CN115286662A - Amino acid hybridized tetranuclear platinum complex, preparation method and application - Google Patents
Amino acid hybridized tetranuclear platinum complex, preparation method and application Download PDFInfo
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 101
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- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 36
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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
-
- 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 belongs to the technical field of medicinal chemistry, and particularly relates to an amino acid hybrid tetranuclear platinum complex, a preparation method and application thereof. The invention designs and successfully synthesizes a novel amino acid hybridized tetranuclear platinum complex, and the in vitro anti-inflammatory and anti-tumor activity test results show that the amino acid group and the anti-tumor active group with anti-inflammatory activity in the amino acid hybridized tetranuclear platinum complex can successfully take effect, have better anti-inflammatory and anti-tumor dual activities on tumors, and particularly the complex [ Pt (glu) (bpy)] 4 The antitumor activity and targeting property of the composition far exceed those of cisplatin, and the composition can provide reference for preparing novel antitumor drugs with higher activity and stronger selectivity and dual anti-inflammatory and antitumor effects.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to an amino acid hybrid tetranuclear platinum complex, a preparation method and application thereof.
Background
There is increasing evidence that the inflammatory response is closely related to the pathological course of the tumor. A large number of inflammatory factors exist in a tumor microenvironment, such as IL-1, IL-6, IL-12, TNF-alpha, TGF-beta and the like, and can not only recruit inflammatory cells to a tumor site, amplify inflammatory effects and promote tumor cell proliferation, but also promote tumor peritoneal new blood vessels and lymphatic formation and promote tumor cell metastasis. In addition, research findings show that IL-6 can also inhibit proliferation of T cells and apoptosis of lymphocytes by down-regulating IL-2 synthesis, trigger tumor cells to activate immune regulation mechanisms to escape immune surveillance, and generate immune tolerance. Meanwhile, the release of a large amount of proinflammatory cytokines such as TNF-alpha, IL-6 and the like in tumor tissues is an important reason for rapid deterioration, poor prognosis and high mortality of tumor patients. Most importantly, a large amount of clinical data show that the chemotherapy effect of the tumor can be improved and consolidated to a certain extent by being assisted with anti-inflammatory drug treatment.
The platinum compound is the most widely used chemotherapeutic drug in clinic at present, and the biological safety and the biological compatibility of the platinum compound are widely accepted. However, the current research on platinum compounds is mainly focused on the antitumor activity of the platinum compounds. Few studies have been reported on whether they can combine anti-inflammatory activity. Therefore, the research on designing and developing an amino acid hybrid tetranuclear platinum complex with stable chemical properties and dual activities of anti-inflammation and anti-tumor and the anti-tumor curative effect thereof are imperative.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide an amino acid hybrid tetranuclear platinum complex, a preparation method and application.
The technical scheme adopted by the invention is as follows: an amino acid hybridized tetranuclear platinum complex, which is shown in a chemical structural formula (I):
R 1 CHNH 2 COOH、R 2 CHNH 2 COOH、R 3 CHNH 2 COOH、R 4 CHNH 2 in COOHAt least one is an amino acid with anti-inflammatory activity.
Preferably, R 1 CHNH 2 COOH、R 2 CHNH 2 COOH、R 3 CHNH 2 COOH、R 4 CHNH 2 COOH is an amino acid with anti-inflammatory activity; r 1 、R 2 、R 3 、R 4 Are all identical radicals or are part of the same radical or are all different radicals.
Preferably, R 1 、R 2 、R 3 、R 4 Are all the same group.
Preferably, the amino acid having anti-inflammatory activity is one or more of arginine (Arg), ornithine (Orn), cysteine (Cys), tryptophan (Trp), methionine (Met), lysine (Lys), glutamic acid (Glu).
