CN110423242A - 6,7- dichloroquinoline -5,8- derovatives transient metal complex and its synthetic method and application - Google Patents
6,7- dichloroquinoline -5,8- derovatives transient metal complex and its synthetic method and application Download PDFInfo
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
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Abstract
The invention discloses a kind of 6,7- dichloroquinoline -5,8- derovatives transient metal complex and its synthetic method and applications.Complex of the present invention has the structure as shown in following formula (I), its synthetic method is that compound shown in metal nitrate and following formula (II)s is taken to be placed in the mixed solvent, complexation reaction is carried out under the conditions of being heated or not heated, reactant is cooling, it stands, volatilization, has crystal to be precipitated to get target compound；Wherein, the mixed solvent is the composition of methanol or ethyl alcohol and methylene chloride；Complex of the present invention has significant inhibitory activity to certain tumor cell lines, and low to the toxicity of Human normal hepatocyte.The difference of compound shown in the formula (I) and formula (II) is as follows:Wherein, M indicates certain divalent metal element in the periodic table of elements period 4；R indicates H or CH3, X expression H2O、CH3OH or CH3CH2OH。
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to 6,7- dichloroquinoline -5,8- derovatives transition metal are matched
Close object and its synthetic method and application.
Background technique
Since Rosenberg in 1969 has found that cis-platinum (cisplatin) has anticancer activity, metal anti-tumor drug
Research and development cause broad interest (Sadler, the P.J. of people；et al.Chem.Commun.,2015,51,9169-
9172.).But cis-platinum metalloid drug has apparent Toxicity of Kidney, bone marrow toxicity, ototoxicity, peripheral nerve toxicity, emetic
And take the side effects such as the drug resistance generated for a long time, and platinum series antineoplastic medicament is not active to certain tumours, these are not
Foot limits application (Metzler-Nolte, the N. of these platinum medicines to a certain extent；et al.Chem.Eur.J.,
2016,22,12487-12494.).In order to overcome the defect of platinum medicine, researcher removes and further researches and develops new platinum medicine
Outside, it is dedicated to developing that drug effect is more preferable, toxic side effect smaller non-platinum metals anti-tumor drug (Lippard, S.J.；et
al.Chem.Sci.,2015,6,1189-1193.)。
Currently, more deep for the understanding of the potential antitumor mechanism of Metal Substrate anticancer drug.It is suitable by selecting
Carrier of the organic ligand as metal ion, the positive coopertive effect that can be formed between active metallic ion and active ligand is to increase
It is strongly active.More efficient, low toxicity, metal complex with anti-tumor activity are constantly discovered and are synthesized, such as non-platinum class
Transition metal or main group metal anti-tumor complex etc..Wherein the essential trace elements such as iron, copper, zinc, manganese, selenium are that organism can not
The element lacked, e.g., they cannot generate and synthesize in vivo, mainly pass through food intake；And they have powerful biology
Science effect (Lanzhou analysis of Gai Ke Trace Elements in Food: Gansu science tech publishing house, 2004:2).It has not yet to see
Having 6,7- dichloroquinoline -5,8- diketone (DQ) or the chloro- 2- Methyl-quinoline -5,8- diketone (DMQ) of 6,7- bis- is active ligand conjunction
At the relevant report of the method and its application of the transient metal complexes such as its zinc, cobalt, nickel, copper, manganese.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of structure novel, to inhibiting tumour cells activity height and to normal
Low 6,7- dichloroquinoline -5, the 8- derovatives transient metal complex of hepatotoxicity and their synthetic method and
Using.
6,7- dichloroquinoline -5,8- derovatives transient metal complex of the present invention is with following formula (I)s
Shown compound or its pharmaceutically acceptable salt:
Wherein, M indicates certain divalent metal element in the periodic table of elements period 4；R indicates H or CH3, X table
Show H2O、CH3OH or CH3CH2OH。
In structure above, M is preferably Zn (II), Co (II), Ni (II), Cu (II) or Mn (II).
