CN113735781B - Copper complex and preparation method and application thereof - Google Patents

Copper complex and preparation method and application thereof Download PDF

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CN113735781B
CN113735781B CN202110947917.2A CN202110947917A CN113735781B CN 113735781 B CN113735781 B CN 113735781B CN 202110947917 A CN202110947917 A CN 202110947917A CN 113735781 B CN113735781 B CN 113735781B
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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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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 into a mixed solvent, regulating the pH value of the system to be alkaline, reacting under heating, cooling reactants, precipitating crystals, and collecting the crystals to obtain the catalyst; wherein the copper salt is selected from CuCl, cuCl 2 ·2H 2 O、Cu(NO 3 ) 2 ·3H 2 O、Cu(NO 3 ) 2 ·6H 2 O、Cu(OAc) 2 ·H 2 O and Cu (ClO) 4 ) 2 ·6H 2 One or more than two of O; the mixed solvent is methanol and acetone according to the proportion of 1:3 in a volume ratio. The test result of the applicant shows that the complex has better inhibition effect on various tumor cell lines, and compared with cisplatin, the complex has obvious high-efficiency inhibition effect on cancer cells and low-toxicity side effect on normal cells, and is expected to be used as an anticancer 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 increases year by year worldwide, severely affecting human health. In recent years, platinum complexes have emerged as a chemotherapeutic agent due to their high efficiency in combination therapy. However, they also show disadvantages such as 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 explore other non-platinum complexes or drugs that are highly effective with less side effects.
Guanidino compounds are one of the most bioactive organic bases that can be protonated in physiological pH media to form positively charged groups that can form electrostatic interactions with substrates; in addition, the guanidine group has a plurality of nitrogen atoms and hydrogen atoms, has high affinity to carbonic ester, phosphate ester and peptide, is easy to form hydrogen bond action, and can form a hydrogen bond structure with geometric configuration; since amino groups and various acids can form water-soluble salts, the drug containing guanidine groups is easy to be transported in vivo, and absorption and permeation are more selective. Through these interactions, physiological functions such as anti-inflammatory action, sympatholytic or inhibitory action, antihistaminic action, antihypertensive action, hypoglycemic action and the like are produced in vivo, but they have not been deeply reported in terms of anticancer activity. Therefore, the application aims to select salicylaldehyde aminoguanidine Schiff base as a raw material to synthesize corresponding complexes and research the anticancer activity of the complexes.
Disclosure of Invention
The invention aims to solve the technical problem of providing a copper complex which is novel in structure and has obvious biological activity and is obtained by in-situ cyclization of salicylaldehyde aminoguanidine, and a preparation method and application thereof.
The copper complex provided by the invention is a compound shown in the following formula (I) or pharmaceutically acceptable salt thereof:
Figure BDA0003217486750000011
the copper complex of the invention belongs to monoclinic P2 1 And/c space group, which is mononuclear complex with unit cell parameters:
Figure BDA0003217486750000012
α＝90°，β＝102.803(3)°，γ＝90°；/>
Figure BDA0003217486750000013
the complex metal center copper ion shows positive bivalent, and the complex is formed by in-situ cyclization of one copper ion and one salicylaldehyde aminoguanidine (1- (2-hydroxy benzyl) -2- (2-hydroxy benzylidene hydrazino) -4- (2-hydroxy phenyl) -6-methyl pyrimidine) ligand (HL) 2- ) The two nitrogen atoms and the two oxygen atoms coordinate to form a mononuclear structure with a planar tetragonal configuration.
The preparation method of the copper complex comprises the following steps: placing salicylaldehyde aminoguanidine Schiff base, salicylaldehyde and copper salt into a mixed solvent, regulating the pH value of the system to be alkaline, reacting under heating, cooling reactants, separating out crystals, and collecting the crystals to obtain a target product; wherein,,
the copper salt is selected from CuCl and CuCl 2 ·2H 2 O、Cu(NO 3 ) 2 ·3H 2 O、Cu(NO 3 ) 2 ·6H 2 O、Cu(OAc) 2 ·H 2 O and Cu (ClO) 4 ) 2 ·6H 2 One or more than two of O;
the mixed solvent is methanol and acetone according to the weight ratio of 1:3 in a volume ratio.
In the preparation method, the molar ratio of salicylaldehyde aminoguanidine Schiff base, salicylaldehyde and copper salt is stoichiometric, and the use amount of salicylaldehyde and copper salt can be relatively excessive 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. Chattopahyay, new J.chem.,2020,44,7319-7328.) and can also be designed and synthesized by itself. The amount of the mixed solvent may be determined as required, and it is usually preferable to dissolve the raw materials participating in the reaction. Specifically, the total amount of the mixed solvent used for 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 common choice in the prior art, and is preferably triethylamine. Preferably, the pH of the system is adjusted to be equal to or greater than 8, more preferably, the pH of the system is adjusted to be equal to or greater than 8.5, and even more preferably, the pH of the system is adjusted to be=9 to 11.
