CN116375769A - Double-target Pt (IV) anticancer prodrug, and preparation method and application thereof - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention discloses a double-target Pt (IV) anticancer prodrug, a preparation method and application thereof, and the chemical name is fac- [ Pt (1R, 2R-cyclohexanediamine) (hydroxy) (3-bromopyruvate) 3 ]I.e. fac- [ Pt (1R, 2R-DACH) (OH) (3-bromoxyruvate) 3 ]The oxaliplatin prodrug contains 3-bromopyruvate (glycolytic inhibitor) ligands in the molecule, can inhibit the replication of tumor cell DNA and glycolytic pathway simultaneously, and has two action targets. Its synthesis is based on cis- [ Pt (1R, 2R-DACH) I 2 ]Or cis- [ Pt (1R, 2R-DACH) Cl 2 ]As a starting material, after hydrolysis of silver sulfate, it was reacted with an alkali metal hydroxide to give cis- [ Pt (1R, 2R-DACH) (OH) 2 ]The solution is then subjected to an axial oxidation with hydrogen peroxide to form the intermediate cis- [ Pt (1R, 2R-DACH) (OH) 4 ]·H 2 And finally, carrying out neutralization reaction with 3 times of 3-bromopyruvate to obtain the target complex. The invention is characterized in thatThe Pt (IV) anticancer prodrug has good water solubility and stability of aqueous solution, strong antitumor effect, low toxicity and low cross drug resistance with oxaliplatin, and is used for chemotherapy of malignant tumor.
Description
Technical Field
The invention relates to a double-target Pt (IV) anticancer prodrug, a preparation method and application thereof, wherein the Pt (IV) anticancer prodrug is a Pt (IV) complex with a chemical formula of fac- [ Pt (1R, 2R-cyclohexanediamine) (hydroxy) (3-bromopyruvate) 3 ]I.e. fac- [ Pt (1R, 2R-DACH) (OH) (3-bromoxyruvate) 3 ]A prodrug of oxaliplatin comprising 3 ligands of 3-bromopyruvate (glycolytic inhibitor, 3-bromopyruvic acid). The Pt (IV) anticancer prodrug can inhibit the replication of tumor cell DNA and glycolysis path simultaneously, has two action targets, has good water solubility and high antitumor activity, can be used for chemotherapy of malignant tumor, and belongs to the field of biological pharmacy.
Background
Malignant tumor is the second most fatal disease following cardiovascular and cerebrovascular diseases. Although targeted therapies and immunotherapies have emerged in recent years to a great extent to improve prognosis of clinical treatment of tumors, surgery, radiotherapy and chemotherapy are essential basic therapies for clinical treatment of malignant tumors, particularly chemotherapy, and show unique advantages against heterogeneity and rapid proliferation characteristics of tumor cells, and can make up for the deficiencies in this respect by being used in combination with targeted therapies and immunotherapies. The chemotherapy is based on chemotherapeutic drugs, and platinum anticancer drugs represented by cisplatin (DDP), carboplatin (CBP) and Oxaliplatin (OXP) are very important chemotherapeutic drugs, the action targets of the platinum anticancer drugs are cancer cell DNA, the anticancer activity is strong, the action mechanism is unique, and the platinum anticancer drugs have synergistic anticancer effects with most natural drugs (such as paclitaxel), targeted drugs (such as gefitinib and trastuzumab), and immunotherapeutic drugs (such as PD-1/PD-L1 immunosuppressant palbociclib/atenolizumab) and are widely used for clinical treatment of common and multiple malignant tumors. According to the latest statistics, more than 50% of chemotherapy schemes mainly use platinum anti-cancer drugs or have platinum anti-cancer drugs to participate in compatibility. However, there are two major drawbacks to the clinical use of platinum-based anticancer drugs: toxic and side effects and drug resistance are easy to occur. Therefore, the development of novel platinum drugs with high anticancer activity, low toxicity and low cross drug resistance with the existing drugs still has important clinical value.
