CN115677785A - Diflunisal platinum complex, preparation thereof and application thereof in preparation of anti-cancer drugs - Google Patents
Diflunisal platinum complex, preparation thereof and application thereof in preparation of anti-cancer drugs Download PDFInfo
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 161
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 title claims abstract description 97
- 229960000616 diflunisal Drugs 0.000 title claims abstract description 97
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 65
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 11
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 11
- 230000001093 anti-cancer Effects 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 47
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- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 22
- 238000002156 mixing Methods 0.000 claims description 21
- XLWPIRNXCTZXMI-UHFFFAOYSA-L cyclohexane-1,1-diamine;dichloroplatinum Chemical compound Cl[Pt]Cl.NC1(N)CCCCC1 XLWPIRNXCTZXMI-UHFFFAOYSA-L 0.000 claims description 20
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Images
Abstract
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a platinum diflunisal complex, a preparation method thereof and application thereof in preparing an anti-cancer drug. The invention provides a diflunisal platinum complex which has a structure shown in a formula I. According to the invention, the cyclonexane platinum is modified by diflunisal, the diflunisal has a good anti-inflammatory effect, shows a synergistic effect on the antitumor activity of the cyclonexane platinum, and has the antitumor activity of causing the cell death of cancer cell lines through apoptosis or a mechanism involving free radicals. The results of the examples show that the platinum diflunisal complex with the structure shown in the formula I has the advantages of anticancer, anti-inflammation and high anticancer toxicity, and compared with oxaliplatin, the platinum diflunisal complex has obviously increased toxicity to human ovarian cancer cells (Caov 3), and is safe to use.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a platinum diflunisal complex, a preparation method thereof and application thereof in preparing an anti-cancer drug.
Background
Cancer is one of the most feared diseases in humans, however, it is also a disease with a high prevalence rate. Currently, chemotherapy still occupies an important position in many clinical cancer treatment methods.
Platinum drugs are one of the most representative drugs in the field of chemotherapy drugs, and have irreplaceable effects in clinical treatment of various cancers due to strong anticancer activity, wide action range, unique action mechanism and no generation of cross drug resistance with other drugs.
However, oxaliplatin which is commonly used at present has low lethality to cancer cells.
Disclosure of Invention
The invention aims to provide a platinum diflunisal complex, a preparation method thereof and application thereof in preparing anticancer drugs.
In order to achieve the above purpose, the invention provides the following technical scheme:
the invention provides a diflunisal platinum complex which has a structure shown in a formula I:
the invention provides a preparation method of a diflunisal platinum complex in the technical scheme, which comprises the following steps:
mixing platinum cyclohexyldiamine hydrate with a structure shown in a formula II, diflunisal and a polar solvent, and performing a coordination reaction under an alkaline condition to obtain a diflunisal platinum complex;
preferably, the preparation method of the cyclohexanediamine platinum hydrate with the structure shown in the formula II comprises the following steps:
under the condition of keeping out of the sun, mixing chloroplatinic acid alkali metal salt, trans-1, 2-cyclohexanediamine and a polar solvent to carry out a first reaction to obtain cyclohexanediamine dichloroplatinum with the structure shown in the formula III;
and (3) mixing the cyclohexanediamine dichloroplatinum with the structure shown in the formula III and the aqueous solution of silver nitrate to perform a second reaction to obtain the cyclohexanediamine platinum hydrate with the structure shown in the formula II.
Preferably, the molar ratio of the platinum cyclohexanediamine hydrate to the diflunisal with the structure shown in formula II is 1.
Preferably, the pH value of the coordination reaction is 7-8; the temperature of the coordination reaction is room temperature; the temperature holding time of the coordination reaction is 24h.
Preferably, the mass ratio of the cyclohexanediamine dichloroplatinum with the structure shown in the formula III to the silver nitrate is 1.
Preferably, the mass ratio of the chloroplatinic acid alkali metal salt to the trans-1, 2-cyclohexanediamine is (3-4): 1.
Preferably, the temperature of the first reaction is room temperature, and the holding time of the first reaction is 23h; the temperature of the second reaction is room temperature, and the heat preservation time of the second reaction is 24 hours.
The invention provides an application of the platinum diflunisal complex in the technical scheme or the platinum diflunisal complex prepared by the preparation method in the technical scheme in preparing an anti-cancer drug.
Preferably, the anti-cancer drug comprises an anti-renal clear cell adenocarcinoma drug, an anti-cervical cancer drug or an anti-breast cancer drug.
