CN114349794A - Diphosphonic acid platinum complex and synthesis method and application thereof - Google Patents
Diphosphonic acid platinum complex and synthesis method and application thereof Download PDFInfo
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- CN114349794A CN114349794A CN202111457415.8A CN202111457415A CN114349794A CN 114349794 A CN114349794 A CN 114349794A CN 202111457415 A CN202111457415 A CN 202111457415A CN 114349794 A CN114349794 A CN 114349794A
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 108
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 56
- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical compound OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims abstract description 33
- 229960003180 glutathione Drugs 0.000 claims abstract description 16
- NJWIMFZLESWFIM-UHFFFAOYSA-N 2-(chloromethyl)pyridine Chemical compound ClCC1=CC=CC=N1 NJWIMFZLESWFIM-UHFFFAOYSA-N 0.000 claims abstract description 14
- 108091006905 Human Serum Albumin Proteins 0.000 claims abstract description 12
- 102000008100 Human Serum Albumin Human genes 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 12
- 108010024636 Glutathione Proteins 0.000 claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 11
- 230000000694 effects Effects 0.000 claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 11
- 229940079593 drug Drugs 0.000 claims abstract description 10
- 201000008968 osteosarcoma Diseases 0.000 claims abstract description 10
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 206010059866 Drug resistance Diseases 0.000 claims abstract description 8
- 239000003446 ligand Substances 0.000 claims abstract description 7
- 238000010791 quenching Methods 0.000 claims abstract description 7
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 6
- AIOVVDWJUJBWCM-UHFFFAOYSA-N CCOP(C(CC1=NC=CC=C1)(CC1=NC=CC=C1)P(OCC)(OCC)=O)(OCC)=O Chemical compound CCOP(C(CC1=NC=CC=C1)(CC1=NC=CC=C1)P(OCC)(OCC)=O)(OCC)=O AIOVVDWJUJBWCM-UHFFFAOYSA-N 0.000 claims abstract description 5
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- 239000002244 precipitate Substances 0.000 claims description 20
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 20
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Abstract
The invention discloses a diphosphonic acid platinum complex and a preparation method thereof, wherein a non-leaving group of the complex is composed of ammonia and a diphosphonic acid bipyridine ligand, and the diphosphonic acid bipyridine ligand and a platinum center form an eight-membered ring. The synthesis method of the complex comprises 2-chloromethylpyridine synthesis, [1, 3-di (2-pyridyl) propane-2, 2-diyl ] di (phosphonic acid) tetraethyl ester synthesis and diphosphonic acid platinum complex synthesis. The complex is difficult to chelate with glutathione, so that the side effect caused by the combination of platinum drugs and glutathione can be greatly reduced, and the complex can be used for overcoming the drug resistance of the platinum drugs; the complex has certain inhibiting effect on osteosarcoma cells; the complex may also interact with human serum albumin by means of static quenching. The research provides a new strategy for solving the problem of the drug resistance of the diphosphonic acid platinum and makes good technical progress.
Description
Technical Field
The invention belongs to the field of chemical biology, and particularly relates to synthesis and biological application of a diphosphonic acid platinum complex.
Background
Cisplatin, also known as cis-diamminedichloroplatinum, is a clinically used platinum-based anticancer drug. The platinum anticancer drugs such as cisplatin and the like can effectively improve the prognosis of osteosarcoma, and the 5-year survival rate of osteosarcoma patients is improved to 60-80%. The main action mechanism of cisplatin is to inhibit the proliferation of rapidly dividing cells by damaging DNA, but the acquired drug resistance and serious toxic and side effects of cisplatin greatly limit the wide use of platinum drugs.
Glutathione (GSH) is a soluble tripeptide formed by combining glutamic acid, cysteine and glycine, is a non-protein tripeptide rich in cells, has the functions of antioxidation and integration detoxification, and has the intracellular concentration of 0.5-10 mM. GSH as a nucleophile that chelates with platinum (II) to form Pt (GS)2The chelate reduces DNA damage generated by bivalent platinum, and reduces the curative effect of the platinum drugs. Thus, the interaction between GSH and pt (ii) complexes is believed to play a critical role in the mechanisms associated with platinum-based drug inactivation, development of drug resistance, and toxic side effects.