Cisplatin, carboplatin and oxaliplatin have the chemical structural formulas:
the platinum drugs which are clinically applied at present comprise cisplatin, carboplatin, oxaliplatin and the like, which are Pt (II) complexes, and Pt (II) belongs to d 8 Valence electron configuration, using d 2 sp 3 Hybridization to form four-coordination plane structure, active coordination substitution reaction kinetics, easy generation of undesirable chemical reaction with biological molecules in blood or intercellular fluid before reaching cancer cell DNA target, and degradation of partial medicine while generating toxic and side effects. The Pt (II) complex forms a hexacoordinated octahedral Pt (IV) complex after axial oxidation, and the general structural formula is cis, trans, cis- [ Pt (IV) A 2 Y 2 X 2 ](wherein A is a pharmacophore, Y is an axial ligand, X is a leaving group), the reaction kinetics is inert, the reaction rate with biological macromolecules is obviously reduced, the reaction can be maintained relatively stable in an in vivo environment, and the toxicity is low. In addition, the tumor tissue belongs to a reducing microenvironment, the concentration of glutathione and vitamin C is obviously higher than that of normal cells, and Pt (IV) can be reduced into a corresponding Pt (II) anticancer drug cis- [ Pt (II) A) 2 X 2 ]. Therefore, the Pt (IV) complex can be regarded as a Prodrug (Prodrug) of the Pt (II) anticancer drug, and provides an effective mode for tumor targeted delivery of the Pt (II) anticancer drug. In addition, the water solubility and fat solubility of the Pt (IV) complex can be adjusted and increased by selecting a proper axial ligand YActing on target spot to improve anticancer activity, etc. Therefore, pt (iv) prodrugs are one of the hot research directions of platinum-based anticancer drugs in recent years.
The supply of human cell energy is mainly derived from glucose, and there are two ways: mitochondrial oxidative phosphorylation and glycolysis. Normal cells rely mainly on mitochondrial oxidative phosphorylation to gain energy; unlike normal cells, tumor cells lack metabolic flexibility, mainly by the glycolytic pathway to power themselves, which is an adaptive response to intermittent hypoxia, and maintain this energy supply even at normal oxygen concentrations, the so-called Warburg effect, but the glycolytic process produces limited energy, so that tumor cells accelerate sugar uptake and metabolism in humans in order to maintain rapid proliferation and other activities, an obvious feature makes the glycolytic pathway an important target for anti-tumor action. 3-bromopyruvate is an organic carboxylic acid small molecule that can inhibit the glycolytic pathway by inhibiting the activity of hexokinase ii (the first rate-limiting enzyme of glycolysis), resulting in the inability of tumor cells to ingest energy for death without affecting surrounding normal tissues and cells; in addition, 3-bromopyruvate can also overcome the multi-drug resistance of tumors and enhance the activity of anticancer drugs such as platinum anticancer drugs. But 3-bromopyruvate is relatively unstable, and can be degraded quickly when entering a human body, and has no obvious anti-tumor curative effect. Thus, the stability of 3-bromopyruvate is a major limiting factor affecting its anti-tumor effect.
Disclosure of Invention
The technical problem solved by the invention is that 3-bromopyruvate is introduced into Pt (IV) prodrug molecules through coordination substitution reaction with the axial and radial hydroxyl groups of Pt (IV), so that the acting target point of the Pt (IV) prodrug is increased, and meanwhile, the stability of 3-bromopyruvate is improved.