The invention provides a diflunisal platinum complex which has a structure shown in a formula I. The diflunisal platinum complex provided by the invention utilizes the coordination capacity of hydroxyl and carboxyl on diflunisal, and uses diflunisal to modify cyclohexanediamine platinum to obtain a diflunisal-cyclohexanediamine complex with a structure shown in a formula I; the diflunisal structural unit provides a good anti-inflammatory effect, shows a synergistic effect on the antitumor activity of the cyclohexanediamine platinum structural unit, and has the antitumor activity of causing cell death of cancer cell lines through apoptosis. The results of the embodiments show that the diflunisal platinum complex with the structure shown in formula I has an anti-cancer and anti-inflammatory effect, is high in anti-cancer toxicity effect and low in toxic and side effects, compared with oxaliplatin, the diflunisal platinum complex has the advantages that the toxicity to human ovarian cancer cells (Caov 3) is obviously increased, and the toxicity to human kidney transparent cell adenocarcinoma cells (786-O), human cervical cancer cells (HeLa) and human breast cancer cells (MCF-7) is reduced.
Meanwhile, the diflunisal platinum complex with the structure shown in the formula I has good bioavailability and long half-life due to the fact that diflunisal is a difluoro derivative of salicylic acid, and is favorable for improving compliance and cost benefit to treatment, particularly under the condition of chronic administration.
The invention provides a preparation method of a diflunisal platinum complex in the technical scheme, which comprises the following steps: mixing the cyclohexyldiamine platinum hydrate with the structure shown in the formula II, diflunisal and a polar solvent, and carrying out a coordination reaction under an alkaline condition to obtain the diflunisal platinum complex. The preparation method provided by the invention is simple, low in energy consumption, safe and environment-friendly, avoids harsh reaction conditions, and is suitable for large-scale production.
Drawings
FIG. 1 is a schematic synthesis scheme of a platinum diflunisal complex according to an embodiment of the present invention;
FIG. 2 is a UV spectrum of a platinum diflunisal complex prepared in example 1 of the present invention;
FIG. 3-1 is an infrared spectrum of diflunisal used in example 1 of the present invention;
FIG. 3-2 is an infrared spectrum of cyclohexanediamine platinum hydrate of the structure shown in FIG. 2, prepared in example 1 of the present invention;
FIGS. 3-3 are infrared spectra of platinum diflunisal complexes prepared in example 1 of the present invention;
FIG. 4-1 shows a platinum diflunisal complex prepared in example 1 of the present invention 1 H-NMR chart;
FIGS. 4-2 are graphs of platinum diflunisal complexes prepared in example 1 of the present invention 13 C-NMR chart;
FIG. 5 is a mass spectrum of a platinum diflunisal complex prepared in example 1 of the present invention;
FIG. 6 is a fluorescence plot of platinum diflunisal complex prepared in example 1 of the present invention;
FIG. 7 is a thermogram of a platinum diflunisal complex prepared according to example 1 of the present invention;
FIG. 8-1 shows the 48h cytotoxic activity of the platinum diflunisal complex drug prepared in example 1 of the present invention on human renal clear cell adenocarcinoma cells (786-O);
FIG. 8-2 shows the 48h cytotoxic activity of the platinum diflunisal complex drug prepared in example 1 of the present invention on human ovarian cancer cells (Caov 3);
FIGS. 8 to 3 show the 48h cytotoxic activity of the platinum diflunisal complex drug against human cervical cancer cells (HeLa) prepared in example 1 of the present invention;
FIGS. 8-4 show the 48h cytotoxic activity of the diflunisal platinum complex formulation of example 1 on human breast cancer cells (MCF-7).
Detailed Description
The invention provides a diflunisal platinum complex which has a structure shown in a formula I:
the invention provides a preparation method of a diflunisal platinum complex in the technical scheme, which comprises the following steps:
mixing (hereinafter referred to as first mixing) cyclohexyldiamine platinum hydrate with a structure shown in formula II, diflunisal and a polar solvent (hereinafter referred to as first polar solvent), and performing a coordination reaction under an alkaline condition to obtain a diflunisal platinum complex;
in the present invention, all the preparation starting materials/components are commercially available products well known to those skilled in the art, unless otherwise specified.
In the present invention, the preparation method of cyclohexanediamine platinum hydrate with the structure shown in formula II preferably comprises the following steps:
mixing an alkali platinochloride, trans-1, 2-cyclohexanediamine and a polar solvent (hereinafter referred to as a second polar solvent) under the condition of keeping out of light to perform a first reaction to obtain cyclohexanediamine dichloroplatinum with a structure shown in a formula III;
and (3) mixing the cyclohexanediamine dichloroplatinum with the structure shown in the formula III and the aqueous solution of silver nitrate (hereinafter referred to as third mixing) to perform a second reaction to obtain the cyclohexanediamine platinum hydrate with the structure shown in the formula II.
