CN110950915A - Novel rhein-platinum (IV) precursor anticancer complex and synthesis method and application thereof - Google Patents
Novel rhein-platinum (IV) precursor anticancer complex and synthesis method and application thereof Download PDFInfo
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- 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
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
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Abstract
The invention discloses a novel rhein-platinum (IV) precursor anticancer complex and a synthesis method and application thereof. The structural formula of the rhein-platinum (IV) precursor anticancer complex is shown as a formula I, and a ligand is synthesized by the complex; the ligand is benzoic acid or ferulic acid or rhein or crotonic acid or cinnamic acid which is used as the ligand, and the ligand and the hydroxyl cisplatin oxide are subjected to coordination reaction to obtain a yellow target product. The novel rhein-platinum (IV) precursor anticancer complex generally shows obvious in-vitro antitumor activity and toxicity selectivity, is cheap in raw materials, convenient to synthesize, economical and practical, has good potential medicinal value, and is expected to be used for preparing various antitumor drugs.
Description
Technical Field
The invention relates to a chemical complex and a synthetic method thereof, in particular to a novel rhein-platinum (IV) precursor anticancer complex and a synthetic method thereof. The invention also relates to the application of the rhein-platinum (IV) precursor anticancer complex in preparing antitumor drugs.
Background
In tumor treatment, platinum drugs play an important role as one of the most successful drugs, and have certain high efficiency and curative effect. However, with the increasing clinical application of cisplatin drugs, the clinical long-term use and curative effect of cisplatin drugs are seriously affected by the defects of low bioavailability, poor targeting property, strong toxic and side effects, easy generation of drug resistance and the like. In addition, the tetravalent platinum compound is used as a prodrug of the divalent platinum drug, so that the high-efficiency broad-spectrum biological activity of the traditional divalent platinum drug is kept, and the tetravalent platinum compound has a plurality of unique advantages (Venkatesh V, Sadler P J. platinum (IV) produgs [ J ]. Met. Ions Life Sci,2018,18: 69-108.). In recent years, tetravalent platinum drugs are prepared into drugs with photodynamic activity through structural improvement, and the drugs are applied to photodynamic therapy (PDT) tumor therapy to achieve a plurality of breakthrough progresses (Venkatesh V, Sadler PJ. platinum (IV) produgs [ J ]. Met. Ions Life Sci,2018,18: 69-108), and the photodynamic platinum drugs with clinical application prospect are expected to be developed.
Disclosure of Invention
The first purpose of the invention is to provide a novel rhein-platinum (IV) precursor anticancer complex.
In order to achieve the first object, the present invention provides the following technical solutions: novel rhein-platinum (IV) precursor anticancer complex [ Pt ]IVCl2(NH3)2(O2C-BA)2](Pt-1)、[PtIVCl2(NH3)2(O2C-FA)2](Pt-2)、[PtIVCl2(NH3)2(O2C-RH)2](Pt-3)、[PtIVCl2(NH3)2(O2C-CA)2](Pt-4) and [ Pt ]IVCl2(NH3)2(O2C-TCA)2](Pt-5) having the formula:
wherein R is one of the following functional groups,
the second purpose of the invention is to provide a synthesis method of the novel rhein-platinum (IV) precursor anticancer complex.
In order to achieve the second object of the present invention, the present invention provides the following technical solutions:
a method for synthesizing novel rheinic acid-platinum (IV) precursor anticancer complex comprises dissolving ligand and cisplatin oxyhydroxide in solvent, and performing coordination reaction; the ligand is benzoic acid, ferulic acid, rhein, crotonic acid or cinnamic acid.
Further, the ratio of the amount of the ligand to the amount of cisplatin oxyhydroxide is 2: 1.
Further, the solvent contains acetic acid and also contains one of methanol, ethanol, dimethyl sulfoxide and N, N-dimethylformamide.
Furthermore, the dosage of the solvent is 5.0-85.0 mL.