The invention uses cis- [ PtA ] 2 I 2 ]Or cis- [ PtA 2 Cl 2 ]As starting material, with equimolar AgSO 4 Hydrolysis reaction is carried out to produceCis- [ PtA 2 (OH 2 ) 2 ](SO 4 ) Then reacted with equimolar alkali metal hydroxide to convert to cis- [ PtA 2 (OH) 2 ]The solution is axially oxidized by hydrogen peroxide to obtain an intermediate cis- [ PtA 2 (OH) 4 ]·H 2 The synthetic route for the O, targeted dual-target Pt (IV) anticancer prodrug can be expressed as:
the above synthetic route is suitable for 2A being 2NH 3 Ammonia/amine ligands such as ethylenediamine, 1, 2-propylenediamine, 1, 3-propylenediamine, 1R,2R-DACH and the like and mixed amine thereof, and finally, the intermediate and 3-bromopyruvate undergo neutralization reaction to form a Pt (IV) complex of the following chemical formula:
(1)fac-[Pt(Ⅳ)A 2 (OH)(3-bromopyruvate) 3 ]；
(2)cis-[Pt(Ⅳ)A 2 (3-bromopyruvate) 4 ]。
the inventor successfully synthesizes 1 Pt (IV) complex fac- [ Pt (1R, 2R-DACH) (OH) (3-bromopyruvic acid) containing 3 molecules through multiple researches and experiments 3 ](code: brPt-4), a prodrug of oxaliplatin in a yield of about 82%, having the chemical structural formula:
a method for preparing a double-target Pt (IV) anticancer prodrug, which comprises the following steps:
step (1): at 45-60 ℃, cis- [ Pt (1R, 2R-DACH) I 2 ]Or cis- [ Pt (1R, 2R-DACH) Cl 2 ]And equimolar Ag 2 SO 4 Stirring and reacting in water solution for 6 hours in dark place, filtering to remove silver iodide or silver chloride precipitate to obtain cis- [ Pt (1R, 2R-DACH) (OH) 2 ) 2 ](SO 4 ) A solution;
step (2): at 15-30 ℃, cis- [ Pt (1R, 2R-DACH) (OH 2 ) 2 ](SO 4 ) And equimolar alkali metal hydroxide are stirred to react for 1 to 4 hours, and alkali Metal Sulfate (MSO) is removed by filtration 4 ) Precipitation to obtain cis- [ Pt (1R, 2R-DACH) (OH) 2 ]A solution;
step (3): at 30-50 ℃, to cis- [ Pt (1R, 2R-DACH) (OH) 2 ]Dropwise adding excessive hydrogen peroxide into the solution, stirring and reacting for 4 hours, decompressing and steaming the obtained solution to the minimum volume, adding a large amount of glacial acetone for reverse precipitation, filtering, drying, and recrystallizing by a water-acetone mixed solvent to obtain an intermediate cis- [ Pt (1R, 2R-DACH) (OH) 4 ]·H 2 O；
Step (4): cis- [ Pt (1R, 2R-DACH) (OH) at 30-40 DEG C 4 ]·H 2 Stirring O and 3-bromopyruvate in 3 times molar amount in water solution for 48-72 hr, freeze drying, filtering, washing with diethyl ether, drying, and re-crystallizing with methanol to obtain target complex fac- [ Pt (1R, 2R-DACH) (OH) (3-bromopyruvate) 3 ]。
Further, the alkali metal hydroxide in the step (2) is any one of strontium hydroxide, calcium hydroxide and barium hydroxide.
Further, in step (3), the cis- [ Pt (1R, 2R-DACH) (OH) 2 ]:H 2 O 2 The molar ratio of (2) is 1:10-25.
The reaction process is as follows:
the inventors found in the synthesis test that, in the aqueous solution system used for the synthesis, even if the amount of 3-bromopyruvate is increased to 6 times the calculated amount, 4 3-bromopyruvate ligands cannot be simultaneously introduced, and the structure thereof is as follows:
the product isolated was still the product BrPt-4 containing 3-bromopyruvate, which is probably due to the fact that when cis- [ Pt (IV) A 2 (OH) 4 ]·H 2 After 3 hydroxyl groups in O are all substituted by 3-bromopyruvate, pK of 3-bromopyruvate a The value is insufficient to replace the 4 th hydroxyl group in the molecule.
BrPt-4 belongs to a prodrug of oxaliplatin and has a water solubility of 12.1mg/mL. At the same time observe it at D 2 In O 1 The change with time of H-NMR was found to be that, when left at room temperature for 72 hours, 1 the H-NMR has no obvious change, so that the BrPt-4 has good stability of aqueous solution and meets the requirements of platinum complex patent medicine.