Under the condition of keeping out of the sun, the chloroplatinic acid alkali metal salt, trans-1, 2-cyclohexanediamine and a second polar solvent are mixed for a second reaction to obtain cyclohexanediamine dichloroplatinum with the structure shown in the formula III.
In the present invention, the alkali metal chloroplatinite is particularly preferably potassium chloroplatinite.
In the present invention, the mass ratio of the alkali metal chloroplatinite to trans-1, 2-cyclohexanediamine is preferably (3 to 4): 1, and preferably (3.2 to 3.5): 1.
In the present invention, the second polar solvent is particularly preferably water. The invention has no special requirement on the dosage of the second polar solvent, and the first reaction carding is ensured to be carried out.
In the present invention, the second mixing preferably comprises the steps of: dissolving chloroplatinic acid alkali metal salt in part of a second polar solvent to obtain chloroplatinic acid alkali metal salt solution; mixing the trans-1, 2-cyclohexanediamine with the rest water to obtain a trans-1, 2-cyclohexanediamine solution; mixing the alkali metal chloroplatinite solution and the trans-1, 2-cyclohexanediamine solution. In the present invention, the volume ratio of the part of the second polar solvent to the remaining second polar solvent is preferably 4.
In the invention, the temperature of the first reaction is preferably room temperature, and the holding time of the first reaction is preferably 23h; the first reaction is preferably carried out under stirring.
In the invention, the first reaction is carried out to obtain a first reaction liquid, and the first reaction liquid is preferably subjected to post-treatment to obtain the cyclohexanediamine dichloroplatinum with the structure shown in the formula III. In the present invention, the post-treatment preferably comprises the steps of: carrying out solid-liquid separation on the first reaction liquid to obtain a solid product; and drying the solid product to obtain the cyclohexanediamine dichloroplatinum with the structure shown in the formula III. In the present invention, the solid-liquid separation is preferably centrifugation, the number of times of centrifugation is preferably 2, and the present invention has no particular requirement on the specific embodiment of the centrifugation. The drying is preferably freeze drying.
After the cyclohexanediamine dichloroplatinum with the structure shown in the formula III is obtained, mixing the cyclohexanediamine dichloroplatinum with the structure shown in the formula III with an aqueous solution of silver nitrate (hereinafter referred to as third mixing) to perform a second reaction to obtain the cyclohexanediamine platinum hydrate with the structure shown in the formula II.
In the present invention, the mass ratio of the cyclohexanediamine dichloroplatinum with the structure represented by the formula III to the silver nitrate is preferably 1.
In the present invention, in the third mixing, the cyclohexanediamine dichloroplatinum having the structure represented by the formula III is preferably used in the form of a suspension of the cyclohexanediamine dichloroplatinum having the structure represented by the formula III. In the present invention, the solvent in the suspension of cyclohexanediaminedichloroplatinum having the structure represented by formula III is preferably water.
In the present invention, the third mixing is preferably performed by mixing a suspension of cyclohexanediamine dichloroplatinum having a structure represented by formula III with the aqueous solution of silver nitrate.
In the present invention, the temperature of the second reaction is preferably room temperature, and the holding time of the second reaction is preferably 24 hours.
In the invention, the second reaction is carried out to obtain a second reaction solution, and the second reaction solution is preferably subjected to post-treatment to obtain the cyclohexanediamine platinum hydrate with the structure shown in the formula II. In the present invention, the post-treatment preferably comprises the steps of: carrying out solid-liquid separation on the second reaction liquid to obtain a liquid-phase product; filtering the liquid-phase product by a membrane to obtain refined filtrate; and drying the refined filtrate to obtain the cyclohexanediamine platinum hydrate with the structure shown in the formula II. In the present invention, the solid-liquid separation is preferably centrifugation. In the present invention, the filtration membrane used for the membrane filtration is preferably a 0.22nM filtration membrane. The drying is preferably freeze drying.
In the present invention, the molar ratio of platinum cyclohexanediamine hydrate to diflunisal having the structure shown in formula II is preferably 1.
In the present invention, the first polar solvent is preferably a polar organic solvent and water; the polar organic solvent is preferably one or more of methanol, dimethyl sulfoxide and dichloromethane, more preferably methanol.
The method preferably adopts methanol which has a low boiling point and is easy to evaporate and recover as the first polar solvent, avoids the purchase and subsequent pollution problems of dichloromethane which is a controlled drug with high toxicity, is safe and environment-friendly, and is suitable for large-scale production.
In the present invention, the ratio of the mass of the diflunisal to the volume of the polar organic solvent is preferably 1g: (580-590) mL.
