CN118239902B - Iron ion chelating agent and preparation method and application thereof - Google Patents
Iron ion chelating agent and preparation method and application thereof Download PDFInfo
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 title claims abstract description 90
- 229910052742 iron Inorganic materials 0.000 title claims abstract description 81
- 239000002738 chelating agent Substances 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- -1 iron ion Chemical class 0.000 claims abstract description 73
- 239000003814 drug Substances 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 9
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
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- 238000006243 chemical reaction Methods 0.000 claims description 14
- 238000006722 reduction reaction Methods 0.000 claims description 14
- VHPXSBIFWDAFMB-UHFFFAOYSA-N 2-amino-Delta(2)-thiazoline-4-carboxylic acid Chemical compound NC1=[NH+]C(C([O-])=O)CS1 VHPXSBIFWDAFMB-UHFFFAOYSA-N 0.000 claims description 13
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 13
- 206010028980 Neoplasm Diseases 0.000 claims description 13
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- 239000000126 substance Substances 0.000 claims description 9
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- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 206010038389 Renal cancer Diseases 0.000 description 5
- 201000010982 kidney cancer Diseases 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
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- 239000013078 crystal Substances 0.000 description 4
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- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010065973 Iron Overload Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
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- 229960001489 deferasirox Drugs 0.000 description 2
- FMSOAWSKCWYLBB-VBGLAJCLSA-N deferasirox Chemical compound C1=CC(C(=O)O)=CC=C1N(N\C(N\1)=C\2C(C=CC=C/2)=O)C/1=C\1C(=O)C=CC=C/1 FMSOAWSKCWYLBB-VBGLAJCLSA-N 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
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- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- 206010038486 Renal neoplasms Diseases 0.000 description 1
- 102000007238 Transferrin Receptors Human genes 0.000 description 1
- 108010033576 Transferrin Receptors Proteins 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
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- 229940088710 antibiotic agent Drugs 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
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- 229960001425 deferoxamine mesylate Drugs 0.000 description 1
- IDDIJAWJANBQLJ-UHFFFAOYSA-N desferrioxamine B mesylate Chemical compound [H+].CS([O-])(=O)=O.CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN IDDIJAWJANBQLJ-UHFFFAOYSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/18—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/04—Chelating agents
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Toxicology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an iron ion chelating agent, a preparation method and application thereof, belonging to the technical field of medicines; the iron ion chelating agent provided by the invention can be effectively chelated with iron ions, so that the iron load in a human body is reduced, and the transport of transferrin to iron ions in blood is also reduced, thereby realizing the inhibition effect on tumor cell separation and growth and achieving the anti-tumor effect. In addition, in the preparation method of the iron ion chelating agent, raw materials are simple and easy to obtain, the synthesis operation is simple, and the yield and purity of the synthesized product are high, so that the method is beneficial to actual production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an iron ion chelating agent, and a preparation method and application thereof.
Background
Iron ion chelators include any therapeutic agent having pharmaceutical utility as a chelate of iron in patients in need of iron chelation, and have been used to treat iron overload due to long-term blood transfusion, with the aim of metabolizing iron accumulated in the body out of the body, typical iron chelators being EDTA, deferoxamine mesylate, deferoxanone, deferasirox, and the like. Iron is an essential nutrition for cancer cell division, is essential ion for mitochondrial oxidation respiratory chain, and can effectively inhibit cancer cell division by reducing the intake of cancer cells to achieve the purpose of treating cancer.
Therefore, the effective iron ion chelating agent has great application prospect.
Disclosure of Invention
The invention aims to provide an iron ion chelating agent with excellent iron ion chelating effect and anti-tumor effect, and a preparation method and application thereof.
To achieve the above object, in a first aspect of the present invention, there is provided an iron ion chelating agent represented by formula i:
The chemical name of the iron ion chelating agent shown in the formula I is 2- ((2, 3,4,5, 6-pentahydroxyhexyl) -amino) -4, 5-dihydrothiazole-4-carboxylic acid, and the chemical name is A102. The iron ion chelating agent A102 provided by the invention has a definite structure and can effectively chelate iron ions.
In a second aspect of the present invention, there is provided a method of preparing the iron ion chelating agent, the method comprising the steps of: 2-amino-4, 5-dihydrothiazole-4-carboxylic acid and glucose are taken as raw materials to obtain the iron ion chelating agent through a combination reaction and a reduction reaction.