The present invention also provides the synthetic methods of compound shown in above-mentioned formula (I), specifically include: taking metal nitrate and following
Compound shown in formula (II) is placed in the mixed solvent, complexation reaction is carried out under the conditions of being heated or not heated, reactant is cooling, quiet
It sets, volatilizees, there is crystal to be precipitated to get target compound；Wherein, the mixed solvent is the combination of methanol and methylene chloride
The composition of object or ethyl alcohol and methylene chloride；
Wherein, R indicates H or CH3。
In above-mentioned synthetic method, the metal nitrate is respectively the corresponding nitrate of each metal, specifically, corresponding to
Zn (II), Co (II), Ni (II), Cu (II) and Mn (II) nitrate be usually Zn (NO3)2·6H2O、Co(NO3)2·6H2O、
Ni(NO3)2·6H2O、Cu(NO3)2·3H2O and Mn (NO3)2·6H2O.Compound shown in the raw material formula (II), when R is indicated
It is 6,7- dichloroquinoline -5,8- diketone (DQ is also referred to as in the application) when H, when R indicates CH3The chloro- 2- of Shi Qiwei 6,7- bis-
Methyl-quinoline -5,8- diketone (is also referred to as DMQ) in the application, which can refer to existing literature (Liang, F.-P.；et
Al.Dalton Trans., 2019,48,5352-5360.) it is prepared.Compound shown in the metal nitrate and formula (II)
Usually stoichiometric ratio, in actual operation, metal nitrate can be relatively excessive.
In above-mentioned synthetic method, the in the mixed solvent, methanol or ethyl alcohol and methylene chloride can with arbitrary proportion into
Row proportion, the preferably volume ratio of methanol or ethyl alcohol and methylene chloride are 1-100:1-100, more preferable mixed solvent be by methanol and
The mixture that methylene chloride is formed by the volume ratio of 1-100:1-100.The dosage of the mixed solvent can determine as needed, lead to
The raw material that reaction is participated in Chang Yineng dissolution is advisable, and specifically, is calculated on the basis of compound shown in the formula (II) of 1mmol, all
Total dosage of mixed solvent used in raw material is generally 5-80mL.It, can be by metal nitrate and formula in specific the step of dissolving
(II) compound shown in uses one of mixed solvent ingredient to dissolve respectively, remixes and reacts together, can also be by metal nitrate
Add mixed solvent dissolution after the mixing of compound shown in salt and formula (II) again.
In specific synthesising target compound, solwution method (not carrying out complexation reaction under heating condition) can be used, it can also
Using solvent-thermal method (carrying out complexation reaction under heating condition).It is preferred that synthesized using solvent-thermal method, it is further preferably anti-
It should be carried out under the conditions of 50-120 DEG C, more preferably reaction carries out under the conditions of 60-100 DEG C.Reaction whether can be used completely TLC with
Track detection.According to the experience of applicant, when reaction carries out under the conditions of 50-120 DEG C, reaction time control 3-72h more
It is suitable for, yield is up to 65.3-92.8% at this time.
In synthetic method of the present invention, first filtered after gained reactant is cooling, then filtrate is stood at room temperature
Volatilization (or reactant first filters, and then collects filtrate and cools down at room temperature again, stands, volatilization), it is generally the case that
Filtrate evaporate into that its volume is mixed solvent investment volume 3/5 it is even less when have crystal precipitation.
Further, it is anti-in preparation that the present invention also provides compounds shown in above-mentioned formula (I) or its pharmaceutically acceptable salt
Application in tumour medicine.
Further, the present invention also provides a kind of pharmaceutical compositions, it contains the above-mentioned formula (I) for treating upper effective dose
Shown compound or its pharmaceutically acceptable salt.
Compared with prior art, the present invention provides a kind of 6,7- dichloroquinoline -5,8- derovatives of structure novel
Transient metal complex and its synthetic method, the applicant to the in vitro test of the target compound the result shows that, they are not
Only with significant anti-tumor activity (and activity is significantly higher than ligand of target compound), to the toxicity of normal liver cell also pole
Low, the anti-tumor activity medicine to develop new provides lead compound.
Detailed description of the invention
Fig. 1 is the crystal structure figure of final product made from the embodiment of the present invention 1；
Fig. 2 is the crystal structure figure of final product made from the embodiment of the present invention 2；
Fig. 3 is the crystal structure figure of final product made from the embodiment of the present invention 3；
Fig. 4 is the crystal structure figure of final product made from the embodiment of the present invention 4；
Fig. 5 is the crystal structure figure of final product made from the embodiment of the present invention 5；
Fig. 6 is the crystal structure figure of final product made from the embodiment of the present invention 6；
Fig. 7 is the crystal structure figure of final product made from the embodiment of the present invention 7；
Fig. 8 is the crystal structure figure of final product made from the embodiment of the present invention 8.
Specific embodiment
The present invention is described in further detail combined with specific embodiments below, content to better understand the invention, but
The present invention is not limited to following embodiments.
