CN110423242B - 6, 7-dichloroquinoline-5, 8-diketone derivative transition metal complex and synthetic method and application thereof - Google Patents

6, 7-dichloroquinoline-5, 8-diketone derivative transition metal complex and synthetic method and application thereof Download PDF

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CN110423242B
CN110423242B CN201910850874.9A CN201910850874A CN110423242B CN 110423242 B CN110423242 B CN 110423242B CN 201910850874 A CN201910850874 A CN 201910850874A CN 110423242 B CN110423242 B CN 110423242B
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邹碧群
何瑞杰
唐洁
方毅林
莫绪
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Abstract

The invention discloses a 6, 7-dichloroquinoline-5, 8-diketone derivative transition metal complex and a synthesis method and application thereof. The complex has a structure shown as a formula (I), and the synthesis method comprises the steps of putting metal nitrate and a compound shown as a formula (II) in a mixed solvent, carrying out coordination reaction under the heating condition or the non-heating condition, cooling a reactant, standing, volatilizing, and precipitating crystals to obtain a target compound; wherein the mixed solvent is a composition of methanol or ethanol and dichloromethane; the complex disclosed by the invention has obvious inhibitory activity on certain tumor cell strains, and has low toxicity on normal human liver cells. The compounds shown in the formula (I) and the formula (II) are respectively as follows:
Figure DDA0002196878160000011
wherein M represents a certain divalent metal element selected from the fourth period of the periodic Table of elements; r represents H or CH3X represents H2O、CH3OH or CH3CH2OH。

Description

6, 7-dichloroquinoline-5, 8-diketone derivative transition metal complex and synthetic method and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a 6, 7-dichloroquinoline-5, 8-diketone derivative transition metal complex and a synthesis method and application thereof.
Background
Research and development of metal antitumor drugs has attracted much interest since the discovery by Rosenberg in 1969 that cisplatin (cissplatin) has anticancer activity (Sadler, P.J.; et al. chem. Commun.,2015,51, 9169-one 9172.). However, cisplatin-based drugs have obvious side effects such as renal toxicity, bone marrow toxicity, ototoxicity, peripheral neurotoxicity, emetic property and drug resistance generated by long-term administration, and platinum-based anti-tumor drugs have no activity on certain tumors, so that the application of the platinum-based drugs is limited to a certain extent (Metzler-Nolte, N.; et al. chem. Eur. J.,2016,22, 12487-12494.). In order to overcome the defects of platinum drugs, researchers are dedicated to developing non-platinum metal antitumor drugs with better drug effect and less toxic and side effects (Lippard, S.J.; et al. chem.Sci.,2015,6,1189-1193.) in addition to further developing new platinum drugs.
Currently, the understanding of the potential anti-tumor mechanisms of metal-based anti-cancer drugs is becoming more profound. By selecting suitable organic ligands as carriers for the metal ions, a positive synergistic effect between the active metal ions and the active ligands can be formed to enhance the activity. Therefore, some high-efficiency, low-toxicity metal complexes with antitumor activity are continuously discovered and synthesized, such as non-platinum transition metal or main group metal antitumor complexes and the like. Wherein the essential trace elements of iron, copper, zinc, manganese, selenium and the like are indispensable elements of organisms, for example, the essential trace elements cannot be generated and synthesized in the bodies and are mainly taken by food; and they have a powerful bioscience role (trade-on. analysis of trace elements in food-Lanzhou: Gansu scientific and technical Press, 2004: 2). At present, no report related to the method for synthesizing the transition metal complexes such as zinc, cobalt, nickel, copper, manganese and the like by using 6, 7-dichloroquinoline-5, 8-Dione (DQ) or 6, 7-dichloro-2-methyl-quinoline-5, 8-Dione (DMQ) as an active ligand and the application of the transition metal complexes is found.
Disclosure of Invention
The invention aims to provide a 6, 7-dichloroquinoline-5, 8-diketone derivative transition metal complex which has a novel structure, high tumor cell inhibition activity and low toxicity to normal liver cells, and a synthetic method and application thereof.
The 6, 7-dichloroquinoline-5, 8-diketone derivative transition metal complex is a compound shown in the following formula (I) or a pharmaceutically acceptable salt thereof:
Figure GDA0003155360320000021
wherein M represents a certain divalent metal element selected from the fourth period of the periodic Table of elements; r represents H or CH3X represents H2O、CH3OH or CH3CH2OH。
In the above formula, M is preferably Zn (II), Co (II), Ni (II), Cu (II) or Mn (II).