The MTT method is adopted to measure that the Pt (IV) complex BrPt-4 has high inhibition activity on proliferation of human non-small cell lung cancer cell strain (A549), human ovarian cancer cell strain (SKOV 3), human gastric cancer cell (MKN-28), human colon cancer cell strain (HCT 116) and human liver cancer cell strain (HepG 2), which indicates that BrPt-4 has high in vitro anticancer cell proliferation activity. Moreover, most importantly, the inhibition activity of BrPt-4 on the proliferation of oxaliplatin-resistant human non-small cell lung cancer cell lines (A549/OXP) is obviously higher than that of oxaliplatin, which suggests that BrPt-4 has quite resistant cancer cells.
On an in vivo model of a mouse transplanted tumor S180, after intraperitoneal injection administration of BrPt-4, the tumor inhibition rate is obviously higher than that of oxaliplatin, and from the changes of the body weight, thymus and spleen index, liver function and kidney function index, blood convention and myeloproliferation degree of the mouse after administration, other toxicity indexes of the BrPt-4 are obviously smaller than that of the oxaliplatin except that the body weight difference of the mouse before and after administration, which indicates that the BrPt-4 has very high anti-tumor activity and smaller toxicity.
As reported in the literature at home and abroad, the anti-tumor activity of the Pt (IV) complex is generally inferior to that of the corresponding Pt (II) drug, which is probably caused by insufficient reduction of Pt (IV) to Pt (II). Whereas BrPt-4 has higher antitumor activity than oxaliplatin, it is likely that part of the antitumor effect from 3-bromopyruvate (3-BrPA), i.e., brPt-4 has two action targets, and its antitumor mechanism can be expressed as:
besides inhibiting the replication of tumor cell DNA, the Pt (IV) complex BrPt-4 can also obtain additional anti-tumor curative effect by inhibiting glycolysis of tumor cells.
In conclusion, the Pt (IV) complex BrPt-4 has good water solubility, high stability, high antitumor activity and low toxicity, can be used as a prodrug of oxaliplatin, and is used for treating malignant tumors (such as lung cancer, ovarian cancer, gastric cancer, colon cancer, liver cancer and the like).
Drawings
Fig. 1: the chemical structural formula of the Pt (IV) complex BrPt-4 is shown in the specification.
Fig. 2: schematic of the effect of intraperitoneal (ip) administration of test compounds on bone marrow of tumor-bearing mice.
Detailed Description
Example 1: intermediate cis- [ Pt (1R, 2R-DACH) (OH) 4 ]·H 2 Synthesis of O
Cis- [ Pt (1R, 2R-DACH) I 2 ](6.26 g,11.12 mmol) or cis- [ Pt (1R, 2R-DACH) Cl 2 ](4.23 g,11.12 mmol) was added to 60mL of water, stirred into a uniform paste, added with an aqueous solution (110 mL) of silver sulfate (3.40 g,10.90 mmol), stirred at 45-60℃for 6 hours in the dark, checked for reaction to endpoint, filtered, washed 3 times with water to give a pale yellow clear filtrate, and added with equimolar alkali metal hydroxide (M (OH) 2 ) Stirring at 15-30 deg.c for 1-4 hr, filtering to obtain colorless clear filtrate, and setting the filtrate at 30-50 deg.cIn a water bath, 30wt% of hydrogen peroxide (25.21-63.01 g) is added dropwise, the reaction is continued to be stirred for 4 hours, the reaction solution is reduced pressure and distilled to the minimum volume to obtain light yellow oily matter, a large amount of glacial acetone is added for reverse precipitation, white to light yellow solid is separated out, the filtration and the glacial acetone washing are carried out for 2 times, the vacuum drying is carried out for 8 hours, and the obtained crude product is recrystallized by a water-acetone mixed solvent to obtain 3.80g of cis- [ Pt (1R, 2R-DACH) (OH) 4 ]·H 2 O, yield 86.26%.