Bisphosphonates (BPs) have long been used to treat bone diseases such as osteoporosis, bone metastasis and multiple myeloma, and are the most commonly used bone targeting molecules in the design of platinum complexes. The Pt-BP complex was found to selectively inhibit Osteosarcoma (OS) cell line U2OS, exhibiting lower acute toxicity, and some of the complexes were found to be dual targeting complexes.
Lipophilic refers to the ability of a substance to dissolve in fats, oils, lipids or non-polar solvents. The lipophilicity parameter (log P) is a key factor affecting transport of a substance across a membrane, and the transmembrane capacity of a substance can be preliminarily judged by its lipophilicity parameter.
DNA is the main target of platinum antineoplastic drugs. To gain a more thorough understanding of the antitumor activity of DBPP, the present patent investigated the effect of DBPP on the conformation of calf thymus DNA (CT-DNA) and the ability to unwind supercoiled pUC19 DNA.
Human Serum Albumin (HSA) plays a crucial role in drug transport due to its remarkable binding properties and abundance in plasma.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a diphosphonic acid dipyridine platinum complex, a synthesis method and a biological application thereof.
In order to achieve the purpose, the technical scheme of the invention is to design a diphosphonic acid dipyridine platinum complex, DBPP for short. The non-leaving group of the diphosphonic acid bipyridine platinum complex consists of ammonia and a diphosphonic acid bipyridine ligand, and the diphosphonic acid bipyridine ligand and the platinum center form an eight-membered ring; the structural formula is as follows:
the diphosphonic acid platinum complex is in CDCl3In (1)1H NMR is shown in figure 1.
Additionally, DBPP is in CDCl3In (1)31P NMR is shown in FIG. 2, which shows two signal peaks at 22.88ppm and 20.55ppm, indicating that the two P atoms in DBPP are magnetically unequal.
DBPP in CDCl3In (1)13C NMR is shown in FIG. 3, which shows C signal peaks at nine positions, consistent with the number of carbon atom species in DBPP.
Of DBPP195The Pt NMR spectrum is shown in FIG. 4, which shows the data of DBPP195Pt NMR showed a single peak at-2287.651 ppm.
Electrospray mass spectrometry (ESI-MS) of DBPP is shown in FIG. 5, which shows DBPP has a peak at m/z 698.33, which is consistent with the calculated value (m/z 699.19) in FIG. 5.
In order to facilitate the synthesis and application of the diphosphonic acid platinum complex, a synthesis method of the diphosphonic acid platinum complex is provided, which comprises the following steps:
s1: synthesizing 2-chloromethylpyridine, dissolving a certain amount of 2-chloromethylpyridine hydrochloride in a certain amount of distilled water, and adding a certain amount of sodium hydroxide into the certain amount of distilled water to prepare an alkaline solution. Mixing the two solutions, extracting, drying to obtain filter residue, and purifying to obtain 2-chloromethylpyridine for later use;
s2: synthesizing tetraethyl [1, 3-di (2-pyridyl) propane-2, 2-diyl ] di (phosphonate), and adding a certain proportion of tetraethyl 2- [ 2-pyridylethyl ] di (phosphonate) and anhydrous DMSO into a certain proportion of a mixture of NaH and DMSO under the protection of nitrogen. The reaction mixture was stirred, 2-chloromethylpyridine was added dropwise, and quenched after completion of the reaction. The mixture was extracted, and the extracts were combined and concentrated. The mixture was dissolved and washed, dried and concentrated to isolate the yellow product to give tetraethyl [1, 3-bis (2-pyridyl) propane-2, 2-diyl ] bis (phosphonate).
S3: synthesizing diphosphonic acid platinum complex, and mixing cis-platinum and AgNO3Stirring in anhydrous DMF under dark condition, filtering to remove precipitate, and adding [1, 3-di (2-pyridyl) propane-2, 2-diyl]Tetraethyl bis (phosphonate). Stirring again, adding silver nitrate, reacting continuously, removing precipitate, and adding CH into the reaction mixture2Cl2Stirring, filtering to remove white precipitate, and concentrating to remove solvent. The product was dissolved in CHCl3And adding diethyl ether to generate yellow precipitate, namely the diphosphonic acid platinum complex DBPP.