The preparation method of the iron ion chelating agent provided by the invention is simple to operate, raw materials are easy to obtain, and the preparation method is favorable for actual production and application.
As a preferred embodiment of the preparation method of the present invention, the preparation method comprises the steps of: mixing 2-amino-4, 5-dihydrothiazole-4-carboxylic acid with aqueous solution of methanol, adding sodium hydroxide for dissolution, adding glucose for chemical combination reaction, adding sodium borohydride in batches after the chemical combination reaction is finished for reduction reaction, adding hydrochloric acid after the reduction reaction is finished, concentrating, and recrystallizing to obtain the iron ion chelating agent.
As a preferred embodiment of the preparation method of the present invention, the molar ratio of 2-amino-4, 5-dihydrothiazole-4-carboxylic acid, glucose and sodium borohydride is 2-amino-4, 5-dihydrothiazole-4-carboxylic acid: glucose: sodium borohydride = 1: (0.9-1.5): (2.5-3.5).
Preferably, the molar ratio of 2-amino-4, 5-dihydrothiazole-4-carboxylic acid, glucose and sodium borohydride is 2-amino-4, 5-dihydrothiazole-4-carboxylic acid: glucose: sodium borohydride = 1:1:2.6.
The present inventors have found that when the molar ratio of 2-amino-4, 5-dihydrothiazole-4-carboxylic acid, glucose and sodium borohydride is further selected within the above range, the yield of the iron ion chelating agent A102 is higher.
As a preferred embodiment of the preparation method of the invention, the temperature of the chemical combination reaction is 22-35 ℃, and the time of the chemical combination reaction is 5-8 hours; the temperature of the reduction reaction is 22-35 ℃, and the time of the reduction reaction is 6-10h.
Preferably, the temperature of the combination reaction is 25 ℃, and the time of the combination reaction is 6 hours; the temperature of the reduction reaction is 25 ℃, and the time of the reduction reaction is 8 hours.
According to the invention, when the temperature and time of the combination reaction and the reduction reaction are further selected within the above ranges, the purity of the prepared product can be higher, the heating or the overlong reaction time can be avoided, the production efficiency is improved, and the production cost is reduced.
As a preferred embodiment of the preparation method of the invention, the volume ratio of methanol to water in the aqueous methanol solution is 1:1.
As a preferred embodiment of the preparation process according to the invention, the molar ratio of sodium hydroxide to 2-amino-4, 5-dihydrothiazole-4-carboxylic acid is 2.5:1.
As a preferred embodiment of the preparation process according to the invention, the addition to sodium borohydride is carried out in batches ranging from 8 to 12.
As a preferred embodiment of the preparation method of the invention, the hydrochloric acid is added after the reduction reaction is finished in an amount to adjust the pH value of the system to 2-4.
As a preferred embodiment of the preparation method of the invention, the solvent used for recrystallization is acetonitrile or ethanol, the temperature of recrystallization is 0-10 ℃, and the added volume of the recrystallization solvent is 0.8-1.5 times of the volume of the methanol aqueous solution.
In a third aspect of the invention, the invention provides the use of said iron ion chelating agent or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for scavenging iron ions in vivo.
The iron ion chelating agent provided by the invention has excellent effect of chelating iron ions, so that the iron ion chelating agent can be used for preparing medicines for removing iron ions in a patient suffering from anemia, such as excessive iron ions and excessive iron load, and can be used for effectively removing iron ions in the patient suffering from anemia, thereby reducing the iron ion load in the patient suffering from anemia and realizing treatment on the patient suffering from anemia.
In a fourth aspect of the invention, the invention provides the use of the iron ion chelating agent or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a tumour.
The iron ion is an essential nutrition for tumor cell division, is necessary ion of mitochondrial oxidation respiratory chain, and the surface of transferrin receptor tumor cells is provided with the iron ion with concentration far exceeding that of normal cells, and the iron ion chelating agent A102 provided by the invention can effectively chelate the iron ion, thereby reducing the transfer of transferrin to the iron ion in blood, inhibiting the separation and growth of tumor cells, and realizing the treatment of tumors.
As a preferred embodiment of the use according to the invention, the neoplasm comprises a renal neoplasm, a lung neoplasm.
The research of the invention discovers that the iron ion chelating agent A102 can effectively inhibit the activity of kidney tumor cells and lung tumor cells, thereby achieving the effects of resisting kidney tumor and lung tumor.