In the preparation method, the mixed solution obtained after the pH value is regulated is usually placed in a container, vacuumized, sealed and then placed under the heating condition for reaction. The reaction is preferably carried out at a temperature of 50℃or higher, more preferably 80 to 100 ℃. When the reaction is carried out at 80-100 ℃, the reaction time is generally controlled to 48-72 hours. The reaction is usually carried out by using a thick-walled hard glass tube with one end closed to contain the mixture obtained after the pH adjustment.
The invention also comprises the application of the copper complex or the pharmaceutically acceptable salt thereof in preparing antitumor drugs, preferably in preparing drugs for resisting bladder cancer and/or liver cancer and/or stomach cancer and/or lung cancer, more preferably in preparing drugs for resisting bladder cancer and/or lung cancer, and even more preferably in preparing drugs for resisting 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 the prior art, the invention provides a copper complex obtained by in-situ cyclization of salicylaldehyde aminoguanidine with a novel structure and a preparation method thereof, and test results of the applicant show that the complex has better inhibition effect on various tumor cell strains, and compared with cisplatin, the complex has obvious high-efficiency inhibition effect on cancer cells and low toxic and side effect on normal cells, and is expected to be used as an anticancer drug.
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FIG. 1 is a high resolution mass spectrum of the final product obtained in example 1 of the present invention.
FIG. 2 is an infrared 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 scheme of the present invention, the present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto. Unless otherwise indicated, features used in the embodiments may be replaced with other features known in the art having equivalent or similar functions or effects without departing from the inventive concept.
The salicylaldehyde aminoguanidine schiff base referred in the following examples was prepared as follows:
salicylaldehyde (1.22 g,10 mmol) was dissolved in methanol in a round bottom flask and triethylamine (1.01 g,10 mmol) was added dropwise. Aminoguanidine was dissolved in methanol and added to the above solution. The resulting mixture was refluxed for 3h, filtered, the filtrate evaporated slowly at room temperature, an off-white solid precipitated, the solid was collected after washing with cold methanol and diethyl ether, dried and the product was collected. The resulting product was characterized by the characterization method described in the literature (A.Mondal, C.Das, M.Corbella, A.Bauza, A.Frontera, M.Saha, S.Mondal, K.Das Saha, s.k. chattopladhyy, new j.chem.,2020,44,7319-7328.) and identified as salicylaldehyde aminoguanidine schiff base.
Example 1
Salicylaldehyde (5.5. Mu.L, 0.05 mmol), salicylaldehyde aminoguanidine Schiff base (0.0089 g,0.05 mmol) and CuCl were taken 2 ·2H 2 O (0.0085 g,0.05 mmol) was placed in a glass tube with one end closed and length of about 20cm, 2mL of a mixed solvent of methanol and acetone (the volume ratio of methanol to acetone was 1:3) was added, and the mixture was dissolved sufficiently by ultrasound, then the pH value of the system was adjusted to 10 with triethylamine (30. Mu.L), and then the glass tube was vacuum-sealed and sealed at high temperature. Placing the sealed glass tube in an oven at 80 ℃ for reaction for 72 hours, slowly cooling to room temperature after stopping the reaction, observing that black and red diamond crystals are separated out from the bottom of the glass tube, collecting the crystals, and drying. Yield 15.6% (0.0038 g, based on Cu) 2+ )。
Characterization of the product obtained in this example:
(1) High resolution mass spectrum, the spectrum of which is shown in figure 1.
HRMS(ESI + )m/z:488.09[M+H] + Wherein M is the molecular weight of the complex.
(2) Infrared spectrum, the spectrum of which is shown in figure 2.
IR(KBr,cm -1 ):3447w,1602s,1562s,1478m,1436m,1386w,1342w,1243m,1146m,905w,850w,754m,486w。
(3) Analysis of the crystal structure:
selecting 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 monochromatization of Mo-K α
Figure BDA0003217486750000031
The rays were used for single crystal testing. As in the present embodimentThe initial crystal structure of the obtained product is solved by adopting a SHELXL-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 crystallography and structure refinement data are shown in the following table 1, the partial bond length and bond angle data are shown in the following tables 2 and 3, the chemical structures of the obtained black-red diamond crystals are shown in fig. 3, and the obtained black-red diamond crystals are determined to be the target products of the present invention.
Table 1 crystallographic data of copper complexes according to the invention:
Figure BDA0003217486750000041
TABLE 2 bond length data for the moieties of the copper complexes of the invention
Figure BDA0003217486750000042
Figure BDA0003217486750000043
TABLE 3 partial bond angle data (°) for copper complexes of 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 target 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 target product were formed.
Comparative examples 1 to 3
Example 1 was repeated except that the volume ratio of methanol and acetone in the mixed solvent was changed to 1:2 or 1:4. as a result, no crystals or precipitates of the target product were formed.
Comparative examples 1 to 4
Example 1 was repeated except that the reaction was modified at normal temperature. As a result, no crystals or precipitates of the target product were formed.
Comparative examples 1 to 5
Example 1 was repeated, except that the pH of the system was adjusted=7. As a result, no crystals or precipitates of the target product were formed.
