CN110357926B - Tropolone and phenanthroline mixed manganese complex and preparation method and application thereof - Google Patents
Tropolone and phenanthroline mixed manganese complex and preparation method and application thereof Download PDFInfo
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- MDYOLVRUBBJPFM-UHFFFAOYSA-N tropolone Chemical compound OC1=CC=CC=CC1=O MDYOLVRUBBJPFM-UHFFFAOYSA-N 0.000 title abstract description 49
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 title abstract description 29
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 title abstract description 16
- 229910052748 manganese Inorganic materials 0.000 title abstract description 16
- 239000011572 manganese Substances 0.000 title abstract description 16
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 238000010668 complexation reaction Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 18
- 239000013078 crystal Substances 0.000 abstract description 17
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- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 abstract description 12
- 239000003960 organic solvent Substances 0.000 abstract description 12
- 229910021380 Manganese Chloride Inorganic materials 0.000 abstract description 9
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical group Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 abstract description 9
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- ISPYRSDWRDQNSW-UHFFFAOYSA-L manganese(II) sulfate monohydrate Chemical compound O.[Mn+2].[O-]S([O-])(=O)=O ISPYRSDWRDQNSW-UHFFFAOYSA-L 0.000 abstract description 4
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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
-
- 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
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
- C07F13/005—Compounds without a metal-carbon linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention discloses a cycloheptatrienol ketone and phenanthroline mixed manganese complex and a preparation method and application thereof. The preparation method of the complex comprises the following steps: placing tropolone, phenanthroline and divalent manganese salt in an organic solvent, adjusting the pH of the system to 9.3-9.5 after dissolving, reacting the obtained mixed solution under the heating condition, cooling the reactant, and separating out crystals to obtain the compound tropolone/phenanthroline/divalent manganese salt composite material; wherein, the divalent manganese salt is manganese chloride and/or manganese sulfate monohydrate; the organic solvent is acetonitrile or a composition of ethanol and methanol. Applicants' experiments show that the complex has an inhibitory activity on certain cancer cells (such as cervical cancer Hela cell line and gastric cancer MGC80-3 cell line) which is equivalent to that of cisplatin, but has less toxicity on normal cells than cisplatin.
Description
Technical Field
The invention relates to a cycloheptatrienol ketone and phenanthroline mixed manganese complex as well as a preparation method and application thereof, belonging to the technical field of medicines.
Background
Cancer (also called malignant tumor) is one of the diseases with the highest death rate in the world at present, and seriously threatens the health of human beings. In recent years, with the clinical application of cisplatin and other drugs, metal-based chelate antitumor drugs have gradually become a research hotspot. The combination of the inherent property of the metal and the bioactive ligand molecule provides a wide space for the research and development of novel drugs with high efficiency, low toxicity, wide spectrum and targeting activity.
Tropolone, also known as tropolone, is mainly present in secondary metabolites of plants and marine organisms as well as fungi. The tropolone compound is a natural product modified by seven-membered aromatic ring and various side group molecules, and has certain anti-inflammatory, antibacterial and antifungal effects. Phenanthroline, also called phenanthroline and phenanthroline, is a common redox indicator, is also a bidentate heterocyclic compound ligand, has a strong chelating effect, and can form a stable complex with most metal ions.
With the increasing role of platinum antineoplastic drugs (cisplatin, carboplatin, oxaliplatin, etc.) in the treatment of diseases, inorganic drug research has become a hot spot worldwide. The platinum antineoplastic drugs have the defects of poor water solubility, strong drug resistance, toxic and side effects on nerves and kidneys and the like, so that the application range of the platinum antineoplastic drugs is limited. It is known that transition metal elements such as manganese, iron, cobalt, nickel, copper, zinc, etc. exist in trace amounts but are widely distributed in the human body or organism, and they chelate and coordinate with proteins or some organic groups to form biomacromolecules such as enzymes, hormones or vitamins, etc. to play important physiological roles in the body. Zn (II), for example, is an essential component of several tens of enzymes such as DNA polymerase; fe (ii) is present in hemoglobin and myoglobin and is involved in oxygen transport and release; mn (II) promotes mitochondrial metabolism and energy conversion, the presence of which activates various enzymatic activities; cu (II) is one of the elements essential to life, and in the living body, a complex formed with an organic ligand widely exists. However, until now, no report has been found about the simultaneous introduction of a cycloheptatrienol ketone and an o-phenanthroline ligand into a manganese complex to obtain a mixed manganese mixture with high tumor cell inhibitory activity and low normal cytotoxicity.