In a fifth aspect of the invention, the invention provides an anti-tumour agent comprising an iron ion chelating agent of the invention or a pharmaceutically acceptable salt thereof.
As a preferred embodiment of the antitumor drug of the present invention, the antitumor drug further comprises a pharmaceutically acceptable carrier.
In a sixth aspect of the present invention, there is provided an antitumor pharmaceutical composition comprising the iron ion chelating agent of the present invention or a pharmaceutically acceptable salt thereof, as well as other conventional antitumor drugs.
As a preferred embodiment of the antitumor drug composition of the present invention, the other conventional antitumor drugs include any one of cytotoxic drugs, antitumor antibiotics, and immunological drugs.
Compared with the prior art, the invention has the beneficial effects that:
The invention provides an iron ion chelating agent and pharmaceutically acceptable salts thereof, which can be effectively chelated with iron ions so as to reduce iron load in a body, and can also reduce the transportation of transferrin to iron ions in blood, thereby realizing the separation and growth inhibition effect of tumor cells and achieving the anti-tumor effect. In addition, in the preparation method of the iron ion chelating agent, raw materials are simple and easy to obtain, the synthesis operation is simple, and the yield and purity of the synthesized product are high, so that the method is beneficial to actual production.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of the iron ion chelating agent A102 prepared in example 1;
FIG. 2 is a bar chart of test results in effect example 2;
FIG. 3 is a bar chart showing the test results in effect example 3;
FIG. 4 is a graph showing the results of the test in effect example 4.
Detailed Description
For a better description of the objects, technical solutions and advantages of the present invention, the present invention will be further described with reference to the following specific examples.
The reagents, methods and apparatus employed in the present invention, unless otherwise specified, are all those conventional in the art; and the raw materials used in parallel experiments are the same batch of raw materials without special description.
Examples
The embodiment of the invention provides an iron ion chelating agent A102, and a preparation method of the iron ion chelating agent A102 comprises the following steps:
2-amino-4, 5-dihydrothiazole-4-carboxylic acid (146 g,1 mol) is added into 1000mL of methanol aqueous solution (the volume ratio of methanol to water is 1:1), and then sodium hydroxide (100 g,2.5 mol) is added, stirred and dissolved to obtain a mixed solution; glucose (180 g,1 mol) was then slowly added to the mixed solution, and after stirring at room temperature (25 ℃) for 6 hours, sodium borohydride (100 g,2.6 mol) was added in 10 batches, and stirring at room temperature (25 ℃) was continued for 8 hours; after the reaction, 240mL of hydrochloric acid is added into the system to adjust the pH value of the system to 3, then spin-drying is carried out, 1000mL of acetonitrile is added to carry out recrystallization for 4 hours at 4 ℃, after recrystallization, filtration is carried out, filter residues are collected and dried, and 123g of iron ion chelating agent A102 (the purity is 99% and the yield is 40%) is obtained.
The nuclear magnetic hydrogen spectrogram of the prepared iron ion chelating agent A102 is shown in figure 1, and the hydrogen spectrum characterization data is ：HNMR:12.08(s,1H),5.84-5.75(m,1H),4.98(t,1H),4.71-4.57(m,2H),4.50(dd,3H),4.29(1H),3.73-3.49(m,6H),3.48-3.33(m,2H),3.33-3.21(m,2H); mass spectrum characterization data which are as follows: MS (ES +,[M+H]+) 311.28.
Effect example 1
The effect example of the invention verifies the chelation of the iron ion by the iron ion chelating agent A102, and specifically comprises the following steps:
50 SPF-class C57 mice were selected, and each half (Zhuhai Baitong biosciences Co., ltd., the license number for producing laboratory animals: SCXK (Yue) 2020-0051) was bred in 4 animals/cage in SPF-class animal houses of Zhuhai Baitong biosciences Co., ltd.). The feeding environment is as follows: the temperature is 20-26 ℃, the humidity is 40-70%, and the lighting is intermittently performed for 12 hours and 12 hours. 50 mice are randomly divided into a blank group, a model group, an A102 high-dose group, an A102 high-low-dose group and a prior art group, 10 mice in each group are subjected to intraperitoneal injection of 80mg/kg for 1 time per day for molding of dextrose crisp iron, and the continuous injection is carried out for 15 days, so that an iron overload mouse model is established. From the day of successful molding, each group was given 1 lavage per day, with the blank and model groups given 1mL saline lavage, the A102 high dose group was lavaged at 120mg/kg, the A102 low dose group was lavaged at 40mg/kg, and the prior art group (deferasirox DFX) was lavaged at 200mg/kg for 14 days. The serum ferritin content of the mice is measured by a full-automatic immunoassay instrument after 14 days of gastric lavage, and the results are shown in table 1;
TABLE 1
| Blank group | Model group | A102 low dose group | A102 high dose group | Prior art group | |
| Serum ferritin (μg/L) | 27.72±1.01 | 102.98±4.76** | 73.91±3.82**ΔΔ | 35.57±3.35**ΔΔ | 85.27±6.82**ΔΔ |
"**" Means that p <0.05 compared to the blank group, and "ΔΔ" means that p <0.05 compared to the model group.