Comparative examples 1 to 6
Example 1 was repeated except that CuBr was used 2 Or CuSO 4 ·5H 2 O replaces CuCl 2 ·2H 2 O, the target product of the present invention was expected to be obtained, but neither was crystalline, indicating that CuBr was used 2 Or CuSO 4 ·5H 2 O cannot reach thermodynamic conditions of copper complex and crystallization obtained by in-situ cyclization of salicylaldehyde aminoguanidine.
Example 2
Example 1 was repeated, except that the reaction was modified at 100 ℃ for 48 hours, and the ph=11 of the system was adjusted with triethylamine.
As a result, black and red diamond crystals were obtained. Yield 15.9% (based on Cu) 2+ )。
And carrying out high-resolution mass spectrometry analysis, infrared analysis and single crystal diffraction analysis on the product obtained in the embodiment, and determining that the obtained black-red diamond crystal is the target product of the invention.
Example 3
Example 1 was repeated, except that the pH of the system was adjusted=8.5.
As a result, black and red diamond crystals were obtained. Yield 14.8% (based on Cu) 2+ )。
And carrying out high-resolution mass spectrometry analysis, infrared analysis and single crystal diffraction analysis on the product obtained in the embodiment, and determining that the obtained black-red diamond crystal is the target product of the invention.
Example 4
Example 1 was repeated, except that CuCl, cu (NO 3 ) 2 ·3H 2 O、Cu(OAc) 2 ·H 2 O or Cu (ClO) 4 ) 2 ·6H 2 O replaces CuCl 2 ·2H 2 O。
As a result, black and red rhombohedral crystals were obtained.
And carrying out high-resolution mass spectrometry analysis, infrared analysis and single crystal diffraction analysis on the obtained black and red diamond crystals, and determining that the black and red diamond crystals are all target products of the invention.
Experimental example: in vitro inhibition activity experiments of the copper complex disclosed by the invention on various human tumor strains:
(1) Selection and culture of cell lines.
The cells used in this example were: human bladder cancer cell line T24, human liver cancer cell line Hep-G2, gastric cancer cell line MGC80-3, non-small cell lung cancer cell line A549, human liver cancer cell line BEL-7402, human embryo lung cell WI-38 and human normal liver cell line HL-7702. All cell lines were placed in DMEM medium containing 10% fetal calf serum and 1% penicillin and 5% CO 2 Culturing in an incubator at 37 ℃.
(2) Cell seeding and anticancer Activity test
Selecting cells in the logarithmic growth phase, washing with PBS for 2 times, digesting the cells from the inner wall of a culture flask by using trypsin, 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 well 6 And a plurality of) are placed in an incubator for incubation. After cells in the hole to be tested grow to 70-80%, 20 mu L of samples to be tested (target product, cis-platinum, salicylaldehyde aminoguanidine Schiff base and CuCl of the invention) with different concentrations are added 2 ·2H 2 O), 5 duplicate wells were set per concentration. After 2 days incubation of the cells in the incubator, 10 μl of MTT was added to each well for further culture. After 4 hours, the culture medium in the wells was discarded and 100 μl DMSO was added to dissolve the formazan, the OD value of each well was measured at 570nm/630nm dual wavelength by an enzyme-labeled instrument after shaking completely by a shaker, 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 OD value of the complex for each fine particle by using SPSS software to process the OD valueIC of cell strain 50 The values and results are shown in Table 5.
TABLE 4 inhibition of the copper complexes of the invention on different cells (%)
Figure BDA0003217486750000061
TABLE 5 IC of copper complexes of the invention for different cells 50 Value (mu M)
Figure BDA0003217486750000062
From the screening results of antitumor activity, it is known that: the complex of the invention shows different inhibition activities to different cancer cell strains, compared with cisplatin, the complex shows more remarkable inhibition effect to T24 cells, and IC 50 The value is 4.42+/-0.48 mu M, and the cytotoxicity of the liver cell HL-7702 is not obviously improved. Therefore, the complex provided by the invention has certain selectivity for different cell strains.

Claims (10)

1. A complex of 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 placed in a mixed solvent, the pH value of the system is regulated 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, so that the target product is obtained; wherein,,
the copper salt is selected from CuCl and CuCl 2 ·2H 2 O、Cu(NO 3 ) 2 ·3H 2 O、Cu(NO 3 ) 2 ·6H 2 O、Cu(OAc) 2 ·H 2 O and Cu (ClO) 4 ) 2 ·6H 2 One or more than two of O;
the mixed solvent is methanol and acetone according to the weight ratio of 1:3 in a volume ratio.
3. The preparation method according to claim 2, wherein the pH of the system is adjusted to be not less than 8.
4. The preparation method according to claim 2, wherein the pH of the system is adjusted to be between 9 and 11.
5. The process according to claim 2, wherein the reaction is carried out at a temperature of 50 ℃.
6. The process according to claim 2, wherein the reaction is carried out at 80 to 100 ℃.
7. The process according to any one of claims 2 to 6, wherein the pH of the system is adjusted to be alkaline with an alkaline substance.
8. Use of the complex of claim 1 or a pharmaceutically acceptable salt thereof for the preparation of an antitumor drug.
9. The use according to claim 8, characterized by the use in the preparation of a medicament against 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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