The invention also provides a synthesis method of the compound shown in the formula (I), which specifically comprises the following steps: placing metal nitrate and a compound shown in a formula (II) in a mixed solvent, carrying out coordination reaction under the heating condition or the non-heating condition, cooling a reactant, standing, volatilizing, and separating out crystals to obtain a target compound; wherein the mixed solvent is a composition of methanol and dichloromethane or a composition of ethanol and dichloromethane;
Figure GDA0003155360320000022
wherein R represents H or CH3。
In the above synthesis method, the metal nitrate is the nitrate corresponding to each metal, specifically, the nitrate corresponding to Zn (II), Co (II), Ni (II), Cu (II) and Mn (II) is usually Zn (NO)3)2·6H2O、Co(NO3)2·6H2O、Ni(NO3)2·6H2O、Cu(NO3)2·3H2O and Mn (NO)3)2·6H2And O. The raw material is represented by the formula (II)A compound which is 6, 7-dichloroquinoline-5, 8-dione (also abbreviated as DQ in this application) when R represents H and which is CH when R represents3When it is 6, 7-dichloro-2-methyl-quinoline-5, 8-dione (also referred to herein as DMQ), the starting material can be prepared by reference to the existing literature (Liang, f. -p.; et al. dalton trans.,2019,48, 5352. one). The metal nitrate and the compound of formula (II) are generally in stoichiometric proportions, and in actual practice, the metal nitrate may be in relative excess.
In the above synthesis method, in the mixed solvent, methanol or ethanol and dichloromethane may be mixed in any proportion, and the volume ratio of methanol or ethanol to dichloromethane is preferably 1-100: 1 to 100, more preferably a mixed solvent of methanol and methylene chloride in a ratio of 1 to 100: 1-100 volume ratio. The amount of the mixed solvent to be used may be determined as required, and it is usually preferable to dissolve the starting materials to be reacted, and specifically, the total amount of the mixed solvent to be used for all the starting materials is usually 5 to 80mL based on 1mmol of the compound represented by the formula (II). In the specific dissolving step, the metal nitrate and the compound represented by the formula (II) may be dissolved in a mixed solvent, and then mixed together for reaction, or the metal nitrate and the compound represented by the formula (II) may be mixed and then dissolved in the mixed solvent.
In the specific synthesis of the target compound, a solution method (i.e., a coordination reaction carried out without heating) or a solvothermal method (i.e., a coordination reaction carried out with heating) may be employed. The synthesis is preferably carried out by a solvothermal method, more preferably the reaction is carried out at 50 to 120 ℃, and even more preferably the reaction is carried out at 60 to 100 ℃. The completion of the reaction can be followed by TLC. According to the experience of the Applicant, it is advisable to control the reaction time between 3 and 72 hours, when the reaction is carried out at a temperature of between 50 and 120 ℃, in order to obtain yields of between 65.3 and 92.8%.
In the synthesis method, the obtained reactant is cooled and then filtered, and the filtrate is kept stand and volatilized at room temperature (or the reactant is filtered firstly, then the filtrate is collected and cooled at room temperature, kept stand and volatilized), and usually, the filtrate is volatilized until the volume of the filtrate is 3/5 or less of the input volume of the mixed solvent, and crystals are separated out.
Furthermore, the invention also provides application of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof in preparing antitumor drugs.
Further, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof.
Compared with the prior art, the invention provides the 6, 7-dichloroquinoline-5, 8-diketone derivative transition metal complex with a novel structure and the synthesis method thereof, and the in vitro test result of the applicant on the target compound shows that the complex not only has obvious antitumor activity (and the activity is obviously higher than that of a ligand of the target compound), but also has extremely low toxicity on normal liver cells, thereby providing a lead compound for developing a new antitumor active medicament.
Drawings
FIG. 1 is a crystal structure diagram of a final product obtained in example 1 of the present invention;
FIG. 2 is a crystal structure diagram of the final product obtained in example 2 of the present invention;
FIG. 3 is a crystal structure diagram of the final product obtained in example 3 of the present invention;
FIG. 4 is a crystal structure diagram of the final product obtained in example 4 of the present invention;
FIG. 5 is a crystal structure diagram of the final product obtained in example 5 of the present invention;
FIG. 6 is a crystal structure diagram of the final product obtained in example 6 of the present invention;
FIG. 7 is a crystal structure diagram of the final product obtained in example 7 of the present invention;
FIG. 8 is a crystal structure diagram of the final product obtained in example 8 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: [ Zn (DQ) ]2(CH3OH)2]Synthesis of (Complex 1)
2.0mmol of DQ and 1.0mmol of Zn (NO) are weighed out3)2·6H2O, placed in a 100.0mL high temperature pressure tube and dissolved in 35.0mL of a mixed solvent (V)Methanol：VMethylene dichloride7: 93) reacting at 65 ℃ for 6.0h, filtering reactants, volatilizing the obtained filtrate at room temperature until the volume of the filtrate is 1/3 of the input volume of the mixed solvent, separating out a large amount of reddish brown blocky crystals, collecting the crystals, washing the crystals with methanol, and drying at 45 ℃ to obtain the reddish brown target complex 1. The yield was 90.0%.