Preferably, in step S1, 2-chloromethylpyridine hydrochloride (5.292g,32mmol) is dissolved in distilled water (7mL), and sodium hydroxide (1.344g,32mmol) is added to distilled water (14mL) to prepare a basic solution. Chloroform extraction, drying of the organic layer over anhydrous magnesium sulfate and removal of the solvent in vacuo. And distilling and purifying the filter residue under reduced pressure to obtain light red 2-chloromethyl pyridine.
Preferably, in step S2, the specific operations include: the method for synthesizing tetraethyl [1, 3-bis (2-pyridyl) propane-2, 2-diyl ] bis (phosphonate) according to claim 2, wherein step S2 is performed by: 20mL of dry DMSO charged with tetraethyl 2- [ 2-pyridylethyl ] bis (phosphonate) (9.31g,24.56mmol) was added to a mixture of 60% NaH (1.08g,29.47mmol) to 20mL of DMSO under nitrogen protection at 273K. The reaction mixture was stirred at 273K for 30min, then at room temperature for 2h, and 2-chloromethylpyridine (2.82g,20mmol) was added dropwise to the stirred reaction mixture. The reaction was stirred at room temperature for a further 96h and then quenched by addition of saturated aqueous ammonium chloride. The crude reaction product was extracted with dichloromethane, the organic layers were combined and concentrated under reduced pressure to remove some of the solvent. The crude product was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by rotary evaporation. And (3) performing column chromatography separation by using an isopropanol/dichloromethane mixed solution to obtain a yellow product [1, 3-di (2-pyridyl) propane-2, 2-diyl ] di (phosphonic acid) tetraethyl ester.
Preferably, in step S3, the specific operations include: cisplatin (75mg,0.25mmol) and silver nitrate (42.5mg,0.25mmol) were placed in anhydrous DMF (4.0mL) and stirred at 325K under dark conditions for 24h, the resulting AgCl precipitate was removed by filtration, and tetraethyl [1, 3-bis (2-pyridyl) propane-2, 2-diyl ] bis (phosphonate) (94.27mg,0.2mmol) was added to the filtrate. After stirring at 325K for 24h, silver nitrate (34.0mg,0.20mmol) was added to the reaction mixture, and after stirring at 325K for 24h, the AgCl precipitate was removed by centrifugation, dichloromethane (100mL) was added to the reaction mixture, stirring was carried out for 15min, the white precipitate was removed by filtration, and the solvent was removed under reduced pressure. After the generated oil is dissolved in chloroform (4mL), diethyl ether (100mL) is added, and the formed yellow precipitate is the diphosphonic acid platinum complex DBPP.
In order to facilitate the application and implementation of the diphosphonic acid platinum complex, several applications of the diphosphonic acid platinum complex are proposed, and the diphosphonic acid platinum complex can be used for preparing antitumor drugs. The diphosphonic acid platinum complex is difficult to chelate with glutathione, can overcome toxic and side effects caused by combination with glutathione when platinum drugs are used for treating osteosarcoma, and relieves the drug resistance of the platinum drugs. The diphosphonic acid platinum complex has certain inhibiting effect on osteosarcoma cells. The cytostatic effect of the bisphosphonic acid platinum complex is associated with the conformational transition of B-DNA to A-DNA and the unwinding of pUC19 DNA. The complex can also interact with human serum albumin by means of static quenching.
Compared with the prior art, the invention has the advantages that:
the invention provides an eight-membered ring diphosphonic acid platinum complex with a novel structure, which adopts bipyridine diphosphonic acid ester as a ligand. The complex has high synthesis yield and stable product, is difficult to chelate with glutathione, can greatly reduce the side effect caused by the glutathione, and can be used for relieving the drug resistance of platinum drugs. The complex has certain inhibiting effect on osteosarcoma cells. The complex may also interact with human serum albumin by means of static quenching. The invention provides a new idea for relieving the drug resistance of the diphosphonic acid platinum complex and has important application value.
Drawings
FIG. 1 is a Bruker DRX-500 test of DBPP in example 11H-NMR(500MHz,CDCl3) The data show that DBPP contains an amino, bipyridyl bisphosphonate.
