CN113735781A - Copper complex and preparation method and application thereof - Google Patents

Copper complex and preparation method and application thereof Download PDF

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CN113735781A
CN113735781A CN202110947917.2A CN202110947917A CN113735781A CN 113735781 A CN113735781 A CN 113735781A CN 202110947917 A CN202110947917 A CN 202110947917A CN 113735781 A CN113735781 A CN 113735781A
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salicylaldehyde
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陈自卢
储波
胡焕成
刘冬成
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Guangxi Normal University
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
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Abstract

The invention discloses a copper complex and a preparation method and application thereof. The preparation method of the copper complex comprises the following steps: placing salicylaldehyde aminoguanidine Schiff base, salicylaldehyde and copper salt in a mixed solvent, adjusting the pH value of the system to be alkaline, reacting under a heating condition, cooling a reactant, separating out crystals, and collecting the crystals to obtain the salicylaldehyde aminoguanidine Schiff base; wherein the copper salt is selected from CuCl and CuCl2·2H2O、Cu(NO3)2·3H2O、Cu(NO3)2·6H2O、Cu(OAc)2·H2O and Cu (ClO)4)2·6H2O is one or a combination of more than two of the components; the mixed solvent is methanol and acetone according to the weight ratio of 1: 3 in volume ratio. The test result of the applicant shows that the complex shows good inhibition effect on a plurality of tumor cell strainsTherefore, compared with cisplatin, the cisplatin has the advantages of showing a remarkable high-efficiency inhibition effect on cancer cells and low-toxicity side effects on normal cells, and is expected to be used as an anti-cancer drug.