In the present invention, the first mixing preferably includes the steps of: dissolving the cyclohexanediamine platinum hydrate with the structure shown in the formula II in water to obtain a cyclohexanediamine platinum hydrate aqueous solution with the structure shown in the formula II; dissolving diflunisal in a polar organic solvent to obtain a diflunisal organic solution; adjusting the pH value of the diflunisal organic solvent to be preferably 7-8 by using a pH regulator to obtain an alkaline diflunisal organic solution; and (3) dropwise adding the alkaline diflunisal organic solution into a cyclohexanediamine platinum hydrate aqueous solution with the structure shown in the formula II to perform a coordination reaction.
In the present invention, the pH value of the coordination reaction is 7 to 8. In the invention, a pH regulator is preferably adopted to regulate the pH value of the coordination reaction, the pH regulator is preferably an aqueous sodium hydroxide solution, and the mass percentage content of the aqueous sodium hydroxide solution is preferably 2%.
In the present invention, the temperature of the coordination reaction is preferably room temperature; the incubation time for the coordination reaction is preferably 24h.
The preparation method provided by the invention avoids harsh reaction conditions and is suitable for large-scale production.
In the invention, the coordination reaction is carried out to obtain a coordination reaction liquid, and the coordination reaction liquid is preferably subjected to post-treatment to obtain the diflunisal platinum complex with the structure shown in the formula I. In the present invention, the post-treatment preferably comprises the steps of: carrying out solid-liquid separation on the coordination reaction liquid to obtain a liquid-phase product; and washing and drying the liquid-phase product in sequence to obtain the diflunisal platinum complex with the structure shown in the formula I. In the present invention, the solid-liquid separation is preferably centrifugation, and the washing solvent is preferably methanol. The number of washing is preferably 2. The drying is preferably rotary drying.
The invention provides an application of the platinum diflunisal complex in the technical scheme or the platinum diflunisal complex prepared by the preparation method in the technical scheme in preparing an anti-cancer drug.
In the present invention, the anticancer drug includes an anti-renal clear cell adenocarcinoma drug, an anti-cervical cancer drug or an anti-breast cancer drug.
Compared with oxaliplatin, the diflunisal platinum complex with the structure shown in the formula I provided by the invention is used as a novel platinum anti-cancer drug, and obviously enhances the toxicity of the platinum drug to human ovarian cancer cells (Caov 3) in the aspect of treating cancers.
In order to further illustrate the present invention, the following detailed description of the technical solutions provided by the present invention is made with reference to the accompanying drawings and examples, but they should not be construed as limiting the scope of the present invention.
Example 1
The synthetic scheme for platinum diflunisal complexes according to formula I shown in figure 1:
weighing 0.4215g (1.0 mmol) of potassium chloroplatinite, dissolving the potassium chloroplatinite in 40mL of deionized water, weighing 0.1240 g (1.0 mmol) of trans-1, 2-cyclohexanediamine, diluting the solution with 50mL of water, adding the solution into a water-soluble potassium chloroplatinite solution, stirring the solution at room temperature in a dark place for reaction for 23 hours to generate yellow precipitate, centrifuging the yellow precipitate for 2 times, and freeze-drying the yellow precipitate to obtain the cyclohexanediamine dichloroplatinum with the structure shown in the formula III, wherein the yield is 0.1969 g.
Weighing 0.1652g (0.5 mmol) of cyclohexanediamine dichloroplatinum with the structure shown in the formula III, stirring the solution into a suspension by using water, placing the suspension on a constant-temperature magnetic stirrer for stirring, weighing 0.1573g (0.9 mmol) of silver nitrate, dissolving the silver nitrate by using water, adding the dissolved silver nitrate into the suspension of the cyclohexanediamine dichloroplatinum with the structure shown in the formula III, stirring the solution at room temperature for reaction for 24 hours, and centrifuging the solution to remove AgCl precipitate to obtain a colorless transparent solution. Filtering the colorless transparent solution by using a 0.22mM filter membrane, and freeze-drying to obtain 0.1494g of white powdery solid, namely the cyclohexanediamine platinum hydrate with the structure shown in the formula II, wherein the yield is 30%.
0.0848g (0.32 mmol) of cyclohexanediamine platinum hydrate with the structure shown in formula II is weighed, 80mL of water is used for stirring to form an emulsion white solution, 0.0685g (0.32 mmol) of diflunisal is weighed and dissolved in 40mL of methanol, and 2% sodium hydroxide solution is used for adjusting the pH value of the solution to 7-8. And (3) dropwise adding the solution into the milky white solution, reacting at room temperature for 24 hours, centrifuging the obtained precipitate, washing with methanol for 2 times, and spin-drying to obtain 0.0705g of a diflunisal platinum complex with a structure shown in the formula I as white powder, wherein the yield is 45.7%, and the record is Hdifl-Pt.