The product obtained in this example was characterized:
(1) x-ray single crystal diffraction:
placing reddish brown blocky crystals with moderate size on Supernova single crystal diffractometer of Agilent company, and adopting Mo-K monochromatized by graphiteα
Figure GDA0003155360320000031
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 table 1 below, the bond length and bond angle data are shown in table 2 below, the bond angle data are shown in table 3 below, and the crystal structure of the obtained reddish brown bulk crystal is shown in fig. 1.
TABLE 1 crystallography and Structure correction data for Complex 1
Figure GDA0003155360320000041
a R1＝Σ||Fo|–|Fc||/Σ|Fo|；b wR2＝[Σw(Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
TABLE 2 bond Length of Complex 1
Figure GDA0003155360320000042
Figure GDA0003155360320000043
Figure GDA0003155360320000051
11-X,-Y,-Z
TABLE 3 bond angle [ ° of Complex 1
Figure GDA0003155360320000052
11-X,-Y,-Z
(2) The results of the elemental analysis are shown in Table 4 below.
TABLE 4 elemental analysis results of complexes 1 to 8
Figure GDA0003155360320000053
In conclusion, the reddish brown bulk crystal obtained in this example was determined to be the target complex [ Zn (DQ) ]2(CH3OH)2](Complex 1) having the structural formula:
Figure GDA0003155360320000062
comparative examples 1 to 1
Example 1 was repeated, except that Zn (NO) was replaced by zinc acetate dihydrate, zinc perchlorate hexahydrate or zinc chloride, respectively3)3·6H2O, to obtain [ Zn (DQ) ]2(CH3OH)2](Complex 1), however, no crystal was precipitated.
Comparative examples 1 to 2
Example 1 was repeated except that the mixed solvent was changed to a single solvent such as water, methanol, ethanol, acetonitrile, DMF or dichloromethane.
As a result, no reddish brown crystals of the objective product were obtained.
Example 2: [ Zn (DMQ)2(CH3OH)2]Synthesis of (Complex 2)
2.0mmol of DMQ and 1.0mmol of Zn (NO) are weighed out3)2·6H2O, placed in a 100.0mL high temperature pressure tube and dissolved in 5.0mL of a mixed solvent (V)Methanol：VMethylene dichloride99: 1) reacting at 65 ℃ for 3.0h, filtering reactants, volatilizing the obtained filtrate at room temperature until the volume of the filtrate is 1/3 of the input volume of the mixed solvent, separating out a large amount of reddish brown blocky crystals, collecting the crystals, washing with methanol, and drying at 45 ℃ to obtain the reddish brown target complex 2. The yield was 65.3%.
The product obtained in this example was characterized:
(1) x-ray single crystal diffraction:
placing reddish brown blocky crystals with moderate size on Supernova single crystal diffractometer of Agilent company, and adopting Mo-K monochromatized by graphiteα
Figure GDA0003155360320000063
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 table 5 below, the bond length and bond angle data are shown in table 6 below, the bond angle data are shown in table 7 below, and the crystal structure of the obtained reddish brown bulk crystal is shown in fig. 2.
TABLE 5 crystallography and Structure correction data for Complex 2
Figure GDA0003155360320000061
Figure GDA0003155360320000071
a R1＝Σ||Fo|–|Fc||/Σ|Fo|；b wR2＝[Σw(Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
TABLE 6 bond Length of Complex 2
Figure GDA0003155360320000074
Figure GDA0003155360320000072
1-X,1-Y,-Z
TABLE 7 bond angle [ ° of Complex 2
Figure GDA0003155360320000073
Figure GDA0003155360320000081
1-X,1-Y,-Z
(2) The results of elemental analysis are shown in Table 4 above.
In conclusion, the reddish brown bulk crystal obtained in this example was determined to be the target complex [ Zn (DMQ) ]2(CH3OH)2](complex 2) having the following structural formula:
Figure GDA0003155360320000082
comparative example 2-1
Example 2 was repeated, except that Zn (NO) was replaced by zinc acetate dihydrate, zinc perchlorate hexahydrate or zinc chloride, respectively3)3·6H2O, in order to obtain [ Zn (DMQ) ]2(CH3OH)2](Complex 2), however, none of the crystals precipitated.