The invention further provides a preparation method of the amino acid hybrid tetranuclear platinum complex, which comprises the following steps:
(1) Amino acid raw material R 1 CHNH 2 COOH、R 2 CHNH 2 COOH、R 3 CHNH 2 COOH、R 4 CHNH 2 COOH reacts with chloroplatinic acid salt under acidic condition and nitrogen protection respectively to obtain corresponding amino acid substituted auxiliary ligand Pt (X) Cl 2 ；
(2) Substitution of amino acids with ancillary ligands Pt (X) Cl 2 In the process, cl is substituted into nitro to obtain intermediate dinitroplatinum (II) complex Pt (X) (NO) 3 ) 2 ；
(3) Intermediate dinitroplatinum (II) complex Pt (X) (NO) 3 ) 2 Reacting with a bridged ligand 4, 4-bipyridine to obtain a product shown in the formula (I).
Preferably, in the step (2), the auxiliary ligand Pt (X) Cl for amino acid substitution is replaced by silver nitrate 2 Wherein Cl is substituted into nitro.
Preferably, in step (3), the intermediate dinitroplatinum (II) complex Pt (X) (NO) 3 ) 2 In a molar amount corresponding to the molar amount of the bridging ligand 4, 4-bipyridine.
The invention further provides the application of the amino acid hybridized tetranuclear platinum complex in preparing antitumor drugs.
Preferably, the tumor is a tumor associated with inflammation.
The invention further provides an antitumor drug, the active ingredient of which comprises the amino acid hybrid tetranuclear platinum complex, and the pharmaceutical preparation is any one of injection, tablets, capsules, aerosol, suppositories, films, dropping pills, ointments, controlled release agents, sustained release agents or nano preparations.
The invention has the following beneficial effects: the invention designs and successfully synthesizes a novel amino acid hybridized tetranuclear platinum complex, and the in vitro anti-inflammatory and anti-tumor activity test results show that the amino acid group and the anti-tumor active group with anti-inflammatory activity in the amino acid hybridized tetranuclear platinum complex can successfully take effect, have better anti-inflammatory and anti-tumor dual activities on tumors, and particularly the complex [ Pt (glu) (bpy)] 4 The antitumor activity and targeting property of the composition far exceed those of cisplatin, and the composition can provide reference for preparing novel antitumor drugs with higher activity and stronger selectivity and dual anti-inflammatory and antitumor effects.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is within the scope of the present invention for those skilled in the art to obtain other drawings based on the drawings without inventive exercise.
FIG. 1 shows the results of the ELASI method of test example 1 for in vitro anti-inflammatory assay.
FIG. 2 shows the results of the MTT assay in test example 2 for in vitro antitumor activity.
FIG. 3 shows the results of the scratch test in test example 3 for in vitro transfer resistance.
Detailed Description
To make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings.
The invention provides an amino acid hybridized tetranuclear platinum complex, which has a chemical structural formula (I):
R 1 CHNH 2 COOH、R 2 CHNH 2 COOH、R 3 CHNH 2 COOH、R 4 CHNH 2 at least one of the COOH is an amino acid having anti-inflammatory activity.
In some embodiments of the invention, the compound obtained by hybridizing one or more amino acid hybrid tetranuclear platinum complexes with anti-inflammatory activity is used for detection and analysis, so that the inflammatory microenvironment of tumor tissues can be effectively relieved, the proliferation and the metastasis of tumor cells can be inhibited, a good tumor treatment effect can be obtained, and the anti-tumor activity and the targeting property of the compound are far superior to those of cisplatin.
In some embodiments of the invention, R 1 CHNH 2 COOH、R 2 CHNH 2 COOH、R 3 CHNH 2 COOH、R 4 CHNH 2 COOH is amino acid with anti-inflammatory activity, which has better tumor treatment effect than COOH.
In some embodiments of the invention, R 1 、R 2 、R 3 、R 4 Are all the same group;
in some embodiments of the invention, R 1 、R 2 、R 3 、R 4 The middle portions (two or three) are the same group;
in some embodiments of the invention, R 1 、R 2 、R 3 、R 4 All are different groups.
Preferably, R 1 、R 2 、R 3 、R 4 All are the same group, and the preparation process is more efficient.
In some embodiments of the invention, the amino acid having anti-inflammatory activity is one or more of arginine (Arg), ornithine (Orn), cysteine (Cys), tryptophan (Trp), methionine (Met), lysine (Lys), glutamic acid (Glu). The seven amino acids are common amino acids at present, the cost is low, and the antitumor activity and the targeting property of the seven amino acids far exceed those of cisplatin. Other amino acids with anti-inflammatory activity may also be synthesized by those skilled in the art.