Test example 1
The ultraviolet absorption spectrum test of the platinum diflunisal complex with the structure shown in the formula I, which is prepared in the example 1, comprises the following steps:
weighing 1mg of diflunisal, placing in a 10mL disposable white transparent tube, dissolving in 10mL dichloromethane, transferring 1mL solution with 1mL pipette, placing in a new tube, diluting 10 times with dichloromethane to obtain a solution with concentration of 4 × 10 -5 mol/L solution.
Weighing 1mg of cyclohexanediamine platinum hydrate with the structure shown in formula II, placing the weighed platinum hydrate into a 10mL disposable white transparent test tube, adding 10mL of dichloromethane to dissolve the platinum hydrate, using a 1mL liquid transfer gun to transfer 1.25 mL of solution into a new test tube, adding CH 2 Cl 2 Diluting 8 times to obtain the concentration of 4 × 10 -5 mol/L solution.
Weighing 1mg of Hdifl-Pt, placing the Hdifl-Pt in a 10mL disposable white transparent test tube, adding 10mL of dichloromethane to dissolve the Hdifl-Pt, transferring 2.5mL of solution by using a 1mL liquid transfer gun, placing the solution in a new test tube, adding dichloromethane to dilute the solution by 4 times to obtain the Hdifl-Pt with the concentration of 4 x 10 -5 mol/L solution.
10mL of dichloromethane were removed as a reference solution.
The ultraviolet absorption spectrum of the platinum diflunisal complex is shown in FIG. 1.
The ultraviolet absorption peak of the diflunisal platinum complex is obviously reduced compared with that of diflunisal, and a blue shift, lambda, occurs max Left shift, λ max Decrease; in the ultraviolet region (for diflunisal, lambda) max =321 nm, a =0.372, calculated from ∈ = a/CL, ∈ =9.3 × 10 3 Lmol -1 Per cm; for the product Hdifl-Pt, lambda max =313nm, A =0.126, likewise ε =3.15 × 10 3 The broad and strong absorption observed in Lmol-1/cm) is the pi-electron to pi-electron transition in a conjugated system of three double bonds on the benzene ring * As a result of the transition of the inverted orbital, i.e. from π → π * And (4) causing.
Test example 2
The infrared spectrum test of the platinum diflunisal complex with the structure shown in the formula I prepared in the example 1 comprises the following steps:
under the drying condition of infrared lamp irradiation, 1-2 mg of diflunisal and 200mg of pure potassium bromide are ground, uniformly ground and tabletted to prepare diflunisal slices, and the diflunisal slices are placed in a sample groove for sample scanning; in the same way, cyclohexanediamine platinum hydrate flakes and Hdifl-Pt flakes of the structure shown in formula II were prepared and scanned.
The infrared characterization of the diflunisal platinum complex (Hdifl-Pt) prepared by the invention is shown in figure 2. Under the drying condition of infrared lamp irradiation, placing potassium bromide crystal in agate mortar, grinding to obtain fine powder (grain size is about 2 μm), placing proper quantity of said fine powder into mould, using (5-10) × 10 7 Pressing the uniform transparent thin sheet on an oil press under Pa pressure to prepare a potassium bromide reference thin sheet, putting the potassium bromide reference thin sheet into a sample groove, and scanning the background.
In the infrared spectrogram of diflunisal in FIG. 3-1, the deformation vibration peak of C-H on the benzene ring is 843cm -1 Nearby, the symmetric and antisymmetric stretching vibration peaks of C-F are respectively at 1140cm -1 And 1195cm -1 Near, the same symmetric and antisymmetric stretching vibration peaks of-COO-are respectively 1340cm -1 And 1688cm -1 Nearby, the peak of the skeleton stretching vibration of C = C is 1446cm -1 Nearby, the symmetric stretching vibration peak of C-H is 3086cm -1 Nearby.
In the IR spectrogram of the cyclohexanediamine platinum hydrate with the structure shown as the formula II in the figure 3-2, the stretching vibration absorption peak of the amino N-H is 3248cm -1 Nearby, the bending vibration absorption peak of amino N-H is 1585cm -1 Near, the peak of the stretching vibration and the peak of the bending vibration, both of which are shifted to low frequencies than those of the free amino group, are within 509 cm -1 A stretching vibration peak of a Pt-N bond appears, and the coordination of Pt in the complex and N on an amino group is shown.