Description

Copper complex and preparation method and application thereof
Technical Field
The invention relates to a copper metal complex, in particular to a copper complex and a preparation method and application thereof.
Background
The incidence of cancer worldwide increases year by year, seriously affecting human health. In recent years, platinum complexes have emerged among chemotherapeutic agents due to their high efficiency in combination therapy. However, they also show disadvantages of toxic side effects and drug resistance. In particular, the clinical use of cisplatin is severely limited by its adverse side effects (including ototoxicity and nephrotoxicity), thereby reducing patient tolerance during treatment and interfering with long-term quality of life. Therefore, there is a need to search for other non-platinum compounds or drugs with high efficacy and less side effects.
The guanidyl compound is one of organic bases with the strongest biological activity, can be protonated in a physiological pH medium to form a positively charged group, and can form electrostatic interaction with a substrate; in addition, the guanidyl has a plurality of nitrogen atoms and hydrogen atoms, has high affinity to carbonate, phosphate and peptide, is easy to form hydrogen bond action, and can form a hydrogen bond structure with a geometric configuration; because the amino and various acids can generate water-soluble salts, the drug containing guanidine group is easy to transport in vivo, and the absorption and permeation are more selective. Through these interactions, physiological functions such as an anti-inflammatory action, a sympathetic nerve stimulating or inhibiting action, an antihistamine action, a hypotensive action, and a hypoglycemic action are produced in vivo, but they have not been reported deeply in terms of anticancer activity. Therefore, the salicylaldehyde aminoguanidine Schiff base is selected as a raw material to synthesize a corresponding complex, and the anticancer activity of the complex is researched.
Disclosure of Invention
The invention aims to provide a copper complex obtained by in-situ cyclization of salicylaldehyde aminoguanidine, which has a novel structure and obvious biological activity, and a preparation method and application thereof.
The copper complex is a compound shown as the following formula (I) or a pharmaceutically acceptable salt thereof:
Figure BDA0003217486750000011
the copper complex of the invention belongs to P2 of monoclinic system1The/c space group is a mononuclear complex, and the unit cell parameters are as follows:
Figure BDA0003217486750000012
α＝90°，β＝102.803(3)°，γ＝90°；
Figure BDA0003217486750000013
the complex has a metal center copper ion shown as positive divalent, and the complex is formed by in-situ cyclization of a copper ion and salicylaldehyde aminoguanidine, namely (1- (2-hydroxybenzyl) -2- (2-hydroxybenzylidenehydrazino) -4- (2-hydroxyphenyl) -6-methylpyrimidine) ligand (HL)2-) The two nitrogen atoms and the two oxygen atoms are coordinated to form a mononuclear structure with a plane tetragonal configuration.
The preparation method of the copper complex comprises the following steps: placing salicylaldehyde aminoguanidine Schiff base, salicylaldehyde and copper salt in a mixed solvent, adjusting the pH value of the system to be alkaline, reacting under a heating condition, cooling a reactant, separating out crystals, and collecting the crystals to obtain a target product; wherein,
the copper salt is selected from CuCl and CuCl2·2H2O、Cu(NO3)2·3H2O、Cu(NO3)2·6H2O、Cu(OAc)2·H2O and Cu (ClO)4)2·6H2O is one or a combination of more than two of the components;
the mixed solvent is methanol and acetone according to the weight ratio of 1: 3 in volume ratio.
In the preparation method, the molar ratio of the salicylaldehyde aminoguanidine Schiff base to the salicylaldehyde to the copper salt is a stoichiometric ratio, and the salicylaldehyde and the copper salt can be used in a relative excess amount in the actual operation process. The salicylaldehyde aminoguanidine schiff base can be prepared by referring to (A.Mondal, C.das, M.Corbella, A.Bauza, A.Frontera, M.Saha, S.Mondal, K.das Saha, S.K.chattopadhyy, New J.chem.,2020,44, 7319-one 7328), and can also be designed and synthesized by self. The amount of the mixed solvent to be used may be determined as required, and it is usually preferable that the raw materials to be reacted are dissolved. Specifically, the total amount of the mixed solvent used by all the raw materials is generally 2-10 mL calculated by taking 1mmol of salicylaldehyde aminoguanidine Schiff base as a reference.
In the preparation method, the pH value of the system is adjusted to be alkaline by adopting an alkaline substance, wherein the alkaline substance can be a conventional choice in the prior art, and triethylamine is preferred. The pH of the adjustment system is preferably not less than 8, more preferably not less than 8.5, and still more preferably 9 to 11.
In the above preparation method, the mixed solution obtained after adjusting the pH value is usually placed in a container, vacuumized, sealed and then placed under heating for reaction. The reaction is preferably carried out at not less than 50 ℃ and more preferably at 80 to 100 ℃. When the reaction is carried out at 80-100 ℃, the reaction time is usually controlled to be 48-72 h. The reaction usually adopts a thick-wall hard glass tube with one closed end to contain the mixed solution obtained after the pH value is adjusted.
The invention also comprises the application of the copper complex or the pharmaceutically acceptable salt thereof in preparing an anti-tumor medicament, preferably in preparing a medicament for resisting bladder cancer and/or liver cancer and/or stomach cancer and/or lung cancer, further preferably in preparing a medicament for treating bladder cancer and/or lung cancer, and more preferably in preparing a medicament for treating bladder cancer.
The invention further includes a pharmaceutical composition comprising a therapeutically effective amount of a copper complex or a pharmaceutically acceptable salt thereof.
Compared with cisplatin, the complex shows remarkable high-efficiency inhibition effect on cancer cells and side effect of low toxicity on normal cells, and is expected to be used as an anti-cancer drug.
Drawings
FIG. 1 is a high resolution mass spectrum of the final product obtained in example 1 of the present invention.
FIG. 2 is an IR spectrum of the final product obtained in example 1 of the present invention.
FIG. 3 is a crystal structure diagram of the final product obtained in example 1 of the present invention.
Detailed Description
In order to better explain the technical solution of the present invention, the present invention is further described in detail with reference to the following examples, but the embodiments of the present invention are not limited thereto. Unless otherwise specified, technical features used in the embodiments may be replaced with other technical features known in the art having equivalent or similar functions or effects without departing from the inventive concept.
The salicylaldehyde aminoguanidine Schiff base referred to in the following examples was prepared as follows:
salicylaldehyde (1.22g, 10mmol) was dissolved in methanol in a round-bottomed flask and triethylamine (1.01g, 10mmol) was added dropwise. Aminoguanidine was dissolved in methanol and added to the above solution. The resulting mixture was refluxed for 3h, filtered, the filtrate was slowly evaporated at room temperature, an off-white solid precipitated, which was collected after washing with cold methanol and ether, dried and the product collected. The resulting product was characterized by reference to the characterization methods in the literature (a. mondal, c.das, m.corbella, a.bauza, a.frontera, m.saha, s.mondal, k.das Saha, s.k.chattopadhyay, New j.chem.,2020,44, 7319-charge 7328.) and was identified as salicylaldehyde aminoguanidine schiff base.
Example 1