Disclosure of Invention
The invention aims to solve the technical problem of providing a tropolone and phenanthroline mixed manganese complex which has the inhibiting activity on tumor cell strains equivalent to that of cisplatin and has lower toxicity on normal human liver cells than cisplatin, a preparation method thereof and application thereof.
The manganese complex mixed by tropolone and phenanthroline is a compound with a structure shown in the following formula (I) or a pharmaceutically acceptable salt thereof:
the invention also provides a preparation method of the compound, which mainly comprises the following steps: placing tropolone, phenanthroline and divalent manganese salt in an organic solvent, adjusting the pH of the system to 9.3-9.5 after dissolving, reacting the obtained mixed solution under the heating condition, cooling the reactant, and separating out crystals to obtain a target product; wherein,
the divalent manganese salt is manganese chloride and/or manganese sulfate monohydrate;
the organic solvent is acetonitrile or a composition of ethanol and methanol.
In the above preparation method, the molar ratio of tropolone to phenanthroline to divalent manganese salt is usually 1-2: 1-2: 1.
in the above preparation method, when the organic solvent is a combination of ethanol and methanol, the proportion of ethanol in the organic solvent is not less than 20 v/v%, preferably not less than 40 v/v%. The amount of the organic solvent to be used may be determined as required, and it is usually preferable to dissolve the starting materials to be reacted. Specifically, the total amount of the organic solvent used for all the raw materials is usually 1 to 5mL based on 0.1mmol of tropolone. In the specific dissolving step, the raw materials can be respectively dissolved by using a certain component in an organic solvent and then mixed together for reaction; or mixing all the raw materials together and adding the organic solvent for dissolving.
In the above preparation method, the existing commonly used alkaline substance (such as ammonia, triethylamine, sodium bicarbonate, sodium carbonate or potassium carbonate, etc.) can be used to adjust the pH value of the system, preferably triethylamine or ammonia is used to adjust the pH value of the system; more preferably, triethylamine is used to adjust the pH of the system to 9.4-9.5.
In the above production method, the reaction is carried out at not less than 50 ℃, more preferably 60 to 100, and still more preferably 75 to 85 ℃. Under the preferable conditions, the reaction time is usually controlled to be 48 to 72 hours, and the reaction time can be prolonged as required.
The invention also comprises the application of the tropolone and phenanthroline mixed manganese complex or pharmaceutically acceptable salt thereof in preparing antitumor drugs.
The invention further comprises a pharmaceutical composition which contains the tropolone and phenanthroline mixed manganese complex or pharmaceutically acceptable salt thereof.
Compared with the prior art, the invention provides a tropolone and phenanthroline mixed manganese complex with a novel structure, and a preparation method and application thereof, and in-vitro test results of an applicant show that the complex has the same inhibitory activity on a cervical cancer Hela cell line and a gastric cancer MGC80-3 cell line as cisplatin, but has far lower toxicity on a normal human hepatocyte HL-7702 than cisplatin, and is expected to be used as an anti-tumor medicament.
Drawings
FIG. 1 is a mass spectrum of the final product obtained in example 1 of the present invention;
FIG. 2 is a crystal structure diagram of the final product obtained in example 1 of the present invention.
Detailed Description
The present invention will be better understood from the following detailed description of specific examples, which should not be construed as limiting the scope of the present invention.
Example 1
Collecting cycloheptatrienol ketone (0.0073g, 0.06mmol), manganese chloride (MnCl)20.0063g, 0.05mmol) and phenanthroline (0.0059g, 0.03mmol) are placed in a Pyrex tube (with the inner diameter of 10mm and the length of 200mm) with one closed end, 1.5mL of acetonitrile is added, then triethylamine is used for adjusting the pH value of the system to be 9.45, the Pyrex tube is vacuumized, and the other end of the Pyrex tube is sealed; and (3) placing the sealed Pyrex tube into an oven at the temperature of 80 ℃ for constant-temperature reaction for 72h, taking out, slowly cooling to room temperature, separating out purplish red strips in the Pyrex tube, collecting crystals, washing with ethanol, and drying to obtain a purplish red solid product (the yield is 24.0%).
The product obtained in this example was subjected to elemental analysis, infrared spectroscopy, mass spectrometry and X single crystal diffraction analysis, with the following specific data:
(1) elemental analysis, anal. elementary analysis calcd (%) for C26H18MnN2O4：C65.45，H 3.80，N 5.87％。Found:C，65.38；H，3.71；N 5.92％。
(2) Infrared Spectrum, IR (KBr) 3705cm-1，1588cm-1，1505cm-1，1423cm-1，1363cm-1，1226cm-1，729cm-1。
(3) Mass Spectrometry, ESI + m/z: C19H13MnN2O2([M-C7H5O2]+) 356.03, as shown in FIG. 1.