The invention further provides a preparation method of the amino acid hybrid tetranuclear platinum complex, which comprises the following steps:
(1) Amino acid raw material R 1 CHNH 2 COOH、R 2 CHNH 2 COOH、R 3 CHNH 2 COOH、R 4 CHNH 2 COOH reacts with chloroplatinic acid salt under acidic condition and nitrogen protection respectively to obtain corresponding amino acid substituted auxiliary ligand Pt (X) Cl 2 ；
(2) Substitution of amino acids with ancillary ligands Pt (X) Cl 2 The intermediate dinitroplatinum (II) complex Pt (X) (NO) is obtained by replacing Cl with nitro 3 ) 2 ；
(3) Intermediate dinitroplatinum (II) complex Pt (X) (NO) 3 ) 2 Reacting with a bridged ligand 4, 4-bipyridine to obtain a product shown in the formula (I).
Further, in some embodiments of the present invention, the specific preparation process is as follows: various anti-inflammatory active amino acids react with potassium chloroplatinite under acidic condition (pH = 5.6) and under the protection of nitrogen to obtain amino acid substituted auxiliary ligand Pt (X) Cl 2 . Continuing to mix the ancillary ligand with silver nitrate (AgNO) 3 ) Dissolving in ultrapure water, adjusting the whole reaction system to be weakly acidic by dilute nitric acid, and heating for reaction in a dark place under the protection of nitrogen. After the reaction is finished, white precipitated silver chloride (AgCl) is filtered to obtain an intermediate dinitroplatinum (II) complex Pt (X) (NO) 3 ) 2 . Mixing the supernatant obtained in the last step with equimolar amount of bridging ligand 4, 4-dipyridyl (4, 4' -dipyridyl) respectively, heating to react for 2-3 days under the protection of nitrogen and avoiding light,after the reaction is finished, concentrating the reaction solution by adopting a vacuum suspension distillation method, adding absolute ethyl alcohol into the concentrated solution to force out a crude product, washing the crude product by using ethyl alcohol and ethyl ether, and drying in vacuum to obtain the target compound.
Preferably, in step (2), the auxiliary ligand Pt (X) Cl substituted by amino acid is silver nitrate 2 Wherein Cl is substituted into nitro.
Preferably, in step (3), the intermediate dinitroplatinum (II) complex Pt (X) (NO) 3 ) 2 In a molar amount corresponding to the molar amount of the bridging ligand 4, 4-bipyridine.
The invention further provides application of the amino acid hybridized tetranuclear platinum complex in preparation of antitumor drugs.
When the tumor is a tumor associated with inflammation, some embodiments of the invention achieve better antitumor effect than cisplatin, especially diseases closely associated with inflammation including ovarian cancer, breast cancer, osteosarcoma, etc.
The invention further provides an antitumor drug, the active ingredient of which comprises the amino acid hybrid tetranuclear platinum complex, and the pharmaceutical preparation is any one of injection, tablets, capsules, aerosol, suppositories, films, dropping pills, ointments, controlled release agents, sustained release agents or nano preparations.
Example 1:
the following is an amino acid hybrid tetranuclear platinum complex [ Pt (glu) (bpy) with superior antitumor activity of the present invention] 4 The synthetic route of (2) is as follows:
the preparation method comprises the following specific steps: glutamic acid (glu) reacts with potassium chloroplatinite under acidic conditions (pH = 5.6) and under the protection of nitrogen to obtain an amino acid substituted auxiliary ligand Pt (glu) Cl 2 . Continuing to mix the ancillary ligand with silver nitrate (AgNO) 3 ) Dissolving in ultrapure water, adjusting the whole reaction system to weak acidity with dilute nitric acid, and heating under nitrogen protection to avoid light for reaction. The reaction is finishedAfter that, the white precipitated silver chloride (AgCl) was filtered off to obtain an intermediate dinitroplatinum (II) complex Pt (glu) (NO) 3 ) 2 . And (2) mixing the supernatant obtained in the last step with equimolar bridging ligand 4, 4-bipyridyl (4, 4' -dipyridyl) respectively, heating to react for 2-3 days in a dark place under the protection of nitrogen, concentrating the reaction solution by a vacuum suspension method after the reaction is finished, adding absolute ethyl alcohol into the concentrated solution, expelling a crude product, washing the crude product by ethyl alcohol and ethyl ether, and drying in vacuum to obtain the target compound.