Further, the heating mode is water bath, the heating temperature is 37-120 ℃, and the heating time is 12-90 hours.
Further, the drying temperature is 40-50 ℃.
The third purpose of the invention is to provide a new application of the novel rhein-platinum (IV) precursor anticancer complex in the aspect of tumor resistance.
Compared with the prior art, the invention has the beneficial effects that:
1. the novel rheinic acid-platinum (IV) precursor anticancer complex is prepared by taking benzoic acid (BA-COOH), ferulic acid (FA-COOH), rheinic acid (RH-COOH), crotonic acid (CA-COOH) and cinnamic acid (TCA-COOH) as ligands to perform complex reaction with cis-platinum oxyhydroxide, and has the advantages of simple synthetic route, mild reaction conditions and high yield.
2. The complex provided by the invention has an inhibiting effect on tumor cells such as non-small cell lung cancer A549 cells and cisplatin-resistant strains 549/DDP (dichloro-Diphenyl-Trichlorophenicol) thereof, and IC (integrated Circuit)50The value range is 0.11-3.87 mu M, and the in vitro anti-tumor activity is far greater than that of corresponding ligands of benzoic acid (BA-COOH), ferulic acid (FA-COOH), rhein (RH-COOH), crotonic acid (CA-COOH), cinnamic acid (TCA-COOH) and classical metal-based anticancer drugs of cisplatin (IC)50>9.26. + -. 0.59. mu.M). In addition, the toxicity of the novel rhein-platinum (IV) precursor anticancer complex to normal cells HL-7702 is far less than that of a clinical drug cisplatin (IC)50>18.05 +/-0.69 mu M), shows good selectivity for inhibiting the growth of tumor cells, and most importantly, in vivo tumor inhibition experiments of tumor-bearing nude mice show that the rhein-platinum complex Pt-3 has good tumor inhibition effect on a nude mouse model of the human non-small cell lung cancer cisplatin-resistant strain A549/DDP, and the inhibition rate is 67.45 percent and is far higher than that of clinical drugs cisplatin (33.05 percent) and ferulic acid-platinum complex Pt-2(28.12 percent). Has good potential medicinal value and is expected to be used for preparing various antitumor medicaments.
Drawings
The technical solutions of the present invention are further described in detail with reference to the specific embodiments in the drawings, but the present invention is not limited thereto.
FIG. 1 is a mass spectrum of a complex Pt-1 prepared in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of a complex Pt-1 prepared in example 1 of the invention;
FIG. 3 is a nuclear magnetic resonance carbon spectrum of a complex Pt-1 prepared in example 1 of the invention;
FIG. 4 is a mass spectrum of a complex Pt-2 prepared in example 1 of the present invention;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of a complex Pt-2 prepared in example 1 of the invention;
FIG. 6 is a nuclear magnetic resonance carbon spectrum of a complex Pt-2 prepared in example 1 of the invention;
FIG. 7 is a mass spectrum of a complex Pt-3 prepared in example 1 of the present invention;
FIG. 8 is a nuclear magnetic resonance hydrogen spectrum of a complex Pt-3 prepared in example 1 of the invention;
FIG. 9 is a nuclear magnetic resonance carbon spectrum of a complex Pt-3 prepared in example 1 of the invention;
FIG. 10 is a mass spectrum of a complex Pt-4 prepared in example 1 of the present invention;
FIG. 11 is a NMR chart of a complex Pt-4 prepared in example 1 of the present invention;
FIG. 12 is a nuclear magnetic resonance carbon spectrum of a complex Pt-4 prepared in example 1 of the invention;
FIG. 13 is a mass spectrum of a complex Pt-5 prepared in example 1 of the present invention;
FIG. 14 is a NMR chart of a complex Pt-5 obtained in example 1 of the present invention;
FIG. 15 shows the NMR spectrum of Pt-5 complex prepared in example 1 of the present invention.
Detailed Description
The following claims are hereby incorporated into the detailed description of the invention, with the understanding that the present disclosure is to be considered as a full and non-limiting example, and any limited number of modifications that fall within the spirit and scope of the claims are intended to be included therein.