Comparative examples 2 to 2
Example 2 was repeated except that the mixed solvent was changed to a single solvent such as water, methanol, ethanol, acetonitrile, DMF or dichloromethane.
As a result, no reddish brown crystals of the objective product were obtained.
Example 3: [ Co (DQ)2(CH3OH)2]Synthesis of (Complex 3)
Weigh 2.0mmol of DQ and 1.0mmol of Co (NO)3)2·6H2O, placed in a 100.0mL high temperature pressure tube and dissolved in 80.0mL of a mixed solvent (V)Methanol：VMethylene dichloride23:77) and (2) reacting a mixed solution of medium methanol and dichloromethane (v: v ═ 23:77) at 120 ℃ for 72.0h, filtering the reactant, volatilizing the obtained filtrate at room temperature until 1/3 of the volume of the mixed solvent is added, separating out a large amount of reddish brown blocky crystals, collecting the crystals, washing the crystals with methanol, and drying the crystals at 45 ℃ to obtain the reddish brown target complex 3. The yield was 92.8%.
The product obtained in this example was characterized:
(1) x-ray single crystal diffraction:
placing reddish brown blocky crystals with moderate size on Supernova single crystal diffractometer of Agilent company, and adopting Mo-K monochromatized by graphiteα
Figure GDA0003155360320000093
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 table 8 below, the bond length and bond angle data are shown in table 9 below, the bond angle data are shown in table 10 below, and the crystal structure of the obtained reddish brown bulk crystal is shown in fig. 3.
TABLE 8 crystallography and Structure correction data for Complex 3
Figure GDA0003155360320000091
a R1＝Σ||Fo|–|Fc||/Σ|Fo|；b wR2＝[Σw(Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
TABLE 9 bond Length of Complex 3
Figure GDA0003155360320000094
Figure GDA0003155360320000092
Figure GDA0003155360320000101
1-X,1-Y,1-Z
TABLE 10 bond angle [ ° of complex 3
Figure GDA0003155360320000102
1-X,1-Y,1-Z
(2) The results of elemental analysis are shown in Table 4 above.
In conclusion, the reddish brown bulk crystal obtained in this example was determined to be the target complex [ Co (DQ) ]2(CH3OH)2](complex 3) having the following structural formula:
Figure GDA0003155360320000103
comparative example 3-1
Example 3 was repeated, except that Co (NO) was replaced by cobalt acetate tetrahydrate, cobalt perchlorate hexahydrate or cobalt chloride, respectively3)2·6H2O, to obtain [ Co (DQ) ]2(CH3OH)2](Complex 3), however, no crystal was precipitated.
Comparative examples 3 to 2
Example 3 was repeated except that the mixed solvent was changed to a single solvent such as water, methanol, ethanol, acetonitrile, DMF or dichloromethane.
As a result, no reddish brown crystals of the objective product were obtained.
Example 4: [ Co (DMQ)2(CH3OH)2]Synthesis of (Complex 4)
Weigh 2.0mmol of DMQ and 1.0mmol of Co (NO)3)2·6H2O, placed in a 100.0mL high temperature pressure tube and dissolved in 50.0mL of a mixed solvent (V)Methanol：VMethylene dichloride63: 27) reacting at 27.0 ℃ for 35.0h, filtering reactants, volatilizing the obtained filtrate at room temperature until 1/3 of the volume of the mixed solvent is added, separating out a large amount of reddish brown blocky crystals, collecting the crystals, washing with methanol, and drying at 45 ℃ to obtain the reddish brown target complex 4. The yield was 78.1%.
The product obtained in this example was characterized:
(1) x-ray single crystal diffraction:
placing reddish brown blocky crystals with moderate size on Supernova single crystal diffractometer of Agilent company, and adopting Mo-K monochromatized by graphiteα
Figure GDA0003155360320000112
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 11, the bond length and bond angle data are shown in the following table 12, the bond angle data are shown in the following table 13, and the crystal structure of the obtained reddish brown bulk crystal is shown in fig. 4. TABLE 11 crystallography and Structure correction data for Complex 4
Figure GDA0003155360320000111
Figure GDA0003155360320000121
a R1＝Σ||Fo|–|Fc||/Σ|Fo|；b wR2＝[Σw(Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
TABLE 12 bond Length of Complex 4
Figure GDA0003155360320000124
Figure GDA0003155360320000122
11-X,1-Y,1-Z
TABLE 13 bond angle [ ° of Complex 4
Figure GDA0003155360320000123
Figure GDA0003155360320000131
11-X,1-Y,1-Z
(2) The results of elemental analysis are shown in Table 4.