Embodiment 1:[Zn (DQ)2(CH3OH)2] (complex 1) synthesis
Weigh the Zn (NO of the DQ and 1.0mmol of 2.0mmol3)2·6H2O is placed in the high-temperature pressure-proof pipe of 100.0mL, molten
Solution is in the mixed solvent (V of 35.0mLMethanol: VMethylene chloride=7:93), 6.0h, reactant filtering are reacted at 65 DEG C, gained filtrate exists
It volatilizees at room temperature, until thering are a large amount of rufous bulk crystals to be precipitated when its volume is that mixed solvent puts into the 1/3 of volume, collecting
Crystal is washed through methanol, 45 DEG C of dryings to get arrive rufous title complex 1.Yield is 90.0%.
The present embodiment products therefrom is characterized:
(1) X-ray single crystal diffraction:
The rufous bulk crystals of moderate dimensions are taken to be placed on agilent company SuperNova single crystal diffractometer, using stone
The Mo-K of black monochromatizationα Ray carries out monocrystalline test.The tial crystalline structure of the present embodiment products therefrom
It is all made of SHELXS-97 direct method to solve, geometry adds hydrogen, and non-hydrogen atom coordinate and anisotropy thermal parameter use SHELXL-97
Through complete matrix least square method refine.Gained crystallography and structure refinement data are as described in Table 1, and bond distance's bond angle data are such as
Shown in following table 2, bond angle data are as described in Table 3, and the crystal structure of gained rufous bulk crystals is as shown in Figure 1.
The crystallography and structural modifications data of 1. complex 1 of table
a R1=Σ | | Fo|–|Fc||/Σ|Fo|；b wR2=[Σ w (Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
The strong length of 2. complex 1 of table
11-X,-Y,-Z
The bond angle [°] of 3. complex 1 of table
11-X,-Y,-Z
(2) elemental analysis, as a result as described in Table 4.
The elemental analysis result of 4. complex 1-8 of table
To sum up, it can determine that rufous bulk crystals obtained by the present embodiment are title complex [Zn (DQ)2(CH3OH)2]
(complex 1), structural formula is as follows:
Comparative example 1-1
Embodiment 1 is repeated, unlike, Zn is substituted with Zinc diacetate dihydrate, perchlorate hexahydrate's zinc or zinc chloride respectively
(NO3)3·6H2O obtains [Zn (DQ) with expectation2(CH3OH)2] (complex 1), but result is precipitated without any crystal.
Comparative example 1-2
Embodiment 1 is repeated, unlike, mixed solvent is changed to water, methanol, ethyl alcohol, acetonitrile, DMF or methylene chloride etc.
Single solvent.
As a result rufous target product crystal is not obtained.
Embodiment 2:[Zn (DMQ)2(CH3OH)2] (complex 2) synthesis
Weigh the Zn (NO of the DMQ and 1.0mmol of 2.0mmol3)2·6H2O is placed in the high-temperature pressure-proof pipe of 100.0mL, molten
Solution is in the mixed solvent (V of 5.0mLMethanol: VMethylene chloride=99:1) in, 3.0h, reactant filtering are reacted at 65 DEG C, gained filtrate exists
It volatilizees at room temperature, until thering are a large amount of rufous bulk crystals to be precipitated when its volume is that mixed solvent puts into the 1/3 of volume, collecting
Crystal is washed through methanol, 45 DEG C of dryings to get arrive rufous title complex 2.Yield is 65.3%.
The present embodiment products therefrom is characterized:
(1) X-ray single crystal diffraction:
The rufous bulk crystals of moderate dimensions are taken to be placed on agilent company SuperNova single crystal diffractometer, using stone
The Mo-K of black monochromatizationα Ray carries out monocrystalline test.The tial crystalline structure of the present embodiment products therefrom
It is all made of SHELXS-97 direct method to solve, geometry adds hydrogen, and non-hydrogen atom coordinate and anisotropy thermal parameter use SHELXL-97
Through complete matrix least square method refine.Gained crystallography and structure refinement data are as described in Table 5, and bond distance's bond angle data are such as
Shown in following table 6, bond angle data are as described in Table 7, and the crystal structure of gained rufous bulk crystals is as shown in Figure 2.