In the IR spectrum of FIGS. 3-3 Hdiffl-Pt, some of the peaks may be shifted from the peaks in the IR spectrum of diflunisal; for example, 3102cm -1 The absorption peak is 3086cm from the C-H antisymmetric telescopic vibration absorption peak of diflunisal -1 The symmetric and antisymmetric stretching vibration peaks of-COO-obtained by displacement are respectively 1340cm -1 And 1688cm -1 The two nearby peaks are also respectively shifted to 1382cm -1 And 1629cm -1 Nearby 1446cm -1 The nearby C = C skeleton stretching vibration peak is shifted to 1481cm in high frequency -1 At the position of the air conditioner,the symmetric and antisymmetric telescopic vibration peaks of C-F are respectively at 1140cm -1 And 1195cm -1 Nearby parts are displaced to 1143cm respectively -1 And 1253cm -1 At position of 843cm -1 The peak position of C-H deformation vibration in the vicinity of the benzene ring was shifted to 813cm -1 Nearby; the shift of these peaks may be due to the environment and space during the reaction.
Compared with diflunisal, hdiffl-Pt also has a plurality of absorption peaks. For example, at 3244cm -1 And 1589 cm -1 The flexural vibration absorption peak at 2940cm of N-H of the adjacent amino group -1 Has C-H symmetric stretching vibration absorption peak in the cyclane of 966cm -1 In cycloalkane, ring vibration absorption Peak, and 480cm -1 The peak appears in the figure, which shows that the platinum atom in the complex and the nitrogen atom on the amino group generate coordinated Pt-N bonds, of course, the peak can also be obtained by infrared peak shift of the cyclohexanediamine platinum hydrate with the structure shown in the formula II. Wherein the peak of neither diflunisal nor platinum cyclohexanediamine hydrate with the structure shown in formula II is 532cm -1 The stretching vibration peak of the Pt-O bond shows that the platinum atom of the complex is coordinated with the oxygen atom in the carboxyl.
Test example 3
Nuclear magnetic resonance (1H-NMR) measurements were made on a platinum diflunisal complex of the structure shown in formula I prepared in example 1, according to the following method:
6.4mg of Hdifl-Pt is weighed and dissolved in 0.8mL of DMSO-d6, the solution is transferred into a clean and dry nuclear magnetic tube, and an AVANCE III HD-400 type high-resolution superconducting nuclear magnetic resonance spectrometer is used for measurement.
In fig. 4-1, δ =6.44 to 7.91, which is a proton peak on the benzene ring, δ is a proton peak on the cycloalkane at 2.5 to 1.0, where δ =2.37 is a proton peak on the amino group; δ =4.50 is the water peak in the solvent and δ =3.55 is the solvent peak.
In fig. 4-2, δ =104.76 to 134.95 represents CH on a benzene ring, and δ =117.45 to δ =175.1 represents C on a benzene ring; δ =39.37 is CH on cycloalkane, δ =31.71 and δ =24.30 are both CH on cycloalkane 2 。
Test example 4
Mass Spectrometry (MS) measurements of the platinum diflunisal complex of formula I prepared in example 1 were performed by:
6.0mg of Hdifl-Pt was weighed out and dissolved in 0.8mL of DMSO-d6, and the measurement was carried out using a MAT 253 type mass spectrometer.
FIG. 5 is a mass spectrum of Hdifl-Pt, where the relative molecular mass of Hdifl-Pt is 557, the relative molecular mass of DMSO is 78, and 636 is [ Hdifl-Pt + H + DMSO +78 because 636 is 636=557+1+78, i.e. 636 is measured as [ Hdifl-Pt + H + DMSO ]] + . Indicating that its molecular formula is C 19 H 20 F 2 N 2 O 3 Pt。
Test example 5
The fluorescence test of the platinum diflunisal complex of formula I prepared in example 1 was carried out by the following method:
weighing 1mg of diflunisal, dissolving in 4mL of DMSO, transferring 20. Mu.l of the dissolved solution into 4mL of distilled water to obtain a concentration of 10 -4 A diflunisal solution in mol/L; similarly, 1mg of Hdifl-Pt is weighed and dissolved in DMSO, and then diluted by distilled water to obtain the concentration of 10 -4 mol/L Hdifl-Pt solution.
In fig. 6, a is the fluorescence curve of Hdifl; b is the fluorescence curve of Hdifl-Pt. When the emission spectrum of diflunisal is 400nm, a strong fluorescence emission band is shown at 424nm, and when the emission spectrum of Hdifl-Pt is 340nm, a strong fluorescence emission band is shown at 423nm, almost no shift occurs because the benzene ring on the diflunisal is not changed; however, the fluorescence intensity of Hdifl-Pt is significantly lower than that of diflunisal, because of the quenching effect of Pt in the transition from the d-orbital to the pi-orbital (i.e. d → pi) during coordination, thus indirectly indicating that the synthesized product is consistent with the ideal.