Structural feature parameters: <1> elemental analysis: measurement values Pt 49.12%, C17.96%, H5.88%, N6.81% (calculated values Pt 49.40%, C18.22%, H5.06%, N7.09%).
Example 2: target complex fac- [ Pt (1R, 2R-DACH) (OH) (3-bromoxyruvate) 3 Synthesis of (BrPt-4)
Cis- [ Pt (1R, 2R-DACH) (OH) 4 ]·H 2 O (1.01 g,2.56 mmol) was dissolved in 10mL of water, and an aqueous solution (5 mL) of 3-bromopyruvate (1.35 g,8.08 mmol) was added thereto, followed by stirring at 30-40℃for 48-72 hours. And gradually separating out a brown yellow solid from the clear solution in the reaction process, after the reaction is finished, freeze-drying, filtering, washing with diethyl ether for 3 times, and vacuum-drying for 8 hours, and recrystallizing and purifying the obtained brown yellow solid with methanol to obtain 1.71g of a product with the yield of 81.12%.
Structural feature parameters:
(1) Elemental analysis
Measurement values Pt 23.38%, C21.47%, H3.08%, N3.01% (calculated values Pt 23.66%, C21.84%, H2.55%, N3.40%);
(2) 1 H NMR(500MHz,DMSO-d 6 )δ6.31-5.49(m,4H,2NH 2 ),3.33(s,H 2 O),2.50(p,J＝1.8Hz,DMSO),2.35(d,J＝15.8Hz,2H,2CH-cyclohexyl),1.98(d,J＝12.6Hz,2H,CH 2 -ax-3-BrPA),1.89(t,J＝13.6Hz,4H,2CH 2 -eq-3-BrPA),1.51(s,2H,CH 2 -cyclohexyl),1.26(d,J＝31.1Hz,4H,2CH 2 -cyclohexyl),1.02(t,J＝10.6Hz,2H,CH 2 -cyclohexyl)；
(3)IR(KBr,cm -1 )：3435(m),3202(m),1687(s),1322(s),573(w),513(w),440(w)；
(4)ESI-MS：825[M+H] + 。
example 3: the Pt (IV) complex BrPt-4 has the inhibition activity on tumor cell proliferation in vitro
Positive control sample oxaliplatin (lot number: L20200428) was purchased from kunming precious pharmaceutical industry limited; tumor cell lines were purchased from Shanghai life sciences institute cell banks, national academy of sciences.
The effect of the compounds BrPt-4 and Oxaliplatin (OXP) on cell proliferation was examined using the MTT method. Taking cells in logarithmic growth phase, including human non-small cell lung cancer cell strain (A549) and oxaliplatin drug-resistant strain thereof (A549/OXP), human ovarian cancer cell strain (SKOV 3), human gastric cancer cell strain (MKN-28), human colon cancer cell strain (HCT 116), human liver cancer cell strain (HepG 2) and human normal liver cells (L02), preparing single cell suspension by conventional digestion, counting, adjusting to a cell suspension with a certain concentration, inoculating into 96-well culture plate, 90 mu L/well, 37 ℃ and 5% CO 2 Culturing in a saturated humidity incubator for 24 hours, and adding the tested drugs with different concentrations after the cells adhere to the wall. All compounds were formulated with glucose injection (5% gs). Different 5 test concentrations were set according to the cells, 4 parallel wells per concentration, 10 μl/well. Adding medicine, culturing in incubator for 48 hr, adding MTT (5 mg/ml) 20 μl into each well, culturing for 4 hr, collecting supernatant, adding DMSO fusion reduction product in amount of 100 μl into each well, measuring OD value of each well at two wavelengths of 570nm and 630nm with enzyme-labeled instrument, calculating inhibition rate, and calculating half inhibition concentration IC by SPSS software according to each concentration inhibition rate 50 The results are shown in Table 1.