The crystallography and structural modifications data of 5. complex 2 of table
a R1=Σ | | Fo|–|Fc||/Σ|Fo|；b wR2=[Σ w (Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
The strong length of 6. complex 2 of table
1-X,1-Y,-Z
The bond angle [°] of 7. complex 2 of table
1-X,1-Y,-Z
(2) elemental analysis, as a result as shown in Table 4 above.
To sum up, it can determine that rufous bulk crystals obtained by the present embodiment are title complex [Zn (DMQ)2(CH3OH)2]
(complex 2), structural formula is as follows:
Comparative example 2-1
Embodiment 2 is repeated, unlike, Zn is substituted with Zinc diacetate dihydrate, perchlorate hexahydrate's zinc or zinc chloride respectively
(NO3)3·6H2O obtains [Zn (DMQ) with expectation2(CH3OH)2] (complex 2), but result is precipitated without any crystal.
Comparative example 2-2
Embodiment 2 is repeated, unlike, mixed solvent is changed to water, methanol, ethyl alcohol, acetonitrile, DMF or methylene chloride etc.
Single solvent.
As a result rufous target product crystal is not obtained.
Embodiment 3:[Co (DQ)2(CH3OH)2] (complex 3) synthesis
Weigh the Co (NO of the DQ and 1.0mmol of 2.0mmol3)2·6H2O is placed in the high-temperature pressure-proof pipe of 100.0mL, molten
Solution is in the mixed solvent (V of 80.0mLMethanol: VMethylene chloride=23:77) in methanol and methylene chloride mixed solution (v:v=23:77),
72.0h, reactant filtering are reacted at 120 DEG C, gained filtrate is volatilized at room temperature, until its volume is that mixed solvent puts into body
When long-pending 1/3, there are a large amount of rufous bulk crystals to be precipitated, collect crystal, washed through methanol, 45 DEG C of drying are to get to rufous
Title complex 3.Yield is 92.8%.
The present embodiment products therefrom is characterized:
(1) X-ray single crystal diffraction:
The rufous bulk crystals of moderate dimensions are taken to be placed on agilent company SuperNova single crystal diffractometer, using stone
The Mo-K of black monochromatizationα Ray carries out monocrystalline test.The tial crystalline structure of the present embodiment products therefrom
It is all made of SHELXS-97 direct method to solve, geometry adds hydrogen, and non-hydrogen atom coordinate and anisotropy thermal parameter use SHELXL-97
Through complete matrix least square method refine.Gained crystallography and structure refinement data are as described in Table 8, and bond distance's bond angle data are such as
Shown in following table 9, bond angle data are as described in Table 10, and the crystal structure of gained rufous bulk crystals is as shown in Figure 3.
The crystallography and structural modifications data of 8. complex 3 of table
a R1=Σ | | Fo|–|Fc||/Σ|Fo|；b wR2=[Σ w (Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
The strong length of 9. complex 3 of table
1-X,1-Y,1-Z
The bond angle [°] of 10. complex 3 of table
1-X,1-Y,1-Z
(2) elemental analysis, as a result as shown in Table 4 above.
To sum up, it can determine that rufous bulk crystals obtained by the present embodiment are title complex [Co (DQ)2(CH3OH)2]
(complex 3), structural formula is as follows:
Comparative example 3-1
Embodiment 3 is repeated, unlike, Co is substituted with four acetate hydrate cobalts, perchlorate hexahydrate's cobalt or cobalt chloride respectively
(NO3)2·6H2O obtains [Co (DQ) with expectation2(CH3OH)2] (complex 3), but result is precipitated without any crystal.
Comparative example 3-2
Embodiment 3 is repeated, unlike, mixed solvent is changed to water, methanol, ethyl alcohol, acetonitrile, DMF or methylene chloride etc.
Single solvent.
As a result rufous target product crystal is not obtained.
Embodiment 4:[Co (DMQ)2(CH3OH)2] (complex 4) synthesis
Weigh the Co (NO of the DMQ and 1.0mmol of 2.0mmol3)2·6H2O is placed in the high-temperature pressure-proof pipe of 100.0mL, molten
Solution is in the mixed solvent (V of 50.0mLMethanol: VMethylene chloride=63:27) in, 35.0h, reactant filtering, gained are reacted at 27.0 DEG C
Filtrate is volatilized at room temperature, until having a large amount of rufous bulk crystals to analyse when its volume is that mixed solvent puts into the 1/3 of volume
Out, crystal is collected, is washed through methanol, 45 DEG C of drying are to get to rufous title complex 4.Yield is 78.1%.