(4) X-ray single crystal diffraction analysis, selecting crystals with size of 0.260 × 0.220 × 0.190mm, and monochromating Mo Kalpha ray with graphite by Agilent Super-Nova diffractometer under 296K
As incident light source, respectively in a certain theta range
And collecting diffraction points in a scanning mode for structural analysis and correction. The non-hydrogen atoms are solved by a direct method, and the coordinates and the anisotropic thermal parameters of the non-hydrogen atoms are corrected by a full matrix least square method. Mixed hydrogenation, wherein hydrogen atoms adopt isotropic thermal parameters; non-hydrogen atoms adopt anisotropic thermal parameters. Resolution of the crystal structure and structural modification were accomplished by the SHELX97(Sheldrick,1990) and SHELXL97(Sheldrick,1997) packages, respectively. Detailed crystal measurement data are shown in table 1 below, and the crystal structure is determined as shown in fig. 2.
TABLE 1 crystallographic parameters of the complexes
aR1＝Σ||Fo|–|Fc||/Σ|Fo|；b wR2＝[Σw(Fo 2–Fc 2)2/Σw(Fo 2)2]1/2
Therefore, it can be determined that the mauve solid product obtained in this embodiment is a target product manganese complex mixed by tropolone and phenanthroline, and the chemical structural formula of the mauve solid product is as follows:
comparative examples 1 to 7
Example 1 was repeated except that the reaction was carried out under ambient temperature conditions. As a result, no crystalline or other shaped (e.g., powdery) product is formed.
Example 1 was repeated except that the reaction was carried out in a hydrothermal reaction kettle equipped with a teflon inner container, the molar amounts of tropolone, manganese chloride and phenanthroline were controlled to 0.1mmol, 0.1mmol and 0.1mmol, respectively, the amount of acetonitrile was changed to 5mL, and the pH of the system was adjusted to 9.6 with ammonia water. As a result, no crystalline or other shaped (e.g., powdery) product is formed.
Example 1 was repeated, except that manganese acetate was used instead of manganese chloride. As a result, no crystalline or other shaped (e.g., powdery) product is formed.
Example 1 was repeated, except that manganese perchlorate hexahydrate was used instead of manganese chloride. As a result, no crystalline or other shaped (e.g., powdery) product is formed.
Example 1 was repeated, except that methanol was used instead of acetonitrile. As a result, no crystalline or other shaped (e.g., powdery) product is formed.
Example 1 was repeated except that a combination of acetonitrile and ethanol (wherein acetonitrile was used in an amount of 1.5mL and ethanol was used in an amount of 0.5mL) was used in place of acetonitrile. As a result, no crystalline or other shaped (e.g., powdery) product is formed.
Example 1 was repeated, except that the pH of the system was adjusted to 8.8. As a result, no crystalline or other shaped (e.g., powdery) product is formed.
Example 2
Example 1 was repeated except that:
1) controlling the molar weight of tropolone, manganese chloride and phenanthroline to be 0.05mmol, 0.05mmol and 0.05mmol respectively;
2) adjusting the pH value of the obtained solution to 9.5 by using ammonia water;
3) the reaction was carried out at 60 ℃.
After the reaction is finished, the reaction product is slowly cooled to room temperature, and purplish red needle-shaped crystals are separated out, and the yield is 12%.
And performing element analysis, infrared spectrum, mass spectrum and X single crystal diffraction analysis on the product obtained in the embodiment, and determining that the obtained mauve solid product is a target product of the manganese complex mixed by tropolone and phenanthroline.
Example 3
Example 1 was repeated except that:
1) controlling the molar weight of tropolone, manganese chloride and phenanthroline to be 0.1mmol, 0.05mmol and 0.05mmol respectively;
2) adjusting the pH value of the obtained solution to 9.3 by triethylamine;
3) the reaction is carried out at 50 ℃ and the reaction time is controlled at 96 h.
After the reaction is finished, the reaction product is slowly cooled to room temperature, and mauve needle-shaped crystals are separated out, and the yield is 5%.
And performing element analysis, infrared spectrum, mass spectrum and X single crystal diffraction analysis on the product obtained in the embodiment, and determining that the obtained mauve solid product is a target product of the manganese complex mixed by tropolone and phenanthroline.