FIG. 2 is a Bruker DRX-500 test of DBPP in example 131P-NMR(202MHz,CDCl3) The data show that DBPP contains two magnetically anisometric P atoms.
FIG. 3 is a Bruker DRX-500 test of DBPP in example 113C-NMR(125MHz,CDCl3) The data show that DBPP contains nine different carbon atoms.
FIG. 4 is a Bruker DRX-500 test of DBPP in example 1195Pt-NMR(107MHz,CDCl3) The data show that Pt peaks at-2287.651 ppm in DBPP.
FIG. 5 is a plot of electrospray ionization mass spectra (ESI-MS) of DBPP from example 1 in methanol using an LCQ fly ESI-MS spectrometer (Thermo Scientific) and using the ISOPRO 3.0 program to simulate the isotope distribution mode of the complex.
FIG. 6 is GSH (2.64X 10) at 310K in example 2-2M) DBPP (1.12X 10)-2M) nuclear magnetic resonance spectra obtained at different time intervals using Bruker DRX-500; (a) is composed of31P-NMR chart, (b) is1H-NMR chart.
FIG. 7 is a graph showing UV absorption spectra of DBPP at different concentrations in phosphate buffer and 1-octanol in example 3 measured by Shimadzu UV 3600 (UV-vis-near-IR): (a) before shaking, (b) after shaking. Inset is a plot of the maximum absorbance of DBPP at 267 nm.
FIG. 8 is a graph showing the uptake of DBPP by U2OS, measured by ELAN9000 ICP-MS, after 24, 48, 72 hours of culture in example 4.
FIG. 9 is a graph showing changes in cell proliferation of U2OS measured by Optical Density (OD) using Thermo Scientific Varioskan Flash after 24 hours of incubation with DBPP in example 5.
FIG. 10 is a graph showing the change in cell proliferation measured by Optical Density (OD) using Thermo Scientific Varioskan Flash after treating cells with DBPP for 24, 48 and 72 hours in example 5.
FIG. 11 shows the differences [ DBPP ] after incubation of (a) CT-DNA (0.1mM) in buffer (5.0mM Tris-HCl, 50mM NaCl, pH 7.4) at 310K for 24h in example 6]/[DNA]Testing the obtained CD spectrogram by using a Jasco J-810 spectrometer in the presence of DBPP (diethylene bis propylene) with a molar ratio; (b) pUC19 plasmid DNA was co-precipitated with DBPP at 310K for 24 hours agarose gel electrophoresis images were obtained using a Bio-Rad gel Doc XR imaging system and quantified using Quantity One software. Lane 1 is DNA control, lanes 2-7 riRespectively 0.30, 0.60, 0.90, 1.20, 1.50 and 1.60.
FIG. 12 is an electron absorption spectrum of HSA (3.0. mu.M) in the presence of DBPP (0.0,3.0,6.0,12.0,18.0,24.0,30.0, 48.0. mu.M) at various concentrations obtained in example 7 using Shimadzu UV 3600 (UV-vis-near-IR). The arrow shows the direction of change in absorbance with increasing concentration of DBPP.
Detailed Description
The following description of the embodiments of the present invention will be made with reference to the accompanying drawings. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
Example 1
The synthesis method of the diphosphonic acid platinum complex comprises the following steps:
s1: synthesis of 2-chloromethylpyridine:
2-chloromethylpyridine hydrochloride (5.292g,32mmol) was dissolved in distilled water (7mL), sodium hydroxide (1.344g,32mmol) was added to distilled water (14mL) to prepare an alkaline solution, the above two solutions were mixed and extracted with chloroform, and the extracted chloroform layer was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. And distilling and purifying the filter residue under reduced pressure to obtain light red 2-chloromethyl pyridine.