The present embodiment products therefrom is characterized:
(1) X-ray single crystal diffraction:
The rufous bulk crystals of moderate dimensions are taken to be placed on agilent company SuperNova single crystal diffractometer, using stone
The Mo-K of black monochromatizationα Ray carries out monocrystalline test.The tial crystalline structure of the present embodiment products therefrom
It is all made of SHELXS-97 direct method to solve, geometry adds hydrogen, and non-hydrogen atom coordinate and anisotropy thermal parameter use SHELXL-97
Through complete matrix least square method refine.Gained crystallography and structure refinement data are as shown in following tables 11, bond distance's bond angle data
As shown in following tables 12, for bond angle data as shown in following tables 13, the crystal structure of gained rufous bulk crystals is as shown in Figure 4.
Table
11. the crystallography and structural modifications data of complex 4
a R1=Σ | | Fo|–|Fc||/Σ|Fo|；b wR2=[Σ w (Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
The strong length of 12. complex 4 of table
11-X,1-Y,1-Z
The bond angle [°] of 13. complex 4 of table
11-X,1-Y,1-Z
(2) elemental analysis is as a result, as shown in table 4.
Hence, it can be determined that it is [Co (DMQ) that resulting product, which is molecular formula,2(CH3OH)2] (4), structural formula is as follows:
Comparative example 4-1
Embodiment 4 is repeated, unlike, Co is substituted with four acetate hydrate cobalts, perchlorate hexahydrate's cobalt or cobalt chloride respectively
(NO3)2·6H2O obtains [Co (DMQ) with expectation2(CH3OH)2] (complex 4), but result is precipitated without any crystal.
Comparative example 4-2
Embodiment 4 is repeated, unlike, mixed solvent is changed to water, methanol, ethyl alcohol, acetonitrile, DMF or methylene chloride etc.
Single solvent.
As a result rufous target product crystal is not obtained.
Embodiment 5:[Ni (DQ)2(CH3OH)2] (complex 5) synthesis
Weigh the Ni (NO of the DQ and 1.0mmol of 2.0mmol3)2·6H2O is placed in the high-temperature pressure-proof pipe of 100.0mL, molten
Solution is in the mixed solvent (V of 18.5mLMethanol: VMethylene chloride=7:3) in, 24.0h, reactant filtering, gained filtrate are reacted at 80 DEG C
It volatilizees at room temperature, until thering are a large amount of rufous bulk crystals to be precipitated when its volume is that mixed solvent puts into the 1/3 of volume, receiving
Collect crystal, washed through methanol, 45 DEG C of drying are to get to rufous title complex 5.Yield is 82.5%.
The present embodiment products therefrom is characterized:
(1) X-ray single crystal diffraction:
The rufous bulk crystals of moderate dimensions are taken to be placed on agilent company SuperNova single crystal diffractometer, using stone
The Mo-K of black monochromatizationα Ray carries out monocrystalline test.The tial crystalline structure of the present embodiment products therefrom
It is all made of SHELXS-97 direct method to solve, geometry adds hydrogen, and non-hydrogen atom coordinate and anisotropy thermal parameter use SHELXL-97
Through complete matrix least square method refine.Gained crystallography and structure refinement data are as shown in following tables 14, bond distance's bond angle data
As shown in following tables 15, for bond angle data as shown in following tables 16, the crystal structure of gained rufous bulk crystals is as shown in Figure 5.
Table
14. the crystallography and structural modifications data of complex 5
a R1=Σ | | Fo|–|Fc||/Σ|Fo|；b wR2=[Σ w (Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
The strong length of 15. complex 5 of table
12-X,-Y,1-Z
The bond angle [°] of 16. complex 5 of table
12-X,-Y,1-Z
(2) elemental analysis, as a result as shown in Table 4 above.
To sum up, it can determine that rufous bulk crystals obtained by the present embodiment are title complex [Ni (DQ)2(CH3OH)2]
(complex 5), structural formula is as follows:
Comparative example 5-1
Embodiment 5 is repeated, unlike, respectively with nickel acetate tetrahydrate, perchlorate hexahydrate's nickel or six water nickel chlorides substitution
Ni(NO3)2·6H2O obtains [Ni (DQ) with expectation2(CH3OH)2] (complex 5), but result is precipitated without any crystal.
Comparative example 5-2
Embodiment 5 is repeated, unlike, mixed solvent is changed to water, methanol, ethyl alcohol, acetonitrile, DMF or methylene chloride etc.
Single solvent.
As a result rufous target product crystal is not obtained.