The raw material cis-platinum oxyhydroxide related to the embodiment of the invention is prepared by referring to the prior literature (Quiroga, A.G.; equivalent. Dalton trans.,2011,40, 344-347.).
Example 1
Weighing 2.0mmol of benzoic acid (BA-COOH) and 1.0mmol of cis-platinum oxyhydroxide, placing the materials in a 100mL round-bottom flask, dissolving the materials in 50.0mL of acetic acid, keeping out of the sun, carrying out coordination reaction at 37 ℃ for 12h, and drying (45 ℃) to obtain a yellow target product Pt-1. The yield was 35.6%.
The obtained yellow product Pt-1 is identified:
(1) electrospray mass spectrometry, the spectrum of which is shown in figure 1.
ESI-MS m/z:647.0for[M-Cl+DMSO+2CH3OH]+Wherein M is the molecular weight of the compound Pt-1.
(2) The NMR spectrum is shown in FIG. 2.
1H NMR(500MHz,DMSO-d6)δ7.95(d,J＝8.3Hz,4H),7.62(t,J＝7.4Hz,2H),7.50(t,J＝7.7Hz,4H),1.92(s,6H).
(3) NMR spectrum of carbon, as shown in FIG. 3.
13C NMR(126MHz,DMSO-d6)δ178.73,172.45,167.85,133.20,131.49,129.72,128.98,23.35,21.52.
(4) The infrared spectrum data of the complex Pt-1 are shown in the following.
IR(KBr):3135,2673,2562,2089,1972,1916,1788,1643,1451,1293,1180,1127,1070,1023,935,806,705,666,549,431cm-1.
(5) The results of elemental analysis are shown in Table 1.
TABLE 1 elemental analysis results of platinum (II) complexes in examples
Thus, the resulting yellow complex Pt-1 can be identified, which has the following structural formula:
example 2
Weighing 2.0mmol of ferulic acid (FA-COOH) and 1.0mmol of cis-platinum oxyhydroxide, placing the ferulic acid and the cis-platinum oxyhydroxide in a 100mL round-bottom flask, dissolving the ferulic acid and the cis-platinum oxyhydroxide in 30.0mL of mixed solution of acetic acid and methanol (v: v ═ 10:1), protecting from light, carrying out coordination reaction at 80 ℃ for 90 hours, and drying (45 ℃) to obtain a yellow target product Pt-2. The yield was 55.7%.
The obtained yellow product Pt-2 is identified:
(1) electrospray mass spectrometry, the spectrum of which is shown in FIG. 4.
ESI-MS m/z:647.6for[M-Cl]+Wherein M is the molecular weight of the compound Pt-2.
(2) NMR spectrum shown in FIG. 5.
1H NMR(500MHz,DMSO-d6)δ9.78(s,2H),7.48(d,J＝15.8Hz,2H),7.28(s,2H),7.08(d,J＝7.6Hz,2H),6.80(d,J＝7.9Hz,2H),6.37(d,J＝15.9Hz,2H),3.82(s,6H),1.91(s,6H).
(3) NMR spectrum of carbon, as shown in FIG. 6.
13C NMR(126MHz,DMSO-d6)δ178.74,168.52,149.55,148.40,144.80,126.29,123.23,116.32,116.03,111.68,56.19,23.36.
(4) The infrared spectrum data of the complex Pt-2 are shown in the following.
IR(KBr):3439,3197,2662,2595,1826,1609,1463,1431,1366,1287,1033,970,943,852,805,753,699,602,576,520cm-1.
(5) The results of the elemental analysis are shown in Table 1 above.