Taking salicylaldehyde (5.5 mu L,0.05mmol), salicylaldehyde aminoguanidine Schiff base (0.0089g,0.05mmol) and CuCl2·2H2O (0.0085g,0.05mmol) is placed in a glass tube with one closed end and the length of about 20cm, 2mL of mixed solvent consisting of methanol and acetone (the volume ratio of the methanol to the acetone is 1: 3) is added, ultrasonic waves are fully dissolved, then triethylamine (30 mu L) is used for adjusting the pH value of the system to 10, and then the glass tube is vacuumized and sealed by high-temperature fusion. And (3) placing the sealed glass tube in an oven at 80 ℃, reacting for 72 hours, slowly cooling to room temperature after the reaction is stopped, observing that black and red rhombus crystals are separated out at the bottom of the glass tube, collecting the crystals, and drying. The yield was 15.6% (0.0038g, based on Cu)2+)。
The product obtained in this example was characterized:
(1) the spectrum of the high-resolution mass spectrum is shown in FIG. 1.
HRMS(ESI+)m/z:488.09[M+H]+Wherein M is the molecular weight of the complex.
(2) The infrared spectrum is shown in figure 2.
IR(KBr,cm-1):3447w,1602s,1562s,1478m,1436m,1386w,1342w,1243m,1146m,905w,850w,754m,486w。
(3) And (3) analyzing a crystal structure:
selecting a black and red diamond crystal with moderate size, placing the black and red diamond crystal on a Supernova single crystal diffractometer of Agilent company, and adopting graphite to monochromate Mo-Kα
Figure BDA0003217486750000031
And (4) performing single crystal test by using rays. The initial crystal structures of the products obtained in the embodiment are solved by adopting a SHELXS-97 direct method, the geometric hydrogenation is carried out, and the non-hydrogen atom coordinates and the anisotropic thermal parameters are refined by adopting a SHELXL-97 full matrix least square method. The obtained crystallographic and structural refinement data are shown in the following table 1, the partial bond length bond angle data are shown in the following tables 2 and 3, respectively, the chemical structure of the obtained black-red rhombohedral crystal is shown in fig. 3, and the obtained black-red rhombohedral crystal is determined to be the target product of the invention.
Table 1 crystallographic data for the copper complexes according to the invention:
Figure BDA0003217486750000041
TABLE 2 bond length data for a portion of the copper complexes of the present invention
Figure BDA0003217486750000042
Figure BDA0003217486750000043
TABLE 3 partial bond Angle data (. degree.) of the copper complexes according to the invention
Figure BDA0003217486750000044
Comparative examples 1 to 1
Example 1 was repeated except that the mixed solvent was changed to a single solvent such as methanol, acetone, acetonitrile, dichloromethane, chloroform, DMF or DMSO. As a result, no crystals or precipitates of the desired product were formed.
Comparative examples 1 to 2
Example 1 was repeated except that methanol in the mixed solvent was replaced with ethanol, acetonitrile, dichloromethane, DMF or DMSO. As a result, no crystals or precipitates of the desired product were formed.
Comparative examples 1 to 3
Example 1 was repeated except that the volume ratio of methanol to acetone in the mixed solvent was changed to 1: 2 or 1: 4. as a result, no crystals or precipitates of the desired product were formed.
Comparative examples 1 to 4
Example 1 was repeated, except that the reaction was carried out at ordinary temperature instead. As a result, no crystals or precipitates of the desired product were formed.
Comparative examples 1 to 5
Example 1 was repeated except that the pH of the system was adjusted to 7. As a result, no crystals or precipitates of the desired product were formed.
Comparative examples 1 to 6
Example 1 was repeated except that CuBr was used2Or CuSO4·5H2O instead of CuCl2·2H2O, the desired target product of the invention, but none of the crystals, is obtained, indicating the use of CuBr2Or CuSO4·5H2O cannot reach the thermodynamic conditions for the formation of copper complexes and crystals obtained by in situ cyclization of salicylaldehyde aminoguanidine.
Example 2
Example 1 was repeated except that the reaction was carried out at 100 ℃ for 48 hours and the pH of the system was adjusted to 11 with triethylamine.
As a result, black and red rhombohedral crystals were obtained. Yield of15.9% (based on Cu)2+)。
The product obtained in the embodiment is subjected to high resolution mass spectrometry, infrared analysis and single crystal diffraction analysis, and the obtained black-red rhombohedral crystal is determined to be the target product of the invention.
Example 3
Example 1 was repeated, except that the pH of the system was adjusted to 8.5.
As a result, black and red rhombohedral crystals were obtained. Yield 14.8% (based on Cu)2+)。
The product obtained in the embodiment is subjected to high resolution mass spectrometry, infrared analysis and single crystal diffraction analysis, and the obtained black-red rhombohedral crystal is determined to be the target product of the invention.
Example 4
Example 1 was repeated except that CuCl and Cu (NO) were used respectively3)2·3H2O、Cu(OAc)2·H2O or Cu (ClO)4)2·6H2O instead of CuCl2·2H2O。
As a result, black and red rhombohedral crystals were obtained.
The obtained black-red rhombohedral crystal is subjected to high-resolution mass spectrometry, infrared analysis and single crystal diffraction analysis, and the black-red rhombohedral crystal is determined to be the target product of the invention.
Experimental example: the copper complex of the invention is used for in vitro inhibitory activity experiments of various human tumor strains:
(1) selection and culture of cell lines.
The cells used in this example were: human bladder cancer cell strain T24, human hepatoma cell strain Hep-G2, gastric cancer cell strain MGC80-3, non-small cell lung cancer cell strain A549, human hepatoma cell strain BEL-7402, human embryonic lung cell WI-38 and human normal liver cell strain HL-7702. All cell lines were placed in DMEM medium containing 10% fetal calf serum and 1% streptomycin in 5% CO2And culturing in an incubator at 37 ℃.
(2) Cell seeding and anti-cancer Activity assays
Selecting cells in logarithmic growth phase, washing with PBS 2 times, and culturing with trypsinDigesting the inner wall of the bottle, and adding a culture medium to prepare a cell suspension for later use. A96-well plate was prepared and 180. mu.L of cell suspension (cell content about 1X 10) was added to each well6One) were placed in an incubator for incubation. After the cells in the test holes grow to 70-80%, 20 mu L of samples to be tested (the target product of the invention, cisplatin, salicylaldehyde aminoguanidine Schiff base and CuCl) with different concentrations are added2·2H2O), 5 multiple wells per concentration were set. After 2 days of incubation in the incubator, 10. mu.L of MTT was added to each well to continue the culture. After 4h, the culture medium in the wells was discarded and 100 μ L of DMSO was added to dissolve the generated formazan, and after shaking by a shaker was completed, the OD value of each well was measured at a dual wavelength of 570nm/630nm using a microplate reader, and the inhibition ratio (inhibition ratio ═ 1-sample group OD value/blank group OD value) × 100%) was calculated, and the results are shown in table 4 below. Calculating the IC of the complex on each cell line by processing OD value through SPSS software50The results are shown in Table 5.
TABLE 4 inhibition ratio (%)
Figure BDA0003217486750000061
TABLE 5 IC of the copper complexes according to the invention on different cells50Value (μ M)
Figure BDA0003217486750000062
From the results of the screening for antitumor activity, it is known that: the complex shows different inhibitory activities on different cancer cell strains, and has a more remarkable inhibitory effect on T24 cells and IC (integrated circuit) compared with cisplatin50The value is 4.42 +/-0.48 mu M, and the cytotoxicity of the liver cell to the normal liver cell HL-7702 is not obviously improved. As can be seen, the complex of the invention has certain selectivity for different cell strains.