Complex [ Pt (glu) (bpy)] 4 Elemental analysis of (2) (% C) 61 H 67 N 12 O 27 Pt 4 ·12H 2 O (2220.77), theoretical value: c, 32.99, H, 4.13, N, 7.57. Experimental values: c, 32.73, H, 4.13 and N, 7.51. Nuclear magnetic platinum spectrum 195 Pt (500MHz, D 2 O): -1675 ppm。
Test example 1:
ELASI method for detecting [ Pt (glu) (bpy)] 4 Anti-inflammatory in vitro: in this test example, a mouse macrophage RAW264.7 was used as an example, and cisplatin (DDP) was used as a positive control, indicating that the conjugate [ Pt (glu) (bpy)] 4 The anti-inflammatory activity of (1). The experiment proves that [ Pt (glu) (bpy)] 4 Has high activity of inhibiting inflammatory reaction in vitro.
In vitro culturing mouse macrophage RAW264.7 induced by LPS, adding prepared amino acid hybridization tetranuclear platinum complex [ Pt (glu) (bpy) with suitable concentration when the cell growth reaches logarithmic growth phase] 4 .24 After h, cell culture fluid is collected, the levels of inflammatory proteins such as IL-6, TNF-alpha and the like are detected by using an ELISA kit, the protein concentration in a corresponding culture dish is quantified, and the inhibition rate of the inflammatory factors is calculated by comparing with a pure culture medium group (shown in figure 1). The above experimental results show that [ Pt (glu) (bpy)] 4 (5 mu M) has good anti-inflammatory activity, and can effectively relieve secretion of mouse macrophage RAW264.7 inflammatory factor IL-6 and TNF-alpha induced by LPS; the same dose of cisplatin (5 μ M) did not have any anti-inflammatory effect.
Test example 2:
MTT method for [ Pt (glu) (bpy)] 4 Has an anti-tumor effectTumor activity:
MTT method was used for further testing [ Pt (glu) (bpy)] 4 Antitumor activity against ovarian cancer and osteosarcoma which are clinically accompanied by high inflammation. In this test example, the human ovarian cancer cell line A2780 and the human osteosarcoma cell line U2OS are used as examples [ Pt (glu) (bpy)] 4 It should be understood that, although the use of the cell line of human ovarian cancer and the cell line of human osteosarcoma as anti-tumor drugs is only exemplified, the cells of the "tumor" referred to in the present invention include, but are not limited to, for example, the cell line of human ovarian cancer A2780, the cell line of human osteosarcoma U2OS, etc.
Respectively inoculating the human ovarian cancer cell strain A2780 and the human osteosarcoma cell strain MG63 in a 96-well plate, wherein the inoculation density is 5000 cells/160 mu L/well, and after the cells adhere to the wall for 6 hours, adding 40 mu L of complex [ Pt (glu) (bpy) containing corresponding concentration formula I] 4 Or an equal volume of medium containing 0.1% DMSO. Incubation was continued for 48h, followed by additional MTT (5 mg/ml) for 4h, the culture terminated and the culture supernatant from the wells carefully aspirated. Add 100ul DMSO/well and shake for 10 minutes to fully melt the crystals. Selecting 490nm wavelength, measuring the light absorption value of each pore on an enzyme-linked immunosorbent assay, recording the result, and calculating the median inhibitory concentrationIC 50 The value is obtained. The first line clinical chemotherapeutic cisplatin (DDP) was added to the control group at the same concentration and the results are shown in FIG. 2. The experimental results show that the complex of formula I [ Pt (glu) (bpy)] 4 Has antitumor activity equivalent to that of cisplatin.