TABLE 1 influence of test compounds on proliferation of different cell lines
As shown in the results of Table 1, the inventive compound BrPt-4 has slightly lower inhibitory activity on proliferation of human non-small cell lung cancer cell line (A549) than oxaliplatin, and has higher inhibitory activity on proliferation of oxaliplatin-resistant human non-small cell lung cancer cell line (A549/OXP) and human ovaryThe proliferation of cancer cell line (SKOV 3), human gastric cancer cell line (MKN-28), human colon cancer cell line (HCT 116) and human liver cancer cell line (HepG 2) has high inhibition activity, and IC 50 Are smaller than the corresponding values for oxaliplatin. In particular, the inhibition activity for the oxaliplatin-resistant lung cancer cell strain A549/OXP proliferation is obviously higher than that of oxaliplatin, and the compound disclosed by the invention is shown to have quite resistant tumor cell resistance.
At the time of the test, we also set up a human normal cell line (L02) for comparison to evaluate the toxicity of the test compounds to normal cells, the results show that: concentration of inhibition of growth of the normal cell line by BrPt-4 IC 50 Is larger than the corresponding oxaliplatin, and shows that BrPt-4 has certain selectivity on tumor cells.
Example 4: in vivo tumor inhibiting effect and preliminary toxicity evaluation of Pt (IV) complex BrPt-4 intraperitoneal injection administration
Kunming (KM) mice, 22-25 g, females, purchased from Hunan Srilk laboratory animal Co., ltd; the mouse sarcoma S180 tumor strain is introduced from Shanghai pharmaceutical research institute of Chinese sciences; the positive control oxaliplatin (lot number: L20200428) was purchased from Kunming Talcro pharmaceutical Co. Both BrPt-4 and oxaliplatin were formulated with 5% GS at the desired concentrations.
Taking out the S180 cells of the mice growing well in the abdominal water type after 5-8 days of inoculation, and regulating the cell concentration to 1.0X10 by using Normal Saline (NS) 7 Per mL, 0.2 mL/mouse right axilla, randomly divided into 3 groups 24h after inoculation, and administered by intraperitoneal injection (ip) for 1 time/day, 13 consecutive days, with half of the dose of oxaliplatin effective against S180 inhibition in mice reported in the dose reference (ED 50 ) And the preliminary test results of this study, 7.6. Mu. Mol/kg were selected. Mice were sacrificed 24h after the last dose, and water was forbidden for 12h before sacrifice. Tumor was removed and weighed, tumor inhibition = (control group mean tumor weight-treatment group mean tumor weight/control group mean tumor weight x 100%) was calculated, data expressed as mean ± standard deviation, and P values were analyzed using SPSS statistical software treatment. The results are shown in Table 2. And simultaneously, the influence of the compound on body weight, important organs and blood indexes is examined after the administration so as to evaluate the preliminary toxicity of the compound.
1. Anti-tumor effect in whole body
The experimental results are shown in Table 2, and compared with the solvent group, oxaliplatin and BrPt-4 have remarkable tumor inhibiting effect, and the inhibition rates are 67.81% and 83.14%, respectively. However, the mice gain weight after administration was also affected, statistically significant compared to vehicle groups, suggesting toxic response. Comprehensively considering the tumor inhibition rate and the weight change of mice after administration, the curative effect of BrPt-4 is better than that of oxaliplatin at equimolar doses.
TABLE 2 influence of intraperitoneal (ip) administration of test compounds on the growth of mouse transplantation tumor S180
Note that: comparison to vehicle control: * P <0.05; * P <0.01; * P <0.001
2. Effects of administration on important viscera and blood index
Thymus and spleen are important immune organs, the most common toxic target organs for cytotoxic anticancer drugs. Liver and kidney are the main viscera of drug metabolism and are also the main toxic targets of platinum drugs. The results in table 3 show that the mice in the dosing group have significantly reduced thymus and spleen gland weights compared to the vehicle control group, suggesting: oxaliplatin and BrPt-4 both have immunosuppressive effects, but oxaliplatin is stronger than BrPt-4 in terms of the extent of alleviation of both compounds. While at a dose of 7.6. Mu. Mol/kg, both oxaliplatin and BrPt-4 had little effect on the liver and kidney coefficients of the mice.