Embodiment 6:[Cu (DMQ)2(CH3OH)2] (complex 6) synthesis
Weigh the Cu (NO of the DMQ and 1.0mmol of 2.0mmol3)2·3H2O is placed in the high-temperature pressure-proof pipe of 100.0mL, molten
Solution is in the mixed solvent (V of 80.0mLMethanol: VMethylene chloride=55:45) in methanol and methylene chloride mixed solution (v:v=55:45),
12.0h, reactant filtering are reacted at 100.0 DEG C, gained filtrate is volatilized at room temperature, until its volume is mixed solvent investment
Volume 1/3 when, there are a large amount of rufous bulk crystals to be precipitated, collect crystal, washed through methanol, 45 DEG C of drying are reddish brown to get arriving
Color title complex 6.Yield is 90.8%.
The present embodiment products therefrom is characterized:
(1) X-ray single crystal diffraction:
The rufous bulk crystals of moderate dimensions are taken to be placed on agilent company SuperNova single crystal diffractometer, using stone
The Mo-K of black monochromatizationα Ray carries out monocrystalline test.The tial crystalline structure of the present embodiment products therefrom
It is all made of SHELXS-97 direct method to solve, geometry adds hydrogen, and non-hydrogen atom coordinate and anisotropy thermal parameter use SHELXL-97
Through complete matrix least square method refine.Gained crystallography and structure refinement data are as shown in following tables 17, bond distance's bond angle data
As shown in following tables 18, for bond angle data as shown in following tables 19, the crystal structure of gained rufous bulk crystals is as shown in Figure 6.
Table
17. the crystallography and structural modifications data of complex 6
a R1=Σ | | Fo|–|Fc||/Σ|Fo|；b wR2=[Σ w (Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
The strong length of 18. complex 6 of table
11-X,-Y,2-Z
The bond angle [°] of 19. complex 6 of table
11-X,-Y,2-Z
(2) elemental analysis, as a result as shown in Table 4 above.
To sum up, it can determine that rufous bulk crystals obtained by the present embodiment are title complex [Cu (DMQ)2(CH3OH)2]
(complex 6), structural formula is as follows:
Comparative example 6-1
Embodiment 6 is repeated, unlike, respectively with a water copper acetate, perchlorate hexahydrate's copper, cupric sulfate pentahydrate or anhydrous chlorine
Change copper and substitutes Cu (NO3)2·3H2O obtains [Cu (DMQ) with expectation2(CH3OH)2] (complex 6), but result is without any crystalline substance
Body is precipitated.
Comparative example 6-2
Embodiment 6 is repeated, unlike, mixed solvent is changed to water, methanol, ethyl alcohol, acetonitrile, DMF or methylene chloride etc.
Single solvent.
As a result rufous target product crystal is not obtained.
Embodiment 7:[Mn (DQ)2(H2O)2] (complex 7) synthesis
Weigh the Mn (NO of the DQ and 1.0mmol of 2.0mmol3)2·6H2O is placed in the high-temperature pressure-proof pipe of 100.0mL, molten
Solution is in the mixed solvent (V of 45.0mLMethanol: VMethylene chloride=7:3) in react 48.0h at 70.0 DEG C, reactant filtering, gained filtrate
It volatilizees at room temperature, until thering are a large amount of rufous bulk crystals to be precipitated when its volume is that mixed solvent puts into the 1/3 of volume, receiving
Collect crystal, washed through methanol, 45 DEG C of drying are to get to rufous title complex 7.Yield is 70.1%.
The present embodiment products therefrom is characterized:
(1) X-ray single crystal diffraction:
The rufous bulk crystals of moderate dimensions are taken to be placed on agilent company SuperNova single crystal diffractometer, using stone
The Mo-K of black monochromatizationα Ray carries out monocrystalline test.The tial crystalline structure of the present embodiment products therefrom
It is all made of SHELXS-97 direct method to solve, geometry adds hydrogen, and non-hydrogen atom coordinate and anisotropy thermal parameter use SHELXL-97
Through complete matrix least square method refine.Gained crystallography and structure refinement data are as shown in following tables 20, bond distance's bond angle data
As shown in following tables 21, for bond angle data as shown in following tables 22, the crystal structure of gained rufous bulk crystals is as shown in Figure 7.
Table
20. the crystallography and structural modifications data of complex 7
a R1=Σ | | Fo|–|Fc||/Σ|Fo|；b wR2=[Σ w (Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
The strong length of 21. complex 7 of table
The bond angle [°] of 22. complex 7 of table
(2) elemental analysis, as a result as shown in Table 4 above.