Test example 3:
scratch detection [ Pt (glu) (bpy)] 4 The ability to inhibit tumor cell metastasis:
the scratch method was used to further detect [ Pt (glu) (bpy)] 4 The ability to inhibit tumor cell metastasis. The human ovarian cancer cells A2780 after the drug is applied are spread in 6-well plates at a density of 50 ten thousand per well, taking care that the medium in the wells does not contain serum. On the next day, three scratches were evenly and vertically scribed in each set of holes using a 300 μ l gun tip. The medium was discarded, washed once with PBS and 2 mL of serum-free medium was added again. Then the 6-well plate is placed in an inverted microscope according to the designated time pointPhotographs of the healing of the scratch were taken at each time point (0 h, 24 h). The results are shown in FIG. 3, comparing the same dose with the duration of action of the drug with cisplatin (DDP), the complex [ Pt (glu) (bpy)] 4 Has stronger capacity of inhibiting tumor cell metastasis.
The above disclosure is only for the purpose of illustrating the preferred embodiments of the present invention, and it is therefore to be understood that the invention is not limited by the scope of the appended claims.
Claims (10)
1. An amino acid hybridized tetranuclear platinum complex, which is characterized in that: the chemical structural formula is shown as formula (I):
R 1 CHNH 2 COOH、R 2 CHNH 2 COOH、R 3 CHNH 2 COOH、R 4 CHNH 2 at least one of the COOH is an amino acid having anti-inflammatory activity.
2. The amino acid hybrid tetranuclear platinum complex of claim 1, characterized in that: r is 1 CHNH 2 COOH、R 2 CHNH 2 COOH、R 3 CHNH 2 COOH、R 4 CHNH 2 COOH is an amino acid with anti-inflammatory activity; r is 1 、R 2 、R 3 、R 4 Are all identical radicals or are part of the same radical or are all different radicals.
3. The amino acid hybrid tetranuclear platinum complex of claim 2, characterized in that: r 1 、R 2 、R 3 、R 4 Are all the same group.
4. The amino acid hybrid tetranuclear platinum complex of claim 1, characterized in that: the amino acid with anti-inflammatory activity is one or more of arginine, ornithine, cysteine, tryptophan, methionine, lysine and glutamic acid.
5. The process for the preparation of amino acid hybrid tetranuclear platinum complexes as claimed in any of claims 1 to 4, characterized in that it comprises the following steps:
(1) Amino acid raw material R 1 CHNH 2 COOH、R 2 CHNH 2 COOH、R 3 CHNH 2 COOH、R 4 CHNH 2 COOH reacts with chloroplatinic acid salt under acidic condition and nitrogen protection respectively to obtain corresponding amino acid substituted auxiliary ligand Pt (X) Cl 2 ；
(2) Ancillary ligands Pt (X) Cl substituted with amino acids 2 In the process, cl is substituted into nitro to obtain intermediate dinitroplatinum (II) complex Pt (X) (NO) 3 ) 2 ；
(3) Intermediate dinitroplatinum (II) complex Pt (X) (NO) 3 ) 2 Reacting with a bridged ligand 4, 4-bipyridine to obtain a product shown in the formula (I).
6. The method of preparing an amino acid hybrid tetranuclear platinum complex according to claim 5, characterized in that: in the step (2), silver nitrate is adopted to substitute amino acid for auxiliary ligand Pt (X) Cl 2 Wherein Cl is substituted into nitro.
7. The method of preparing an amino acid hybrid tetranuclear platinum complex according to claim 5, characterized in that: in the step (3), an intermediate dinitroplatinum (II) complex Pt (X) (NO) 3 ) 2 In a molar amount corresponding to the molar amount of the bridging ligand 4, 4-bipyridine.
8. Use of the amino acid hybrid tetranuclear platinum complex as claimed in any one of claims 1 to 4 for the preparation of an antitumor medicament.
9. The use of the amino acid hybrid tetranuclear platinum complex according to claim 8 for the preparation of antitumor drugs, characterized in that: the tumor is a tumor associated with inflammation.
10. An antitumor agent characterized by: the effective component of the compound contains the amino acid hybrid tetranuclear platinum complex as shown in any one of claims 1 to 4, and the medicinal preparation is any one of injection, tablets, capsules, aerosol, suppositories, films, pills, ointments, controlled release agents, sustained release agents or nano preparations.
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