Thus, it was confirmed that the obtained product was represented by the formula [ Co (DMQ) ]2(CH3OH)2](4) The structural formula is as follows:
Figure GDA0003155360320000132
comparative example 4-1
Example 4 was repeated, except that Co (NO) was replaced by cobalt acetate tetrahydrate, cobalt perchlorate hexahydrate or cobalt chloride, respectively3)2·6H2O, to obtain [ Co (DMQ) ]2(CH3OH)2](Complex 4), but as a result, no crystal precipitated.
Comparative examples 4 to 2
Example 4 was repeated except that the mixed solvent was changed to a single solvent such as water, methanol, ethanol, acetonitrile, DMF or dichloromethane.
As a result, no reddish brown crystals of the objective product were obtained.
Example 5: [ Ni (DQ) ]2(CH3OH)2]Synthesis of (Complex 5)
Weighing 2.0mmol DQ and 1.0mmol Ni (NO)3)2·6H2O, placed in a 100.0mL high temperature pressure tube and dissolved in 18.5mL of a mixed solvent (V)Methanol：VMethylene dichloride7: 3) reacting at 80 ℃ for 24.0h, filtering reactants, volatilizing the obtained filtrate at room temperature until the volume of the filtrate is 1/3 of the input volume of the mixed solvent, separating out a large amount of reddish brown blocky crystals, collecting the crystals, washing with methanol, and drying at 45 ℃ to obtain the reddish brown target complex 5. The yield was 82.5%.
The product obtained in this example was characterized:
(1) x-ray single crystal diffraction:
placing reddish brown blocky crystals with moderate size on Supernova single crystal diffractometer of Agilent company, and adopting Mo-K monochromatized by graphiteα
Figure GDA0003155360320000133
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 resulting crystallographic and structural refinement data are shown in Table 14 below, the bond length and bond angle data are shown in Table 15 below, the bond angle data are shown in Table 16 below, and the results are obtainedThe crystal structure of the reddish brown bulk crystal is shown in FIG. 5. TABLE 14 crystallography and Structure correction data for Complex 5
Figure GDA0003155360320000141
a R1＝Σ||Fo|–|Fc||/Σ|Fo|；b wR2＝[Σw(Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
TABLE 15 bond Length of Complex 5
Figure GDA0003155360320000143
Figure GDA0003155360320000142
Figure GDA0003155360320000151
12-X,-Y,1-Z
TABLE 16 bond angles [ ° of Complex 5
Figure GDA0003155360320000152
12-X,-Y,1-Z
(2) The results of elemental analysis are shown in Table 4 above.
In conclusion, the reddish brown bulk crystal obtained in this example was determined to be the target complex [ Ni (DQ) ]2(CH3OH)2](Complex 5) having the following structural formula:
Figure GDA0003155360320000153
comparative example 5-1
Example 5 was repeated, except that Ni (NO) was replaced by nickel acetate tetrahydrate, nickel perchlorate hexahydrate or nickel chloride hexahydrate, respectively3)2·6H2O, to obtain [ Ni (DQ) ]2(CH3OH)2](Complex 5), however, no crystal was precipitated.
Comparative examples 5 to 2
Example 5 was repeated except that the mixed solvent was changed to a single solvent such as water, methanol, ethanol, acetonitrile, DMF or dichloromethane.
As a result, no reddish brown crystals of the objective product were obtained.
Example 6: [ Cu (DMQ)2(H2O)2]Synthesis of (Complex 6)
Weigh 2.0mmol of DMQ and 1.0mmol of Cu (NO)3)2·3H2O, placed in a 100.0mL high temperature pressure tube and dissolved in 80.0mL of a mixed solvent (V)Methanol：VMethylene dichloride55:45) and (2) reacting a mixed solution of medium methanol and dichloromethane (v: v ═ 55:45) at 100.0 ℃ for 12.0h, filtering the reaction product, volatilizing the obtained filtrate at room temperature until 1/3 of the volume of the mixed solvent is added, separating out a large amount of reddish brown blocky crystals, collecting the crystals, washing the crystals with methanol, and drying the crystals at 45 ℃ to obtain the reddish brown target complex 6. The yield was 90.8%.