Thus, the resulting yellow complex Pt-2 can be identified by the following structural formula:
example 3
Weighing 2.0mmol of rhein (RH-COOH) and 1.0mmol of cis-platinum oxyhydroxide, placing the rhein and the cis-platinum oxyhydroxide in a 100mL round-bottom flask, dissolving the rhein and the cis-platinum oxyhydroxide in 85.0mL of mixed solution of acetic acid and dimethyl sulfoxide (v: v ═ 100:3), keeping away from light, carrying out coordination reaction at 120 ℃ for 72 hours, and drying (45 ℃) to obtain a yellow target product Pt-3. The yield was 50.1%.
The obtained yellow product Pt-3 is identified:
(1) electrospray mass spectrometry, the spectrum of which is shown in FIG. 7.
ESI-MS m/z:696.4for[M-(OC-RH)+3CH3OH]-Wherein M is the molecular weight of the compound Pt-3.
(2) NMR spectrum as shown in FIG. 8.
1H NMR(500MHz,DMSO-d6)δ11.90(s,2H),8.16–8.09(m,1H),7.83(td,J＝7.9,2.9Hz,1H),7.78–7.68(m,2H),7.40(dd,J＝8.2,3.2Hz,1H),6.54(s,6H).
(3) NMR spectrum of carbon film as shown in FIG. 9.
13C NMR(126MHz,DMSO-d6)δ191.81,178.69,172.51,165.98,161.91,161.59,138.08,134.21,133.68,125.07,124.60,119.90,119.32,119.03,116.62,40.50,40.33,40.16,40.00,39.83,39.66,39.49.
(4) The infrared spectrum data of the complex Pt-3 are shown in the following.
IR(KBr):3433,3269,3207,3064,2604,1693,1629,1608,1570,1452,1364,1269,1189,1076,1004,942,900,842,762,751,701,600,465,445cm-1.
(5) The results of the elemental analysis are shown in Table 1 above.
Thus, the resulting yellow complex Pt-3 can be identified, which has the following structural formula:
example 4
Weighing 2.0mmol of crotonic acid (CA-COOH) and 1.0mmol of cis-platinum oxyhydroxide, placing the mixture in a 100mL round-bottom flask, dissolving the mixture in 45mL of acetic acid and N, N-dimethylformamide (v: v ═ 60:40), keeping out of light, carrying out coordination reaction at 80 ℃ for 36h, and drying (45 ℃) to obtain a yellow target product Pt-4. The yield was 39.8%.
The obtained yellow product Pt-4 is identified:
(1) electrospray mass spectrometry, the spectrum of which is shown in FIG. 10.
ESI-MS m/z:647.6for[M-Cl+2DMSO+(HOAc)]+Wherein M is the molecular weight of the compound Pt-4.
(2) NMR spectrum as shown in FIG. 11.
1H NMR(500MHz,DMSO-d6)δ6.81(dq,J＝13.8,6.9Hz,2H),5.80(d,J＝1.5Hz,1H),5.77(d,J＝1.5Hz,1H),1.90(s,6H),1.82(dd,J＝6.9,1.5Hz,6H).
(3) NMR spectrum of the sample, as shown in FIG. 12.
13C NMR(126MHz,DMSO-d6)δ178.72,167.46,144.63,123.83,23.34,21.51,18.00,17.53.
(4) The infrared spectrum data of the complex Pt-4 are shown in the following.
IR(KBr):3549,3211,2607,1705,1654,1430,1406,1364,1277,1226,1103,1047,1023,968,942,843,700,613,537,514cm-1.
(5) The results of the elemental analysis are shown in Table 1 above.
Thus, the resulting yellow complex Pt-4 can be identified by the following structural formula:
example 5
Weighing 2.0mmol of cinnamic acid (TCA-COOH) and 1.0mmol of cis-platinum oxyhydroxide, placing the cinnamic acid and the cis-platinum oxyhydroxide in a 100mL round-bottom flask, dissolving the cinnamic acid and the cis-platinum oxyhydroxide in 15mL of mixed solution of acetic acid and ethanol (v: v ═ 1:50), keeping away from light, carrying out coordination reaction at 60 ℃ for 70h, and drying (45 ℃) to obtain a yellow target product Pt-5. The yield was 53.0%.