Test example 6
The thermogravimetric test of the platinum diflunisal complex of formula I prepared in example 1 was carried out by:
accurately weighing 6.0mg of diflunisal, placing the diflunisal into a sample cell, and performing thermogravimetric analysis on the diflunisal by adopting a DSC/DTA-TG analyzer under the conditions that the scanning temperature range is 25-800 ℃, the heating rate is 10 ℃/min and the gas atmosphere is nitrogen.
Thermogravimetric analysis of platinum cyclohexanediamine hydrate and Hdifl-Pt having the structure shown in formula II was carried out by DSC/DTA-TG analyzer in the same manner as described above.
In FIG. 7, a is the thermogravimetric curve of Hdifl, b is the thermogravimetric curve of cyclohexanediamine platinum hydrate with the structure shown in formula II, and c is the thermogravimetric curve of Hdifl-Pt. As can be seen from the figure, hdifl has a significant mass loss around 200 ℃, with a second mass loss around 300 ℃; the cyclohexanediamine platinum hydrate with the structure shown in the formula II has obvious mass loss near 350 ℃; the mass loss of Hdifl-Pt occurs near 240 ℃ and the second mass loss occurs near 270 ℃, which is probably caused by the modification of diflunisal, and the result shows that the diflunisal is successfully attached to the cyclohexanediamine platinum.
Test example 7
Anticancer activity study of platinum diflunisal complex of formula I prepared in example 1:
four cells were selected for this test example: human renal clear cell adenocarcinoma cells (786-O), human ovarian carcinoma cells (Caov 3), human cervical carcinoma cells (HeLa), and human breast carcinoma cells (MCF-7). The experimental method comprises the following steps: an MTT [3- (4, 5-dimethyl-2-thiazolyl) -2, 5-diphenyl tetrazolium bromide ] method is adopted, and the MTT method is a method for detecting the number of living cells. It mainly utilizes that succinate dehydrogenase contained in mitochondria of living cells can reduce exogenous MTT, and produces water-insoluble blue-purple crystal formazan and precipitates out, while dead cells do not have the function. DMSO can dissolve formazan in cells, and the light absorption value is measured by an enzyme labeling instrument, which can indirectly reflect the number of living cells.
The cancer cells were cultured in DMEM medium supplemented with 10% (v/v) fetal bovine serum under air (5% CO) with 95% humidity 2 ) And a temperature of 37 ℃. The growth inhibitory activity of the three samples (Hdifl, oxaliplatin, hdifl-Pt) on cells was determined by the MTT method. 96-well plates (10000 cells per well, 200. Mu.L). After 24h adherent growth, 100 μ L of samples of different concentrations were added to each well. The cells are cultured for 48h after adding medicine, then 20 mu L of MTT solution (5 mg/mL) is added into each hole, and the mixture is kept stand for 4h for drug actionThen, the mitochondria and MTT in the remaining living cells produced a purple precipitate, the supernatant culture solution was discarded, 200. Mu.L of DMSO was added to dissolve the precipitate, and the absorbance of each well at 490nm was measured on a microplate reader. The percentage of viable cells was calculated relative to the non-medicated control group and was determined in triplicate for each group of experiments. The evaluation formula of the drug effect of the sample on the cancer cells is as follows:
in formula 1, OD sample Is the OD value, OD, of the added sample control Is the OD value, OD, of the no-added sample blank Is the blank OD value without cells. Final IC 50 Values were calculated as the average of three replicates.
The results of half lethal dose of the drug on different cell strains are shown in table 1, and it can be seen from table 1 that diflunisal has no toxicity to four cells, oxaliplatin has different toxicity to the four cells, has small toxicity to Caov3, and has large toxicity to the other three cells; hdifl-Pt has different toxicity to four cells, less toxicity to Caov3 and greater toxicity to three other cells, but Hdifl-Pt has IC for human renal clear cell adenocarcinoma (786-O), human cervical carcinoma (HeLa) and human breast cancer (MCF-7) 50 The values were all increased compared to oxaliplatin, indicating that Hdifl-Pt reduced toxicity to human renal clear cell adenocarcinoma cells (786-O), human cervical carcinoma cells (HeLa), and human breast cancer cells (MCF-7). In addition, compared with oxaliplatin, hdifl obviously enhances the toxicity of platinum drugs on human ovarian cancer cells (Caov 3).