The product obtained in this example was characterized:
(1) x-ray single crystal diffraction:
placing reddish brown blocky crystals with moderate size on Supernova single crystal diffractometer of Agilent company, and adopting Mo-K monochromatized by graphiteα
Figure GDA0003155360320000162
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 resulting crystallographic and structural refinement data are shown in Table 17 below, bond length and bond angle numberAs shown in Table 18 below, the bond angle data are shown in Table 19 below, and the crystal structure of the resulting reddish brown bulk crystal is shown in FIG. 6. TABLE 17 crystallography and Structure correction data for Complex 6
Figure GDA0003155360320000161
Figure GDA0003155360320000171
a R1＝Σ||Fo|–|Fc||/Σ|Fo|；b wR2＝[Σw(Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
TABLE 18 bond Length of Complex 6
Figure GDA0003155360320000174
Figure GDA0003155360320000172
11-X,-Y,2-Z
TABLE 19 bond angle [ ° of Complex 6
Figure GDA0003155360320000173
Figure GDA0003155360320000181
11-X,-Y,2-Z
(2) The results of elemental analysis are shown in Table 4 above.
In conclusion, the reddish brown bulk crystal obtained in this example was determined to be the target complex [ Cu (DMQ) ]2(H2O)2](Complex 6) having the following structural formula:
Figure GDA0003155360320000182
comparative example 6-1
Example 6 was repeated, except that Cu (NO) was replaced with copper acetate monohydrate, copper perchlorate hexahydrate, copper sulfate pentahydrate or anhydrous copper chloride, respectively3)2·3H2O, in order to obtain [ Cu (DMQ) ]2(H2O)2](Complex 6), however, no crystal was precipitated.
Comparative examples 6 to 2
Example 6 was repeated except that the mixed solvent was changed to a single solvent such as water, methanol, ethanol, acetonitrile, DMF or dichloromethane.
As a result, no reddish brown crystals of the objective product were obtained.
Example 7: [ Mn (DQ)2(H2O)2]Synthesis of (Complex 7)
Weighing 2.0mmol DQ and 1.0mmol Mn (NO)3)2·6H2O, placed in a 100.0mL high temperature pressure tube and dissolved in 45.0mL of a mixed solvent (V)Methanol：VMethylene dichloride7: 3) reacting at 70.0 ℃ for 48.0h, filtering reactants, volatilizing the obtained filtrate at room temperature until 1/3 of the volume of the mixed solvent is added, separating out a large amount of reddish brown blocky crystals, collecting the crystals, washing with methanol, and drying at 45 ℃ to obtain the reddish brown target complex 7. The yield was 70.1%.
The product obtained in this example was characterized:
(1) x-ray single crystal diffraction:
placing reddish brown blocky crystals with moderate size on Supernova single crystal diffractometer of Agilent company, and adopting Mo-K monochromatized by graphiteα
Figure GDA0003155360320000184
And (4) performing single crystal test by using rays. The initial crystal structure of the product obtained in this example was found to be uniformSolving by a SHELXS-97 direct method, geometrically hydrogenating, and refining non-hydrogen atom coordinates and anisotropic thermal parameters by a whole matrix least square method by adopting SHELXL-97. The obtained crystallographic and structural refinement data are shown in the following table 20, the bond length and bond angle data are shown in the following table 21, the bond angle data are shown in the following table 22, and the crystal structure of the obtained reddish brown bulk crystal is shown in fig. 7. TABLE 20 crystallography and Structure correction data for Complex 7
Figure GDA0003155360320000183
Figure GDA0003155360320000191
a R1＝Σ||Fo|–|Fc||/Σ|Fo|；b wR2＝[Σw(Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
TABLE 21 bond Length of Complex 7
Figure GDA0003155360320000193
Figure GDA0003155360320000192
TABLE 22 bond angles [ ° of Complex 7
Figure GDA0003155360320000201
(2) The results of elemental analysis are shown in Table 4 above.
In conclusion, the reddish brown bulk crystal obtained in this example was determined to be the target complex [ Mn (DQ) ]2(H2O)2](Complex 7) having the following structural formula:
Figure GDA0003155360320000202
comparative example 7-1
Example 7 was repeated, except that Mn (NO) was replaced with manganese acetate tetrahydrate, manganese perchlorate hexahydrate, manganese sulfate or manganese chloride tetrahydrate, respectively3)2·6H2O, to obtain [ Mn (DQ) ]2(H2O)2](Complex 7), however, no crystal was precipitated.
Comparative examples 7 to 2
Example 7 was repeated except that the mixed solvent was changed to a single solvent such as water, methanol, ethanol, acetonitrile, DMF or dichloromethane.
As a result, no reddish brown crystals of the objective product were obtained.