Claims (10)

1. A complex represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0003217486740000011
2. the preparation method of the complex as claimed in claim 1, wherein the salicylaldehyde aminoguanidine Schiff base, salicylaldehyde and copper salt are put into a mixed solvent, the pH value of the system is adjusted to be alkaline, the reaction is carried out under the heating condition, the reactant is cooled, crystals are separated out, and the crystals are collected to obtain the target product; wherein,
the copper salt is selected from CuCl and CuCl2·2H2O、Cu(NO3)2·3H2O、Cu(NO3)2·6H2O、Cu(OAc)2·H2O and Cu (ClO)4)2·6H2O is one or a combination of more than two of the components;
the mixed solvent is methanol and acetone according to the weight ratio of 1: 3 in volume ratio.
3. The process according to claim 2, wherein the pH of the system is adjusted to 8 or more.
4. The method according to claim 2, wherein the pH of the system is adjusted to 9 to 11.
5. The process according to claim 2, wherein the reaction is carried out at 50 ℃ or higher.
6. The method according to claim 2, wherein the reaction is carried out at 80 to 100 ℃.
7. The method according to any one of claims 2 to 6, wherein the pH of the system is adjusted to be alkaline by an alkaline substance.
8. Use of the complex of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor medicament.
9. The use according to claim 8, wherein the use is for the preparation of a medicament for treating bladder cancer and/or liver cancer and/or stomach cancer and/or lung cancer.
10. A pharmaceutical composition comprising a therapeutically effective amount of the complex of claim 1 or a pharmaceutically acceptable salt thereof.
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CN114702441B (en) * 2022-05-12 2023-04-14 山西农业大学 Cuprous complex with anti-tumor activity and preparation method and application thereof

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