As can be seen from table 1, the iron ion chelating agent a102 provided by the invention has excellent iron ion chelating effect; especially, when the stomach is irrigated at the dosage of 120mg/kg, the serum ferritin content can be obviously reduced; and compared with the prior art group, the A102 low-dose group and the A102 high-dose group can show more excellent iron ion chelating effect under the condition that the dosage of the A102 is obviously lower than that of the prior art group.
Effect example 2
The effect example of the invention verifies the inhibition effect of the iron ion chelating agent A102 on kidney tumor cells, and specifically comprises the following steps:
human renal cancer cells OS-RC-2 (available from the GmbH of the life sciences Co., ltd.) were inoculated at a density of about 10000 pieces/well into 96-well plates and cultured in DMEM high-sugar medium containing 10% fetal bovine serum (culture conditions: 37 ℃ C., 5% CO 2). When the cell density reached 70-80%, A102 with gradient concentration of 5. Mu.M, 10. Mu.M, 20. Mu.M, 50. Mu.M, 100. Mu.M, 200. Mu.M was added as experimental group, and cells treated with 150uLDMSO per well were used as negative control group and blank group without cells were added, each group was provided with three multiplex wells. After further culturing for 24 hours, 48 hours and 72 hours, respectively, the morphology was observed under an inverted microscope. 100uL of MTT culture solution with the final concentration of 5mg/mL is added into each hole, the culture solution is sucked after the continuous culture is carried out for 4 hours, 100uL of DMSO solution is added into each hole, dissolved purple crystals are sucked and beaten, and the mixture is placed into a shaking incubator for shake culture for 10 minutes until the crystal purple is fully dissolved, and the absorbance is measured at 470nm of an enzyme-labeled instrument. Cell viability= [ (experimental group mean OD value-blank group mean OD value)/(negative control group mean OD value-blank group mean OD value) ]x100%.
The results obtained by the test are shown in fig. 2, wherein the ordinate represents the survival rate of the kidney cancer cells, the abscissa represents the concentration of the iron ion chelating agent A102, and as can be seen from fig. 2, the iron ion chelating agent A102 is in the range of 0-200 mu M, the survival rate of the kidney cancer cells is obviously reduced and then is stable along with the increase of the concentration, and the survival rate of the kidney cancer cells is obviously reduced along with the increase of the action time under different concentrations. Meanwhile, as can be seen from fig. 2, the iron ion chelating agent A102 provided by the invention has obvious inhibition effect on renal cancer cells.
Effect example 3
The effect example of the invention verifies the inhibition effect of the iron ion chelating agent A102 on lung tumor cells, and specifically comprises the following steps:
Human non-small cell lung cancer cells A549 (available from the Marinotte life technologies Co., ltd.) were inoculated at a density of about 10000 cells/well into 96-well plates and cultured in DMEM high-sugar medium containing 10% fetal bovine serum (culture conditions 37 ℃, 5% CO 2). When the cell density reached 70-80%, A102 with a gradient of 5. Mu.M, 10. Mu.M, 20. Mu.M, 50. Mu.M, 100. Mu.M, 200. Mu.M was added as the experimental group, and the cells treated with 150uLDMSO per well were used as the negative control group and the blank group without cells were added, each group was provided with three duplicate wells. After further culturing for 24 hours, 48 hours and 72 hours, respectively, the morphology was observed under an inverted microscope. 100uL of MTT culture solution with the final concentration of 5mg/mL is added into each hole, the culture solution is sucked after the continuous culture is carried out for 4 hours, 100uL of DMSO solution is added into each hole, dissolved purple crystals are sucked, and the mixture is placed into a shaking incubator for shaking culture for 10 minutes until the crystal purple is fully dissolved, and the absorbance is measured at 470nm of an enzyme-labeled instrument. Cell viability= [ (experimental group mean OD value-blank group mean OD value)/(negative control group mean OD value-blank group mean OD value) ]x100%.