TABLE 1 results of median lethal doses for different cell lines
| Medicine | 786-O(μM) | Caov3(μM) | Hela(μM) | MCF-7(μM) |
| Hdifl | >100 | >100 | >100 | >100 |
| Oxaliplatin | 8.6±2.8 | 58.1±1.9 | 6.8±1.3 | 1.8±0.6 |
| Hdifl-Pt | 18.4±4.4 | 27.4±1.8 | 20.1±4.6 | 11.7±3.7 |
Although the above embodiments have been described in detail, they are only a part of the embodiments of the present invention, not all of the embodiments, and other embodiments can be obtained without inventive step according to the embodiments, and all of the embodiments belong to the protection scope of the present invention.
Claims (10)
1. A diflunisal platinum complex is characterized by having a structure shown in formula I:
2. the method of preparing a platinum diflunisal complex of claim 1 comprising the steps of:
mixing platinum cyclohexyldiamine hydrate with a structure shown in a formula II, diflunisal and a polar solvent, and performing a coordination reaction under an alkaline condition to obtain a diflunisal platinum complex;
3. the preparation method of claim 2, wherein the preparation method of the cyclohexanediamine platinum hydrate with the structure shown in formula II comprises the following steps:
under the condition of keeping out of the sun, mixing chloroplatinic acid alkali metal salt, trans-1, 2-cyclohexanediamine and a polar solvent for carrying out a first reaction to obtain cyclohexanediamine dichloroplatinum with the structure shown in formula III;
and (3) mixing the cyclohexanediamine dichloroplatinum with the structure shown in the formula III and the aqueous solution of silver nitrate to perform a second reaction to obtain the cyclohexanediamine platinum hydrate with the structure shown in the formula II.
4. The method according to claim 2, wherein the molar ratio of the platinum cyclohexanediamine hydrate to the diflunisal having the structure shown in formula II is 1.
5. The production method according to claim 2 or 4, wherein the pH value of the coordination reaction is 7 to 8; the temperature of the coordination reaction is room temperature; the heat preservation time of the coordination reaction is 24 hours.
6. The preparation method according to claim 3, wherein the mass ratio of the cyclohexanediamine dichloroplatinum with the structure shown in the formula III to the silver nitrate is 1.
7. The method according to claim 3, wherein the mass ratio of the alkali metal chloroplatinite to trans-1, 2-cyclohexanediamine is (3-4): 1.
8. The preparation method according to claim 3, wherein the temperature of the first reaction is room temperature, and the holding time of the first reaction is 23 hours; the temperature of the second reaction is room temperature, and the heat preservation time of the second reaction is 24h.
9. Use of the platinum diflunisal complex of claim 1 or the platinum diflunisal complex prepared by the method of any one of claims 2 to 8 in the preparation of an anti-cancer medicament.
10. The use of claim 9, wherein the anti-cancer drug comprises an anti-renal clear cell adenocarcinoma drug, an anti-cervical cancer drug, or an anti-breast cancer drug.
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| CN1557822A (en) * | 2004-02-11 | 2004-12-29 | 昆明贵金属研究所 | Platinum complex having anti-tumor activity |
| CN1683379A (en) * | 2005-02-22 | 2005-10-19 | 昆明贵金属研究所 | Novel liposoluble platinum (II) anti-tumor ligand |
| WO2015013566A1 (en) * | 2013-07-25 | 2015-01-29 | Nemucore Medical Innovations, Inc. | Nanoemulsions of hydrophobic platinum derivative |
| CN107296794A (en) * | 2017-07-27 | 2017-10-27 | 中国药科大学 | Amphipathic non-steroidal anti-inflammatory closes platinum nanoparticle and preparation method thereof |
| CN108014852A (en) * | 2016-10-31 | 2018-05-11 | 韩国科学技术研究院 | For the catalyst of synthesizing methanol or its precursor, the preparation method of catalyst and the method using Catalyst Production methanol or its precursor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1557822A (en) * | 2004-02-11 | 2004-12-29 | 昆明贵金属研究所 | Platinum complex having anti-tumor activity |
| CN1683379A (en) * | 2005-02-22 | 2005-10-19 | 昆明贵金属研究所 | Novel liposoluble platinum (II) anti-tumor ligand |
| WO2015013566A1 (en) * | 2013-07-25 | 2015-01-29 | Nemucore Medical Innovations, Inc. | Nanoemulsions of hydrophobic platinum derivative |
| CN108014852A (en) * | 2016-10-31 | 2018-05-11 | 韩国科学技术研究院 | For the catalyst of synthesizing methanol or its precursor, the preparation method of catalyst and the method using Catalyst Production methanol or its precursor |
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