To sum up, it can determine that rufous bulk crystals obtained by the present embodiment are title complex [Mn (DQ)2(H2O)2] (match
Close object 7), structural formula is as follows:
Comparative example 7-1
Embodiment 7 is repeated, unlike, respectively with four water manganese acetates, perchlorate hexahydrate's manganese, manganese sulfate or tetrahydrate manganese chloride
Substitute Mn (NO3)2·6H2O obtains [Mn (DQ) with expectation2(H2O)2] (complex 7), but result is precipitated without any crystal.
Comparative example 7-2
Embodiment 7 is repeated, unlike, mixed solvent is changed to water, methanol, ethyl alcohol, acetonitrile, DMF or methylene chloride etc.
Single solvent.
As a result rufous target product crystal is not obtained.
Embodiment 8:[Mn (DMQ)2(H2O)2] (complex 8) synthesis
Weigh the Mn (NO of the DMQ and 1.0mmol of 2.0mmol3)2·6H2O is placed in the high-temperature pressure-proof pipe of 100.0mL, molten
Solution is in the mixed solvent (V of 25.0mLMethanol: VMethylene chloride=78:22) in, 50.0h, reactant filtering, gained are reacted at 58.0 DEG C
Filtrate is volatilized at room temperature, until having a large amount of rufous bulk crystals to analyse when its volume is that mixed solvent puts into the 1/3 of volume
Out, crystal is collected, is washed through methanol, 45 DEG C of drying are to get to rufous title complex 8.Yield is 75.6%.
The present embodiment products therefrom is characterized:
(1) X-ray single crystal diffraction:
The rufous bulk crystals of moderate dimensions are taken to be placed on agilent company SuperNova single crystal diffractometer, using stone
The Mo-K of black monochromatizationα Ray carries out monocrystalline test.The tial crystalline structure of the present embodiment products therefrom
It is all made of SHELXS-97 direct method to solve, geometry adds hydrogen, and non-hydrogen atom coordinate and anisotropy thermal parameter use SHELXL-97
Through complete matrix least square method refine.Gained crystallography and structure refinement data are as shown in following tables 23, bond distance's bond angle data
As shown in following tables 24, for bond angle data as shown in following tables 25, the crystal structure of gained rufous bulk crystals is as shown in Figure 2.
The crystallography and structural modifications data of 23. complex 8 of table
a R1=Σ | | Fo|–|Fc||/Σ|Fo|；b wR2=[Σ w (Fo 2–Fc 2)2/Σw(Fo 2)2]1/2.
The strong length of 24. complex 8 of table
1-X,-Y,-Z
The bond angle [°] of 25. complex 8 of table
1-X,-Y,-Z
(2) elemental analysis, as a result as shown in Table 4 above.
To sum up, it can determine that rufous bulk crystals obtained by the present embodiment are title complex [Mn (DMQ)2(H2O)2] (match
Close object 8), structural formula is as follows:
Comparative example 8-1
Embodiment 8 is repeated, unlike, respectively with four water manganese acetates, perchlorate hexahydrate's manganese, manganese sulfate or tetrahydrate manganese chloride
Substitute Mn (NO3)2·6H2O obtains [Mn (DMQ) with expectation2(H2O)2] (complex 8), but result is analysed without any crystal
Out.
Comparative example 8-2
Embodiment 8 is repeated, unlike, mixed solvent is changed to water, methanol, ethyl alcohol, acetonitrile, DMF or methylene chloride etc.
Single solvent.
As a result rufous target product crystal is not obtained.
Embodiment 9:[Zn (DQ)2(CH3CH2OH)2] (complex 9) synthesis
Embodiment 1 is repeated, unlike, methanol is replaced with ethyl alcohol in the composition of mixed solvent.As a result rufous is obtained
Bulk crystals.
Rufous bulk crystals obtained by the present embodiment are analyzed through X-ray single crystal diffraction and elemental analysis, are determined as target and match
Close object [Zn (DQ)2(CH3CH2OH)2] (complex 9).
Embodiment 10:[Cu (DQ)2(H2O)2] (complex 10) synthesis
Embodiment 6 is repeated, unlike, DMQ is replaced with DQ, reaction temperature is changed to 30.0 DEG C, and reaction controls in a twinkling
72h.As a result rufous bulk crystals are obtained.