S2: synthesis of [1, 3-bis (2-pyridyl) propane-2, 2-diyl ] bis (phosphonic acid) tetraethyl ester:
20mL of anhydrous DMSO supplemented with tetraethyl 2- [ 2-pyridylethyl ] bis (phosphonate) (9.31g,24.56mmol) was added to a mixture of 60% NaH (1.08g,29.47mmol) in 20mL of DMSO under nitrogen protection at 273K. The reaction mixture was stirred at 273K for 30min, then at room temperature for 2h, and 2-chloromethylpyridine (2.82g,20mmol) was added dropwise to the stirred reaction mixture. The reaction was stirred at room temperature for a further 96h and then quenched by addition of saturated aqueous ammonium chloride. The crude reaction product was extracted with dichloromethane, the organic layers were combined and concentrated under reduced pressure to remove some of the solvent. The crude product was taken up in toluene, washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation. And (3) performing column chromatography separation by using an isopropanol/dichloromethane mixed solution to obtain a yellow product [1, 3-di (2-pyridyl) propane-2, 2-diyl ] di (phosphonic acid) tetraethyl ester.
S3: synthesizing a dipyridyl diphosphonate platinum complex DBPP:
cisplatin (75mg,0.25mmol) and silver nitrate (42.5mg,0.25mmol) were put in anhydrous DMF (4.0mL) and stirred under protection from light at 325K for 24h, the AgCl precipitate generated was removed by filtration, and tetraethyl [1, 3-bis (2-pyridyl) propane-2, 2-diyl ] bis (phosphonate) (94.27mg,0.20mmol) was added to the filtrate. After stirring at 325K for 24h, silver nitrate (34.0mg,0.20mmol) was added to the reaction mixture, and after stirring at 325K for 24h, the AgCl precipitate was removed by centrifugation, dichloromethane (100mL) was added to the reaction mixture, stirring was carried out for 15min, the white precipitate was removed by filtration, and the solvent was removed under reduced pressure. After the generated oil is dissolved in chloroform (4mL), diethyl ether (100mL) is added, and the formed yellow precipitate is the diphosphonic acid platinum complex (DBPP). The characterization of the complexes is shown in FIGS. 1-5.
Example 2
The reaction activity of the diphosphonic acid platinum complex DBPP prepared in example 1 and GSH is explored, and the steps are as follows:
the platinum bisphosphate complex DBPP (0.0056mmol) was dissolved in deuterium water and phosphate buffer solution (PBS 7.87mM, pH 7.4, D)2O0.5 mL), the above liquid was put into a nuclear magnetic resonance tube. Adding GSH (2.45mg,0.0132mmol) into the same NMR tube, incubating in 310K water bath at different time intervals31P NMR and1h NMR detects the solution in the tube, and the detection result is shown in figure 6.
FIG. 6a shows that the peak values of DBPP are at 24.88 and 20.09ppm, respectively, and no significant change in data is observed after 168h of incubation, indicating that DBPP has some inertness to glutathione; similar results can be observed with the data of figure 6 b. The results show that DBPP is difficult to chelate with glutathione, toxic and side effects caused by glutathione can be overcome, and obvious technical progress is achieved.
Example 3
The lipophilicity of the platinum bisphosphonates DBPP prepared in example 1 was explored by the following steps:
the lipophilicity coefficient is measured by adopting an n-octanol shake flask method. DBPP solutions were added (50,100,150,200. mu.M) to 10mM, pH 7.4 phosphate buffer, 2.0mL of each of the above solutions was mixed with an equal volume of 1-octanol, placed in a thermostatted (25.0. + -. 0.1 ℃) air bath orbital shaker, and centrifuged at 200rpm for 4 h. Centrifuging at 2500rpm for 15min to separate the sample into two phases; using an ultraviolet-visible spectrophotometer (lambda)max267nm) and calculating the DBPP concentration in the n-octanol phase and the log P value of the DBPP concentration to obtain the lipid water distribution coefficient of DBPP, see fig. 7 and the calculation results in attached table 1.
The data in FIG. 7 shows that DBPP is regularly distributed between n-octanol and water. The data in Table 1 show that the calculated log P is 1.14. + -. 0.13, indicating that the DBPP is fat soluble.
TABLE 1
Example 4
The cellular uptake of the diphosphonic acid platinum complex DBPP prepared in example 1 was investigated by the following steps:
u2OS cells (15X 10)4) Inoculated in a 6-well plate, cultured for 18h, and then added with DBPP (50.0. mu.M, 100.0. mu.M) to incubate for 24h, 48h and 72h, respectively. At the end of incubation, the culture medium was removed, each well was washed three times with Phosphate Buffered Saline (PBS), trypsinized, viable cells counted and heated for 2h with 0.5mL concentrated nitric acid ≈ 90 ℃. ICP-MS determined the total uptake of platinum by cells per well, and the results of the analysis are shown in FIG. 8, and the platinum content data are shown in Table 2.