The obtained yellow product Pt-5 is identified:
(1) electrospray mass spectrometry, the spectrum of which is shown in FIG. 13.
ESI-MS m/z:701.1for[M-Cl+DMSO+2CH3OH]+Wherein M is the molecular weight of the compound Pt-5.
(2) NMR spectrum as shown in FIG. 14.
1H NMR(500MHz,DMSO-d6)δ7.68(dd,J＝6.7,2.9Hz,4H),7.60(d,J＝16.0Hz,2H),7.43(q,J＝3.1,2.3Hz,6H),6.54(d,J＝15.9Hz,8H).
(3) NMR spectrum of the sample, as shown in FIG. 15.
13C NMR(126MHz,DMSO-d6)δ178.72,172.56,168.15,144.21,134.75,130.65,129.38,128.64,119.98.
(4) The infrared spectrum data of the complex Pt-5 are shown in the following.
IR(KBr):3441,3202,2562,1676,1579,1311,1025,980,943,769,701,768,612,591,543,482cm-1.
(5) The results of the elemental analysis are shown in Table 1 above.
Thus, the resulting yellow complex Pt-5 can be identified by the following structural formula:
the application test of the product in the antitumor drug comprises the following steps:
the novel rhein-platinum (IV) precursor anticancer complex is adopted to carry out in-vitro antitumor activity experiments on human non-small cell lung cancer A549 cells and cisplatin-resistant strain A549/DDP thereof.
1. Cell lines and cell cultures
The experiment selects 3 human cell strains such as human non-small cell lung cancer A549 cells and cisplatin-resistant strains A549/DDP thereof, human normal liver cells (HL-7702) and the like.
The cell strain is cultured in RPMI-1640 containing 10 wt% calf blood, 100U/mL penicillin and 100U/mL streptomycin, and the cell strain is placed at 37 ℃ and contains 5% CO by volume concentration2Culturing in an incubator. The growth of the cells was observed by inverted microscope, and the cells were passed through digestion with 0.25% trypsin and used in the experiment in the logarithmic phase.
2. Preparation of test Compounds
The novel rhein-platinum (IV) precursor anticancer complex is a product prepared in the embodiments 1-5 of the invention, the purity of the product is more than or equal to 95%, a DMSO stock solution is diluted into a final solution of 20 mu mol/L by a physiological buffer solution (the final concentration of DMSO is less than or equal to 1%, and the inhibition rate of the novel rhein-platinum (IV) precursor anticancer complex on the proliferation of normal cells or selected tumor cells under the concentration of 20 mu mol/L is tested.
3. Cell growth inhibition assay (MTT method)
(1) Taking tumor cells in logarithmic growth phase, digesting by trypsin, preparing a cell suspension with the concentration of 5000/mL by using a culture solution containing 10% calf serum, inoculating 190 mu L of the cell suspension into a 96-hole culture plate, and enabling the density of cells to be detected to be 1000-10000 per hole (the edge holes are filled with sterile PBS);
(2)5％CO2incubating for 24h at 37 ℃ until a cell monolayer is paved on the bottom of each well, adding 10 mu L of medicine with a certain concentration gradient into each well, and arranging 4 compound wells in each concentration gradient;
(3)5％CO2incubating at 37 ℃ for 48 hours, and observing under an inverted microscope;
(4) add 10. mu.L of MTT solution (5mg/mL PBS, i.e., 0.5% MTT) to each well and continue culturing for 4 h;
(5) terminating the culture, carefully removing the culture solution in the wells, adding 150. mu.L DMSO into each well to sufficiently dissolve formazan precipitate, mixing uniformly by using an oscillator, and measuring the optical density of each well by using an microplate reader with a wavelength of 570nm and a reference wavelength of 450 nm;
(6) simultaneously, a zero setting hole (culture medium, MTT, DMSO) and a control hole (cells, a drug dissolving medium with the same concentration, a culture solution, MTT, DMSO) are arranged.