Example 4
Example 1 was repeated except that:
4) manganese chloride was replaced with manganese sulfate monohydrate, the molar amounts of tropolone, manganese sulfate monohydrate, and phenanthroline were controlled to 0.05mmol, and 0.025mmol, respectively, and the organic solvent was changed from acetonitrile to a composition of methanol and ethanol (the volume ratio of methanol to ethanol was 3: 2) the total dosage of the organic solvent is changed to 2.5 mL;
5) adjusting the pH value of the obtained solution to 9.0 by using ammonia water;
6) the reaction is carried out at 90 ℃ and the reaction time is controlled to be 48 h.
After the reaction is finished, the reaction solution is slowly cooled to room temperature, and mauve needle-shaped crystals are separated out, and the yield is 14%.
And performing element analysis, infrared spectrum, mass spectrum and X single crystal diffraction analysis on the product obtained in the embodiment, and determining that the obtained mauve solid product is a target product of the manganese complex mixed by tropolone and phenanthroline.
Experimental example: in-vitro antitumor activity experiment of tropolone and phenanthroline mixed manganese complex (hereinafter referred to as complex)
1. Inoculation and culture of cells
The tumor cell strains selected in the experiment are respectively as follows: human ovarian cancer SK-OV-3 cell strain, gastric cancer MGC80-3 cell strain, cervical cancer HeLa cell strain, non-small cell lung cancer A549 cell strain and human normal liver cell HL-7702. The selected tumor cell strain is cultured in DMEM medium containing 10% fetal calf serum and 1% streptomycin dual antibody, and is placed at 37 deg.C and 5% CO2Culturing under constant condition, when the cell grows to 80-90% of the culture bottle area, then digesting with digestive juice, and after passage for 3-5 times, taking the cell in good state and in cell log phase for experiment.
2. Cell growth inhibition assay (MTT method)
Selecting cells with good growth condition and in logarithmic growth phase, washing twice with Phosphate Buffered Saline (PBS), digesting with trypsin, adding culture solution containing 10% of fresh bovine serum and 1% of streptomycin, homogenizing to obtain cell suspension, adding into 96-well plate, adding into each well, adding 180 μ L, and about 1 × 10 cells5And (c) a cell suspension of cells. Equal volume of PBS buffer was added around the well plate. After the cells adhere to the wall and grow to 50-70% of the area of the hole, 20 μ L of drugs with different concentrations (prepared by the complex in the invention example 1, and other drugs are directly purchased) are respectively added into each hole, 5 parallel tests are set for each concentration, the final concentration of the cosolvent DMSO in the hole is less than or equal to 1%, and a blank control group is set at the same time. Cells were incubated at 37 ℃ and 5% CO, respectively2Incubate under atmosphere for 48 hours. After completion of the culture, 10. mu.L of MTT reagent (concentration 5 mg/m) was added to each wellL); at 37 ℃ 5% CO2After incubation for 4-6 h in atmosphere, discarding the culture solution, adding 150 μ L of DMSO into each hole of each dosing and blank group, and performing shake reaction on a shaker for 10-15 min to fully dissolve blue-purple formazan crystals in cells; and (3) measuring the absorbance (OD) value after the background light absorption value is removed by using a microplate reader at a double wavelength of 570nm/630 nm. In the primary screening, the complex with better inhibition rate on tumor cells selects 5 appropriate concentration gradients as the IC of corresponding cell strains50Values, averaged after 3 replicates of all experiments, are shown in table 2 below.
TABLE 2 half Inhibitory Concentration (IC) of the Complex against different tumor cell lines50，μM)
As can be seen from table 2, for these 5 cancer cells, the anticancer activities of simple tropolone and phenanthroline ligand are not high, and after coordination with manganese ions, the anticancer activity is greatly improved. The obtained complex has better activity on a cervical cancer Hela cell line and a gastric cancer MGC80-3 cell line, and is equivalent to cisplatin, but the toxicity of the complex on human normal liver cells HL-7702 is obviously lower than that of the cisplatin. Therefore, the two ligands of the cycloheptatrienol ketone and the phenanthroline are coordinated with manganese ions, so that the complex has the inhibition performance equivalent to that of cisplatin on certain cancer cells (such as a cervical cancer Hela cell line and a gastric cancer MGC80-3 cell line), but the toxicity of the complex to normal cells is lower than that of the cisplatin.
Claims (2)
1. The application of a compound with a structure shown in the formula (I) or pharmaceutically acceptable salt thereof in preparing an anti-tumor medicament;
2. a pharmaceutical composition characterized by: contains a therapeutically effective amount of a compound having a structure represented by the following formula (I) or a pharmaceutically acceptable salt thereof;
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