FIG. 8 and the data in Table 2 show that the intracellular platinum concentrations after 24h treatment of U2OS cells with DBPP (50.0 and 100.0. mu.M) were 0.58. + -. 0.46 and 1.38. + -. 0.54. mu.g/106A cell. After 48 and 72h of DBPP (50.0 and 100.0. mu.M) treatment, the intracellular platinum concentrations rose to 0.78. + -. 0.92 and 3.70. + -. 0.51, 1.34. + -. 0.86 and 4.97. + -. 0.33. mu.g/106A cell.
TABLE 2
Example 5
The antitumor activity of the platinum bisphosphonate complex prepared in example 1 was studied, comprising the following steps:
u2OS, MG-63, MCF-7 and HeLa cells were cultured in different media in 96-well plates. U2OS was cultured in DMEM containing 10% fetal bovine serum. MG-63, MCF-7 and HeLa cells were cultured in 1640 with 10% fetal bovine serum. Subsequently, different concentrations of the bisphosphonic acid platinum complex DBPP were added to the above culture solution. After 48h incubation, MTT (20. mu.L, 5mg mL in PBS) was added to each well-1). After incubation for 4h, the solution was removed from each well, DMSO (200 μ L) was added to each well, and the absorbance of the dissolved formazan (formazan) was measured at 570nm using an enzyme-linked immunosorbent assay (ELISA) on-board apparatus, with the experimental results shown in fig. 9, fig. 10, and table 3. Inhibition ratio IC50Is the average of three independent results.
As shown by the data in FIG. 9, MG-63, MCF-7 and HeLa cells did not die significantly after 24 hours incubation with DBPP at 50 and 100. mu.M concentrations. As shown in fig. 10, DBPP showed strong inhibitory effect on U2OS cells under the same conditions. The data in Table 3 show that the relative survival rate of the cells after 24h culture at DBPP concentration of 50 and 100. mu.M is 85.76 +/-1.65% and 55.72 +/-3.02%, respectively; with the increase of the incubation time from 24h to 48h, the relative survival rate of the cells is respectively reduced to 65.62 +/-3.77 percent and 48.15 +/-0.88 percent; when the culture time is prolonged to 72 hours, the relative survival rate of the cells is respectively reduced to 58.32 +/-4.83 percent and 30.75 +/-1.56 percent. The half-inhibition rate of DBPP to U2OS was about 60. mu.M, which was higher than CDDP, and the above results were consistent with the uptake of DBPP and CDDP by U2OS cells.
TABLE 3
Example 6
The interaction between the diphosphonic acid platinum complex DBPP prepared in example 1 and DNA is explored, and the method comprises the following steps:
w1: different concentrations of DBPP were bound to CT-DNA in Tris-HCl/NaCl buffer (5mM Tris-HCl, 50mM NaCl, pH 7.4). After incubation of CT-DNA with different ratios of DBPP at 310K for 24 hours in the dark, CD spectra were recorded at wavelengths of 220-320 nm. After background subtraction, each sample was assayed in triplicate and averaged. The results of the experiment are shown in FIG. 11.
FIG. 11a shows the CD spectra of CT-DNA in the presence of different concentrations of DBPP, wherein the negative band at 245nm and the positive band at 275nm represent the characteristics of B-DNA. As the ratio [ DBPP ]/[ DNA ] increases from 0 to 0.8, the negative band absorption intensity decreases and the positive band absorption intensity increases. In addition, the maximum wavelength of the negative band tends to be red-shifted. This trend indicates a conformational transition from B-DNA to A-DNA.
W2: the cutting of the plasmid DNA by DBPP was examined by agarose gel electrophoresis. pUC19 plasmid DNA (200ng) was treated with different concentrations of DBPP at 310K for 24 h. Finally, all samples were added to a solution containing EB (0.5. mu.g mL)-1) In a 1% agarose gel. In TAE buffer (50mM acetate and 1mM)Ethylenediaminetetraacetic acid) for 2 h. Imaging was performed using a Bio-Rad Gel Doc XR imaging system. See fig. 11b for experimental results.
