-8) concentrations, each concentration is also required to be provided with 3-5 secondary holes, the inhibition rate of each different concentration is obtained through experiments, and then the IC of the compound is calculated in SPSS software50The values, results are shown in Table 1.
Table 1: the IC50 value (mu M) of the palladium complex C1-C5 on different cell lines shows that the lower the value, the better the inhibition activity of the compound is.
2. Verification of the inhibition effect of the palladium complex C3 on the activity of the FTO enzyme
The study was carried out using 15-mer ssRNA (5' -CUUGUCA (m6A) CAGCAGA-3) as substrate. The specific experimental procedure was to prepare 50. mu.L of a reaction system containing 50mM Tris-HCI (pH 7.5), 2.0. mu.M ssRNA,2.0nM FTO,1.0mM alpha KG, 280. mu.M (NH)2Fe(SO4)22mM L-ascorbic acid, Compound C3 (0.2. mu.M, 0.8. mu.M, 2.0. mu.M, 4.0. mu.M, 10.0. mu.M, 20.0. mu.M and 100.0. mu.M) and H 20, centrifuging, incubating for 0.5h at room temperature, and then reacting for 5min at 95 ℃ to inactivate the FTO protein. After centrifugation, nuclease P1(1Unit) and ammonium acetate (100. mu.M, 5. mu.L) were added to the reaction system, and the reaction was carried out at 42 ℃ for 4 hours to cleave ssRNA. After centrifugation, ammonium bicarbonate (1.0M, 5. mu.L) and alkaline phosphatase CIP (0.5Unit) were added to the reaction system, and the mixture was reacted at 37 ℃ for 3 hours to dephosphorylate the reaction mixture. Centrifugation and detection by Thermo TSQ Quantum Ultra LC/MS (Waters XTerra @ MS C183.5. mu.M 2.1X100mm column, sample size 10. mu.L, flow rate 180. mu.L/min). And quantitative analysis is carried out by comparing with a standard curve of pure nucleotide, the result is shown in figure 6, the IC50 value of the complex C3 on the ssRNA demethylation inhibition effect of FTO is 4.52 mu M, and the complex C3 shows a dose-dependent relationship, which indicates that the palladium complex C1-C5 is a competitive or allosteric FTO small-molecule inhibitor.
Claims (2)
1. The use of a palladium complex in the preparation of an FTO small molecule inhibitor is characterized in that the structural formula of the palladium complex is shown as the following formulas C3 and C5:
2. use of a palladium (ll) complex according to claim 1 in the preparation of an FTO small molecule inhibitor, wherein the synthesis route of the palladium complex represented by C3 and C5 is as follows:
the synthesis method of the palladium complex shown as C3 comprises the following steps:
(1) dissolving 4, 4-dimethyl-3-thiosemicarbazide in anhydrous CH3OH, adding 2-pyridylaldehyde, condensing and refluxing at 65 ℃, filtering, volatilizing the filtrate at room temperature to separate out crystals, and washing with anhydrous CH3OH to obtain a ligand L3;
the molar ratio of the thiosemicarbazide to the 2-pyridylaldehyde is 1: 1;
(2) putting ligand L3 and PdCl2 into a flask, adding anhydrous CH3OH for dissolving, carrying out condensation reflux reaction at 80 ℃, filtering while hot, volatilizing the filtrate at room temperature, separating out solids, and recrystallizing with anhydrous ethanol to obtain palladium complex crystals;
the molar ratio of the ligand L3 to PdCl2 is 1: 1;
the synthesis method of the palladium complex shown as C5 comprises the following steps:
dissolving thiosemicarbazide in anhydrous CH3OH, adding 2-pyridylaldehyde and PdCl2 into a flask, carrying out condensation reflux reaction at 80 ℃, filtering while hot, volatilizing the filtrate at room temperature, and separating out transparent yellow crystals to obtain a palladium complex C5;
the mol ratio of the thiosemicarbazide to the 2-pyridylaldehyde to the PdCl2 is 1:1: 1.
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