(7) Determining the number of living cells according to the measured optical density (OD value), wherein the larger the OD value, the stronger the cell activity
Using the formula:
and (4) calculating the inhibition rate of the compound on the growth of tumor cells.
Calculating the inhibition rate of the novel rhein-platinum (IV) precursor anticancer complex on the growth of the selected cells, and calculating the IC of each tested compound on each selected cell strain by a Bliss method50The value is obtained. The results are shown in table 2 below.
TABLE 2 IC of novel rhein-platinum (IV) precursor anticancer complexes on various cell lines50Value (μ M)
Slave IC50According to the activity screening result, the novel rhein-platinum (IV) precursor anticancer complex shows certain proliferation inhibition activity on selected cancer cells, and the proliferation inhibition activity is higher than that of corresponding ligands of benzoic acid (BA-COOH), ferulic acid (FA-COOH), rhein (RH-COOH), crotonic acid (CA-COOH) and cinnamic acid (TCA-COOH). The novel rhein-platinum (IV) precursor anticancer complex shows excellent antitumor activity, especially on A549/DDP cells and IC thereof50The values are respectively 3.01 +/-1.22, 0.75 +/-0.21, 0.11 +/-0.03, 3.87 +/-0.26 and 0.91 +/-0.75 mu M, and the in vitro antitumor activity of the compound is far greater than that of a classical metal-based anticancer drug cis-platinum (50.12 +/-1.06 mu M). On the other hand, the toxicity of the novel rhein-platinum (IV) precursor anticancer complex to normal cells HL-7702 is far less than that of a clinical drug cisplatin, and good selectivity is shown in the aspect of inhibiting the growth of tumor cells.
In vivo tumor suppression experiment for tumor-bearing nude mice
(1) Animal requirements:
strain: BALB/c-nu; grade: an SPF level; the week age is as follows: 5-6 w; weight: 18-20 g; sex: male;
(2) animal sources:
beijing Huafukang biotech GmbH, license number: SCXK (Jing) 2014-.
(3) Site of animal experiment:
department of radiology research (tianjin) of the academy of Chinese medical sciences, the license number used by the laboratory: SYXK 2014-0002
(4) The requirements of the breeding environment are as follows:
SPF class, IVC independent ventilation system; keeping constant temperature (26 +/-2 ℃) and humidity (40-70%), and turning on and off the lamp for 12h respectively.
(5) Feed:
SPF mouse breeding feed is selected and purchased from Australian cooperative feed Co., Ltd, Beijing.
(6) Main reagents and instruments used for the experiments:
reagent: DMSO, 0.9% of normal saline, 75% of medical alcohol and 4% of paraformaldehyde; the apparatus is as follows: surgical scissors, forceps, a trocar and an electronic vernier caliper.
(7) Basic procedure and operation of the experiment
① cell culture
For experimental cell lines and cell cultures, please refer to the above section.
② preparation of nude mouse subcutaneous transplantation tumor model of lotus A549/DDP
Collecting A549/DDP cells in logarithmic growth phase, and modulating to 5 × 10 with serum-free medium cells7Viable cell concentration suspension per mL. 0.2mL of the suspension, approximately 1X 10, was withdrawn using a 1.0mL syringe7The living cells are inoculated to the subcutaneous part of the right armpit of the nude mouse until the subcutaneous tumor grows to about 1cm3In time, the tumor source was generated as a subcutaneous tumor model and passaged on nude mice. A549/DDP is passed on nude mouse for 4 generations, after its growth is stable, tumor-bearing mouse with vigorous tumor growth and no break is selected, cervical vertebra is killed by dislocation, animal skin is sterilized with 75% medical alcohol, tissue block is dissected off, necrotic part is removed, tumor tissue is cut into 1.5mm3The left and right small blocks are inoculated under the skin of the right axilla of the nude mouse by a trocar. Measuring the tumor diameter of the transplanted tumor by using an electronic vernier caliper until the tumor volume grows to 100-3At time, animals were randomly grouped.