Example 8: [ Mn (DMQ)2(H2O)2]Synthesis of (Complex 8)
Weighing 2.0mmol of DMQ and 1.0mmol of Mn (NO)3)2·6H2O, placed in a 100.0mL high temperature pressure tube and dissolved in 25.0mL of a mixed solvent (V)Methanol：VMethylene dichloride78: 22) reacting at 58.0 ℃ for 50.0h, filtering the reactant, volatilizing the obtained filtrate at room temperature until 1/3 of the volume of the mixed solvent is added, separating out a large amount of reddish brown blocky crystals, collecting the crystals, washing with methanol, and drying at 45 ℃ to obtain the reddish brown target complex 8. The yield was 75.6%.
The product obtained in this example was characterized:
(1) x-ray single crystal diffraction:
placing reddish brown blocky crystals with moderate size on Supernova single crystal diffractometer of Agilent company, and adopting Mo-K monochromatized by graphiteα
Figure GDA0003155360320000212
And (4) performing single crystal test by using rays. The initial crystal structures of the products obtained in the example are all solved by a SHELXS-97 direct method, the geometric hydrogenation is carried out, and the non-hydrogen atom coordinates and the anisotropic thermal parameters are all solved by SHELXL-97And refining by a matrix least square method. The obtained crystallographic and structural refinement data are shown in table 23 below, the bond length and bond angle data are shown in table 24 below, the bond angle data are shown in table 25 below, and the crystal structure of the obtained reddish brown bulk crystal is shown in fig. 2.
TABLE 23 crystallography and Structure correction data for Complex 8
Figure GDA0003155360320000211
Figure GDA0003155360320000221
a R1＝Σ||Fo|–|Fc||/Σ|Fo|；b wR2＝[Σw(Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
TABLE 24 bond Length of Complex 8
Figure GDA0003155360320000224
Figure GDA0003155360320000222
1-X,-Y,-Z
TABLE 25 bond angles [ ° of Complex 8
Figure GDA0003155360320000223
Figure GDA0003155360320000231
1-X,-Y,-Z
(2) The results of elemental analysis are shown in Table 4 above.
In conclusion, the reddish brown bulk crystal obtained in this example was determined to be the target complex [ Mn (DMQ) ]2(H2O)2](Complex 8) having the following structural formula:
Figure GDA0003155360320000232
comparative example 8-1
Example 8 was repeated, except that Mn (NO) was replaced with manganese acetate tetrahydrate, manganese perchlorate hexahydrate, manganese sulfate or manganese chloride tetrahydrate, respectively3)2·6H2O, in order to obtain [ Mn (DMQ) ]2(H2O)2](Complex 8), however, no crystal was precipitated.
Comparative examples 8 to 2
Example 8 was repeated except that the mixed solvent was changed to a single solvent such as water, methanol, ethanol, acetonitrile, DMF or dichloromethane.
As a result, no reddish brown crystals of the objective product were obtained.
Example 9: [ Zn (DQ) ]2(CH3CH2OH)2]Synthesis of (Complex 9)
Example 1 was repeated except that ethanol was used instead of methanol in the composition of the mixed solvent. As a result, reddish brown bulk crystals were obtained.
The reddish brown bulk crystal obtained in this example was determined to be the target complex [ Zn (DQ) by X-ray single crystal diffraction analysis and elemental analysis2(CH3CH2OH)2](Complex 9).
Example 10: [ Cu (DQ) ]2(H2O)2]Synthesis of (Complex 10)
Example 6 was repeated except that DQ was used instead of DMQ, the reaction temperature was changed to 30.0 ℃ and the flash time of the reaction was controlled at 72 h. As a result, reddish brown bulk crystals were obtained.
The reddish brown bulk crystal obtained in this example was determined to be the target complex [ Cu (DQ) ] by X-ray single crystal diffraction analysis and elemental analysis2(H2O)2](Complex compounds)10)。
Example 11: [ Mn (DQ)2(CH3CH2OH)2]Synthesis of (Complex 11)
Example 8 was repeated, except that DQ was used instead of DMQ, ethanol was used instead of methanol in the composition of the mixed solvent, the reaction temperature was changed to 120 ℃, and the reaction time was controlled to 30 hours. As a result, reddish brown bulk crystals were obtained.
The reddish brown bulk crystal obtained in this example was determined to be the target complex [ Mn (DQ) ] by X-ray single crystal diffraction analysis and elemental analysis2(CH3CH2OH)2](Complex 11).
Experimental example: the complex 1-8 of the invention is used for the proliferation inhibition activity experiment of various human tumor cell strains:
1. cell lines and cell cultures
The experiment selects 5 human tumor cell strains such as human cervical carcinoma cells HeLa, human breast cancer cells MCF-7, human bladder cancer cells T-24, human liver cancer cells Hep-G2, human ovarian cancer cells SK-OV-3 and the like, and human normal liver cells HL-7702.