The results obtained by the test are shown in fig. 3, wherein the ordinate represents the survival rate of the human non-small cell lung cancer cells, the abscissa represents the concentration of the iron ion chelating agent A102, and as can be seen from fig. 3, the iron ion chelating agent A102 is in the range of 0-200 mu M, the survival rate of the human non-small cell lung cancer cells is obviously reduced and then is stable along with the increase of the concentration, and the survival rate of the human non-small cell lung cancer cells is obviously reduced along with the increase of the action time under different concentrations. Meanwhile, as can be seen from fig. 3, the iron ion chelating agent A102 provided by the invention has obvious inhibition effect on human non-small cell lung cancer cells.
Effect example 4
The effect example of the invention verifies the inhibition effect of the iron ion chelating agent A102 on lung tumor, and specifically comprises the following steps:
5 x 10 6 non-small cell lung cancer cells A549 were resuspended in PBS containing 50% matrigel without phenol red, and then inoculated subcutaneously into female BALB/c nude mice purchased from Shanghai Baitong Biotechnology Co., ltd. The length of the transplanted tumor and the length perpendicular thereto were measured with a vernier caliper 1 time per week, and the volume of the transplanted tumor was calculated. After about two weeks, molding was considered successful when the tumor volume was greater than 200mm 3. Randomly dividing 30 bare mice successfully molded into 3 groups, and filling corresponding substances once daily for two weeks, wherein each group comprises 10 nude mice; specifically, the control group was filled with 0.5mL of sterilized normal saline daily, the A102 low dose group was filled with A102 at a dose of 40mg/kg daily, and the A102 high dose group was filled with A102 at a dose of 120mg/kg daily. The volume of the transplanted tumor was monitored during this period, and the results obtained are shown in fig. 4.
As can be seen from fig. 4, the iron ion chelating agent a102 provided by the invention can effectively inhibit the growth of tumors in vivo.
Finally, it should be noted that the above-mentioned embodiments illustrate rather than limit the scope of the invention, and that those skilled in the art will understand that changes can be made to the technical solutions of the invention or equivalents thereof without departing from the spirit and scope of the technical solutions of the invention.
Claims (9)
1. An iron ion chelating agent of formula i, and pharmaceutically acceptable salts thereof:
2. the method of preparing an iron ion chelating agent according to claim 1, wherein said method of preparing comprises the steps of: 2-amino-4, 5-dihydrothiazole-4-carboxylic acid and glucose are taken as raw materials to obtain the iron ion chelating agent through a combination reaction and a reduction reaction.
3. The preparation method according to claim 2, characterized in that the preparation method comprises the steps of: mixing 2-amino-4, 5-dihydrothiazole-4-carboxylic acid with aqueous solution of methanol, adding sodium hydroxide for dissolution, adding glucose for chemical combination reaction, adding sodium borohydride in batches after the chemical combination reaction is finished for reduction reaction, adding hydrochloric acid after the reduction reaction is finished, concentrating, and recrystallizing to obtain the iron ion chelating agent.
4. A process according to claim 3, wherein the molar ratio of 2-amino-4, 5-dihydrothiazole-4-carboxylic acid, glucose and sodium borohydride is 2-amino-4, 5-dihydrothiazole-4-carboxylic acid: glucose: sodium borohydride = 1: (0.9-1.5): (2.5-3.5).
5. The method according to claim 4, wherein the temperature of the combination reaction is 22-35 ℃ and the time of the combination reaction is 5-8 hours; the temperature of the reduction reaction is 22-35 ℃, and the time of the reduction reaction is 6-10h.
6. Use of an iron ion chelating agent of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for scavenging iron ions in vivo.
7. Use of the iron ion chelating agent of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a tumor; the tumor is selected from kidney tumor and lung tumor.
8. An antitumor drug comprising the iron ion chelating agent of claim 1 or a pharmaceutically acceptable salt thereof.
9. An anti-tumor pharmaceutical composition comprising the iron ion chelating agent of claim 1 or a pharmaceutically acceptable salt thereof, and other conventional anti-tumor agents.
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