FIG. 11b shows the agarose gel electrophoresis of DBPP-unwound pUC19 DNA. After co-incubation with DBPP, blockage of supercoiled DNA was observed, indicating that binding of DBPP to pUC19 DNA helicized pUC19 DNA. Furthermore, the separation between supercoiled and relaxed DNA decreases with increasing molar ratio (ri). The polylinker ri (c) for complete removal of supercoiled DNA was 1.8, higher than cisplatin (ri (c) ═ 0.076). The results indicate that DBPP does not interfere as effectively with the tertiary structure of supercoiled DNA as cisplatin, consistent with their cytotoxic activity.
Example 7
The interaction of the platinum bisphosphonate complex prepared in example 1 with HSA was explored, comprising the following steps:
DBPP was reacted with HSA in PBS (10mM, pH 7.4) and the reaction was detected by ultraviolet-visible spectroscopy (UV-Vis). 310K in PBS solution HSA (3.0. mu.M) and different concentrations (0.0,3.0,6.0,12.0,18.0,24.0,30.0, 48.0. mu.M) DBPP were continuously reacted for 24 hours in the dark to obtain absorption spectra, and the detection results are shown in FIG. 12.
The data in FIG. 12 show that the absorption intensity of HSA is enhanced with the addition of DBPP, with a significant blue shift of about 12nm (from 278 to 266nm), indicating a change in the microenvironment of tryptophan (Trp), tyrosine (Tyr) and phenylalanine (Phe) residues. The results indicate that there is static quenching between DBPP and HSA.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the technical principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. The diphosphonic acid platinum complex is characterized in that a non-leaving group of the complex consists of ammonia and a diphosphonic acid bipyridine ligand, and the diphosphonic acid bipyridine ligand and a platinum center form an eight-membered ring; the structural formula is as follows:
2. a process for the synthesis of a platinum bisphosphonate complex according to claim 1, comprising the steps of:
s1: synthesis of 2-chloromethylpyridine: dissolving a certain amount of 2-chloromethylpyridine hydrochloride in a proper amount of distilled water, adding a sodium hydroxide solution, extracting a reaction solution by using trichloromethane after reaction, and drying an extract liquid to obtain 2-chloromethylpyridine for later use;
s2: synthesis of [1, 3-bis (2-pyridyl) propane-2, 2-diyl ] bis (phosphonic acid) tetraethyl ester: under the protection of nitrogen, adding a certain proportion of tetraethyl 2- [ 2-pyridylethyl ] bis (phosphonate) and dry DMSO into a certain proportion of a mixture of NaH and DMSO, stirring the reaction mixture, dropwise adding 2-chloromethylpyridine, continuing to react for a plurality of hours after the dropwise addition is finished, and then quenching; extracting the mixture, combining the extracts, removing the solvent, dissolving the mixture with toluene, washing, drying, concentrating and separating a yellow product to obtain tetraethyl [1, 3-bis (2-pyridyl) propane-2, 2-diyl ] bis (phosphonate);
s3: synthesizing diphosphonic acid platinum complex, putting cisplatin and silver nitrate into anhydrous DMF, stirring and reacting in dark place, centrifuging to remove precipitate, and adding [1, 3-di (2-pyridyl) propane-2, 2-diyl into filtrate]Tetraethyl bis (phosphonate); stirring, adding appropriate amount of silver nitrate into the reaction solution, centrifuging to remove precipitate, and adding CH into the reaction mixture2Cl2Stirring, centrifuging to remove white precipitate, removing solvent by rotary evaporation, and dissolving the product in CHCl3Adding ether to obtain yellow precipitate, i.e. diphosphonic acid dipyridine platinum complex.
3. The method for synthesizing a platinum bisphosphonate complex according to claim 2, wherein in step S1, 5.292g of 2-chloromethylpyridine hydrochloride is dissolved in 7mL of distilled water, a sodium hydroxide solution is added, after the reaction, the reaction solution is extracted with chloroform, and the extract is dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain 2-chloromethylpyridine for use.