All cell lines were cultured in RPMI-1640 medium containing 10 wt% calf blood, 100U/mL penicillin and 100U/mL streptomycin, and placed at 37 ℃ in a volume concentration of 5% CO2Culturing in an incubator.
2. Preparation of test Compounds
The purity of the used complex 1-8 is more than or equal to 95 percent (respectively prepared by the method of the embodiment 1-8 of the invention), the DMSO stock solution is diluted by physiological buffer solution to prepare 20 mu mol/L final solution, wherein the final concentration of the cosolvent DMSO is less than or equal to 1 percent, and the inhibition degree of the complex 1-8 on the growth of various tumor cells under the concentration is tested.
3. Cell growth inhibition assay (MTT method)
(1) Taking tumor cells in logarithmic growth phase, digesting by trypsin, preparing cell suspension with the number concentration of 5000/mL by using culture solution containing 10% calf serum, inoculating 190 mu L of the cell suspension into a 96-hole culture plate, and enabling the cell density to be detected to reach 1000-10000 holes (the edge holes are filled with sterile PBS);
(2)5％CO2incubating for 24h at 37 ℃ until a cell monolayer is paved on the bottom of each well, adding 10 mu L of medicine with a certain concentration gradient into each well, and arranging 4 compound wells in each concentration gradient;
(3)5％CO2incubating at 37 ℃ for 48 hours, and observing under an inverted microscope;
(4) add 10. mu.L of MTT solution (5mg/mL PBS, i.e., 0.5% MTT) to each well and continue culturing for 4 h;
(5) terminating the culture, carefully removing the culture solution in the wells, adding 150 μ L of DMSO into each well to sufficiently dissolve formazan precipitate, mixing uniformly with an oscillator, and measuring the optical density of each well with a microplate reader at a wavelength of 570nm and a reference wavelength of 450 nm;
(6) simultaneously, a zero setting hole (culture medium, MTT, DMSO) and a control hole (cells, a drug dissolving medium with the same concentration, a culture solution, MTT, DMSO) are arranged.
(7) The number of living cells was judged from the measured optical density values (OD values), and the larger the OD value, the stronger the cell activity. Using the formula:
Figure GDA0003155360320000241
calculating the inhibition rate of the drug to the growth of tumor cells, and calculating the IC of the complexes 1-8 to the cell lines by a Bliss method50The value is obtained. The results are shown in table 26 below.
Table 26: IC of 1-8 complex for different tumor cell strains50Value (μ M)
Figure GDA0003155360320000251
From IC in table 2650As a result, the complexes 1 to 8 show certain proliferation inhibition activity on 5 human tumor cell lines, especially have the best inhibition effect on human cervical carcinoma cells HeLa, and IC50The values are respectively 3.03 +/-0.28, 1.08 +/-0.15, 5.08 +/-1.08, 4.34 +/-0.81, 10.21 +/-0.44, 4.01 +/-1.05, 9.01 +/-1.84 and 6.21 +/-0.55 mu M, which are obviously higher than cisplatin, corresponding ligands and metal salts; on the other hand, the complexes are aligned 1-8Normal cell HL-7702 has almost no toxicity (IC)50>60.0 mu M) with better cytotoxicity selectivity. This is a positive result, which indicates that complexes 1-8 have low hepatotoxicity while exhibiting a certain broad-spectrum anti-tumor activity, i.e., complexes 1-8 have a certain cytotoxicity selectivity.
In conclusion, the complexes 1-8 of the invention generally show obvious in vitro antitumor activity and toxicity selectivity, have good potential medicinal value and are expected to be used for preparing various antitumor medicaments.

Claims (3)

1. The application of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof in preparing antitumor drugs;
Figure DEST_PATH_IMAGE001
(I)；
wherein M represents Zn (II), Co (II), Ni (II), Cu (II) or Mn (II); r represents H or CH3(ii) a X represents H2O、CH3OH or CH3CH2OH。
2. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof;
Figure 518948DEST_PATH_IMAGE001
(I)；
wherein M represents Co (II); r represents H or CH3(ii) a X represents CH3OH。
3. The application of a pharmaceutical composition in preparing antitumor drugs, wherein the pharmaceutical composition contains a therapeutically effective dose of a compound shown in the following formula (I) or a pharmaceutically acceptable salt thereof;
Figure 498405DEST_PATH_IMAGE001
(I)；
wherein M represents Zn (II), Co (II), Ni (II), Cu (II) or Mn (II); r represents H or CH3(ii) a X represents H2O、CH3OH or CH3CH2OH。
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