TABLE 3 influence of intraperitoneal (ip) administration of test Compounds on the weights of spleen, thymus, liver and kidney in tumor-bearing mice
Note that: comparison to vehicle group: * P <0.05; * P <0.01; * P <0.001.
Glutamic-pyruvic transaminase ALT and glutamic-oxaloacetic transaminase AST are liver function indexes reflecting the presence or absence and severity of liver cells, and exist in the liver cells, and when liver cell membranes are damaged or cells are necrotized, the enzymes enter serum to be increased; serum creatinine CREA concentration can accurately reflect the extent of impairment of glomerular filtration function to some extent. When kidney function is normal, creatinine excretion rate is constant, and when kidney essence is damaged, glomerular filtration rate is reduced. When the filtration rate is reduced to a certain degree, the concentration of the blood creatinine is increased sharply; urea nitrogen BUN is a metabolic product of human protein, mainly discharged from the body along with urine through glomerular filtration, and when kidney parenchyma is damaged, glomerular filtration rate is reduced, so that urea nitrogen concentration in blood is increased, and therefore, by measuring urea nitrogen, the glomerular filtration function can be known. Table 4 shows the changes in liver and kidney function index of S180 mice given oxaliplatin and BrPt-4 by intraperitoneal injection (ip). Compared to vehicle group, brPt-4 had little effect on liver and kidney function, whereas AST of oxaliplatin group was elevated and statistically different suggesting its effect on liver function. Oxaliplatin has little effect on renal function, and the result is consistent with domestic and foreign reports.
TABLE 4 influence of intraperitoneal (ip) administration of test compounds on liver and kidney function in tumor-bearing mice
Note that: comparison to vehicle control: * P <0.05; * P <0.01.
Myelosuppression is also the most common toxicity of platinum drugs, often dose limiting toxicity, and is a major factor in death of mice in acute toxicity tests. Myelosuppression results in a decrease in blood cell number, with a particularly pronounced decrease in Platelets (PLT) and White Blood Cells (WBC). The results in Table 5 show that, following administration of oxaliplatin and BrPt-4 to tumor-bearing mice, WBC, PLT, RBC (erythrocytes) all showed a somewhat decreased trend, wherein the decrease in oxaliplatin group was particularly pronounced, with a significant difference compared to the vehicle group, indicating that oxaliplatin bone marrow suppression was more severe than BrPt-4.
Further mouse sternal bone marrow smear experiments can be seen (as shown in fig. 2), with oxaliplatin mice myelodysplasia in an extremely reduced state and BrPt-4 bone marrow in a hyperplastic active state compared to vehicle control, suggesting: oxaliplatin has a greater bone marrow toxicity than the present invention BrPt-4.
TABLE 5 influence of intraperitoneal (ip) administration of test compounds on blood convention in tumor-bearing mice
Note that: comparison with the negative control group: * P <0.05; * P <0.01; * P <0.001.