③ test of drug action
Nude mice with Holo A549/DDP tumor were randomly divided into a vehicle group, a drug-added group and a cisplatin positive control group, each group containing 7 animals. The intraperitoneal injection administration is started on the grouping day, the compound is administered every two days, and the cisplatin is administered every other day. The tumor diameter was measured every three days with an electronic vernier caliper, and the body weight was measured. On day 13, cervical dislocation was sacrificed, tumors were dissected away, weighed, photographed, and tumor inhibition rate was calculated.
Tumor volume calculation formula: v ═ a × b2A is a long diameter, and b is a short diameter;
relative tumor volume RTV ═ Vt/V0In which V istVolume at each measurement, V0Volume when grouped;
relative tumor proliferation rate T/C ═ TRTV/CRTV)×100％；
The tumor growth inhibition ratio (%) (mean tumor weight in vehicle group-mean tumor weight in treatment group)/mean tumor weight in vehicle group × 100%.
The experimental results in Table 3 show that the rhein-platinum complex Pt-3 has good tumor inhibition effect on a human non-small cell lung cancer cisplatin-resistant strain A549/DDP nude mouse model, and the inhibition rate is 67.45 percent and is far higher than that of clinical drugs cisplatin (33.05 percent) and ferulic acid-platinum complex Pt-2(28.12 percent).
In conclusion, the novel rhein-platinum (IV) precursor anticancer complex shows excellent in vitro and in vivo antitumor activity and good cytotoxicity selectivity, and the design idea and the synthesis method of the synthesized novel antitumor platinum complex are feasible. The novel rhein-platinum (IV) precursor anticancer complex has good potential medicinal value due to the antitumor activity, and is expected to be used for preparing various antitumor medicaments.
TABLE 3 in vivo anti-tumor results of Compounds on human A549/DDP bearing nude mice
amean p<0.05,p vs control.
The above description is only exemplary of the invention, and any modification, equivalent replacement, and improvement made within the spirit and scope of the present invention should be considered within the scope of the present invention.
Claims (10)
1. A novel rhein-platinum (IV) precursor anticancer complex is characterized in that the structural formula is shown as the formula I:
wherein R is one of the following functional groups,
2. the method for synthesizing novel rhein-platinum (IV) precursor anticancer complex according to claim 1, wherein the ligand and cisplatin oxyhydroxide are dissolved in a solvent to perform a coordination reaction, thereby obtaining the rhein-platinum (IV) precursor anticancer complex; the ligand is benzoic acid, ferulic acid, rhein, crotonic acid or cinnamic acid.
3. The method for synthesizing the novel rhein-platinum (IV) precursor anticancer complex according to claim 2, wherein the mass ratio of the ligand to the cisplatin oxyhydroxide is 2: 1.
4. The method for synthesizing a novel rhein-platinum (IV) precursor anticancer complex according to claim 2 or 3, wherein the solvent contains acetic acid and one of methanol, ethanol, dimethyl sulfoxide and N, N-dimethylformamide.
5. The method for synthesizing a novel rhein-platinum (IV) precursor anticancer complex according to claim 3 or 4, wherein the total amount of the solvent is 5.0-85.0 mL.
6. The method for synthesizing the novel rhein-platinum (IV) precursor anticancer complex according to claim 5, wherein the reaction temperature of the coordination reaction is 37-120 ℃; the reaction time is 12-90 h.
7. The method for synthesizing novel rhein-platinum (IV) precursor anticancer complex according to claim 3, wherein after the coordination reaction is completed, the reaction solution is filtered, washed and dried.
8. The method for synthesizing novel rhein-platinum (IV) precursor anticancer complex according to claim 7, wherein the drying temperature is 45 ℃.
9. The use of the novel rhein-platinum (IV) precursor anticancer complex as defined in claim 1 in the preparation of an antitumor medicament.
10. An antitumor agent comprising the novel rhein-platinum (IV) precursor anticancer complex as claimed in claim 1 as an active ingredient.
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