4. The method for synthesizing a bisphosphate platinum complex according to claim 2, wherein in step S2, the specific operations are: in a three-necked flask, 20mL of anhydrous DMSO solution containing 9.31g of tetraethyl 2- [ 2-pyridylethyl ] bis (phosphonate) was added to 20mL of DMSO mixture containing 1.08g of NaH under 273K nitrogen protection, and the reaction mixture was stirred at 273K for 30min and then at room temperature for 2 h; dropwise adding 2.82g of 2-chloromethylpyridine into the reaction system, reacting at room temperature, continuing stirring for 96 hours, and then adding saturated ammonium chloride aqueous solution for quenching; extraction with dichloromethane, combination of the organic layers, concentration, dissolution of the mixture in excess toluene, washing with distilled water and brine in turn, drying over anhydrous sodium sulfate and concentration under vacuum; and separating the yellow product by using isopropanol/dichloromethane column chromatography to obtain the tetraethyl [1, 3-di (2-pyridyl) propane-2, 2-diyl ] di (phosphonate).
5. The method for synthesizing a diphosphonic acid platinum complex according to claim 2, wherein in step S3, the specific operations are as follows: 75mg of cisplatin and 42.5mg of silver nitrate were put in 4.0mL of anhydrous DMF, stirred at 325K for 24h under dark conditions, filtered to remove the produced AgCl precipitate, and tetraethyl [1, 3-bis (2-pyridyl) propane-2, 2-diyl ] bis (phosphonate) (94.27mg,0.20mmol) was added to the filtrate; stirring at 325K in the dark for 24h, continuously adding 34.0mg of silver nitrate into the reaction solution, stirring at 325K for 24h, centrifuging to remove AgCl precipitate, adding 100mL of dichloromethane into the reaction mixture, stirring for 15min, filtering to remove white precipitate, and removing the solvent; after the generated oil is dissolved in 4mL of trichloromethane, 100mL of diethyl ether is added, and the formed yellow precipitate is the diphosphonic acid platinum complex DBPP.
6. Use of the platinum bisphosphate complex of claim 1 for the preparation of a medicament for the treatment of an antitumor drug.
7. Use of a platinum bisphosphonate complex according to claim 1 for the preparation of a medicament for the treatment of osteosarcoma.
8. The use of claim 7, wherein the bisphosphonate platinum complex is resistant to glutathione chelation, and can overcome toxic and side effects caused by glutathione binding when platinum drugs are used for treating osteosarcoma, and reduce platinum drug resistance.
9. The use according to claim 6, wherein the platinum bisphosphonate complex interacts with human serum albumin by means of static quenching to exert a tumor treating effect.
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| US20110034714A1 (en) * | 2007-07-06 | 2011-02-10 | Hisao Ekimoto | Metal complex compound, cancer therapeutic agent composition containing the metal complex compound as an active ingredient, and intermediate for the metal complex compound |
| CN102731580A (en) * | 2012-07-12 | 2012-10-17 | 江苏省原子医学研究所 | Binuclear platinum (II)-diphosphonic acid coordination compound, preparation method and application thereof |
| CN105622674A (en) * | 2016-02-29 | 2016-06-01 | 东南大学 | Tetravalent platinum complex with bioactive group and preparation method of tetravalent platinum complex |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060173185A1 (en) * | 2003-06-27 | 2006-08-03 | Akira Odani | Bisphosphonate complexes |
| US20110034714A1 (en) * | 2007-07-06 | 2011-02-10 | Hisao Ekimoto | Metal complex compound, cancer therapeutic agent composition containing the metal complex compound as an active ingredient, and intermediate for the metal complex compound |
| CN102731580A (en) * | 2012-07-12 | 2012-10-17 | 江苏省原子医学研究所 | Binuclear platinum (II)-diphosphonic acid coordination compound, preparation method and application thereof |
| CN105622674A (en) * | 2016-02-29 | 2016-06-01 | 东南大学 | Tetravalent platinum complex with bioactive group and preparation method of tetravalent platinum complex |
Non-Patent Citations (1)
| Title |
|---|
| HANNA K. MALISZEWSKA ET AL.: "Allene-derived gold and platinum complexes: synthesis and first applications in catalysis", 《DALTON TRANS.》, vol. 49, pages 4034 - 4038 * |
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