Claims (10)
1. A double-target Pt (IV) anticancer prodrug is characterized in that the chemical name of the Pt (IV) anticancer prodrug is fac- [ Pt (1R, 2R-cyclohexanediamine) (hydroxy) (3-bromopyruvate) 3 ]The molecule contains 3 glycolysis inhibitor 3-bromopyruvate ligands, and the chemical structural formula is as follows:
2. a method of preparing a dual-target Pt (iv) anticancer prodrug according to claim 1, comprising the steps of:
step (1): at 45-60 ℃, cis- [ Pt (1R, 2R-DACH) I 2 ]Or cis- [ Pt (1R, 2R-DACH) Cl 2 ]And equimolar Ag 2 SO 4 Stirring in water solution for reaction in dark place, filtering to remove silver iodide or silver chloride precipitate to obtain cis- [ Pt (1R, 2R-DACH) (OH) 2 ) 2 ](SO 4 ) A solution;
step (2): at 15-30 ℃, cis- [ Pt (1R, 2R-DACH) (OH 2 ) 2 ](SO 4 ) And equimolar alkali metal hydroxide, and filtering to remove alkali Metal Sulfate (MSO) 4 ) Precipitation to obtain cis- [ Pt (1R, 2R-DACH) (OH) 2 ]A solution;
step (3): at 30-50 ℃, to cis- [ Pt (1R, 2R-DACH) (OH) 2 ]Dropwise adding excessive hydrogen peroxide into the solution, stirring for reaction, performing rotary evaporation under reduced pressure to obtain solution, adding glacial acetone for reverse precipitation, filtering, drying, and recrystallizing with water-acetone mixed solvent to obtain intermediate cis- [ Pt (1R, 2R-DACH) (OH) 4 ]·H 2 O；
Step (4): cis- [ Pt (1R, 2R-DACH) (OH) at 30-40 DEG C 4 ]·H 2 Stirring O and 3 times of 3-bromopyruvate in a molar quantity in an aqueous solution for reaction, freeze-drying the obtained solution, filtering, washing with diethyl ether, drying, and recrystallizing with methanol to obtain a target complex fac- [ Pt (1R, 2R-DACH) (OH) (3-bromopyruvate) 3 ]。
3. The method according to claim 2, wherein the alkali metal hydroxide in the step (2) is any one of strontium hydroxide, calcium hydroxide and barium hydroxide.
4. The method according to claim 2, wherein in step (3) the cis- [ Pt (1R, 2R-DACH) (OH) 2 ]:H 2 O 2 The molar ratio of (2) is 1:10-25.
5. The process according to any one of claims 2 to 4, wherein the reaction is carried out in step (1) with stirring in the absence of light for 6 hours.
6. The process according to any one of claims 2 to 4, wherein the reaction is carried out with stirring in the step (2) for 1 to 4 hours.
7. The process according to any one of claims 2 to 4, wherein the reaction is carried out for 4 hours with stirring in step (3).
8. The process according to any one of claims 2 to 4, wherein the reaction is carried out with stirring in the step (4) for 48 to 72 hours.
9. Use of a dual-target Pt (iv) anticancer prodrug according to claim 1 for the preparation of an antitumor drug for clinical malignancy chemotherapy.
10. The use according to claim 9, wherein the malignancy includes lung cancer, ovarian cancer, gastric cancer, colon cancer and liver cancer.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE898614A (en) * | 1984-01-05 | 1984-05-02 | Abello Quimicos Farma Prod Sa | Antitumour and antiparasitic platinum complexes - contg. 1,2-di:amino-cyclohexane ligand |
| US20070203074A1 (en) * | 2006-02-16 | 2007-08-30 | Ko Young H | Composition and method for the efficacious and safe administration of halopyruvate for the treatment of cancer |
| CN102387801A (en) * | 2009-01-29 | 2012-03-21 | 高荣禧 | Compositions and methods for the treatment of cancer |
| CN114605475A (en) * | 2022-02-18 | 2022-06-10 | 昆明贵金属研究所 | Oral Pt (IV) anticancer prodrug containing 3-bromopyruvate ligand axially |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE898614A (en) * | 1984-01-05 | 1984-05-02 | Abello Quimicos Farma Prod Sa | Antitumour and antiparasitic platinum complexes - contg. 1,2-di:amino-cyclohexane ligand |
| US20070203074A1 (en) * | 2006-02-16 | 2007-08-30 | Ko Young H | Composition and method for the efficacious and safe administration of halopyruvate for the treatment of cancer |
| CN102387801A (en) * | 2009-01-29 | 2012-03-21 | 高荣禧 | Compositions and methods for the treatment of cancer |
| CN114605475A (en) * | 2022-02-18 | 2022-06-10 | 昆明贵金属研究所 | Oral Pt (IV) anticancer prodrug containing 3-bromopyruvate ligand axially |
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