Rufous bulk crystals obtained by the present embodiment are analyzed through X-ray single crystal diffraction and elemental analysis, are determined as target and match
Close object [Cu (DQ)2(H2O)2] (complex 10).
Embodiment 11:[Mn (DQ)2(CH3CH2OH)2] (complex 11) synthesis
Embodiment 8 is repeated, unlike, DMQ is replaced with DQ, replaces methanol with ethyl alcohol in the composition of mixed solvent, instead
Temperature is answered to be changed to 120 DEG C, the reaction time controls in 30h.As a result rufous bulk crystals are obtained.
Rufous bulk crystals obtained by the present embodiment are analyzed through X-ray single crystal diffraction and elemental analysis, are determined as target and match
Close object [Mn (DQ)2(CH3CH2OH)2] (complex 11).
Experimental example: the proliferation inhibition activity experiment of 1-8 pair of a variety of human tumor cell line of complex of the present invention:
1, cell strain and cell culture
Human cervical carcinoma cell HeLa, human breast cancer cell line Bcap-37, human bladder cancer cell T-24, human liver cancer are selected in this experiment
5 kinds of human tumor cell lines such as cell Hep-G2, Proliferation of Human Ovarian Cell SK-OV-3 and Human normal hepatocyte HL-7702.
All cell strains cultivate containing the small ox blood of 10wt%, 100U/mL penicillin, 100U/mL streptomysin RPMI-
In 1640 culture medium, 37 DEG C of 5%CO containing volumetric concentration are set2It is cultivated in incubator.
2, the preparation of untested compound
Purity >=95% (being made respectively by 1-8 of embodiment of the present invention the method) of complex 1-8 used, by it
DMSO liquid storage is configured to the whole solution of 20 μm of ol/L after being diluted with physiological buffer, wherein final concentration≤1% of cosolvent DMSO,
Test the inhibition level of 1-8 pair of various growth of tumour cell of complex under the concentration.
3, cell growth inhibition test (mtt assay)
(1) tumour cell of logarithmic growth phase is matched after trypsin digestion with the culture solution containing 10% calf serum
The cell suspension that number concentration is 5000/mL is made, is inoculated in 96 well culture plates with every 190 μ L of hole, makes cell density to be measured
To the hole 1000-10000 (the sterile PBS of edge hole is filled)；
(2) 5%CO2, 37 DEG C are incubated for for 24 hours, until cell monolayer is paved with bottom hole, the drug 10 of a certain concentration gradient is added in every hole
μ L, each concentration gradient set 4 multiple holes；
(3) 5%CO2, 37 DEG C are incubated for 48 hours, observe under inverted microscope；
(4) the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L is added in every hole, continues to cultivate 4h；
(5) culture is terminated, culture solution in hole is carefully sucked, the DMSO that 150 μ L are added in every hole sufficiently dissolves first a ceremonial jade-ladle, used in libation precipitating, vibration
It swings after device mixes, with wavelength is 570nm in microplate reader, reference wavelength is the OD value that 450nm measures each hole；
(6) it is arranged zeroing hole (culture medium, MTT, DMSO) simultaneously, (the drug dissolution of cell, same concentrations is situated between control wells
Matter, culture solution, MTT, DMSO).
(7) according to the OD value (OD value) measured, to judge living cells quantity, OD value is bigger, and cell activity is stronger.Benefit
With formula:
Drug is calculated to the inhibiting rate of growth of tumour cell, then with Bliss method calculate separately 1-8 pair of complex it is above-mentioned several
The IC of cell strain50Value.Its result is as shown in following tables 26.
Table 26: IC of the complex 1-8 to different tumor cell lines50It is worth (μM)
By IC in table 2650As a result as can be seen that 1-8 pair of 5 kinds of human tumor cell line of complex show certain proliferation
Inhibitory activity, especially best to human cervical carcinoma cell HeLa inhibiting effect, IC50Value 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 μM, bright
It is aobvious to be higher than cis-platinum, corresponding ligand and metal salt；On the other hand, 1-8 couple of normal cell HL-7702 of complex is almost without toxicity
(IC50> 60.0 μM), there is preferable cytotoxic selectivity.This, which is one, has positive effect as a result, showing complex 1-8
While showing certain broad-spectrum anti-tumor activity, also there is lower hepatotoxicity, i.e. complex 1-8 has centainly thin
Cellular toxicity selectivity.
In conclusion complex 1-8 of the present invention, aggregate performance have gone out apparent anti tumor activity in vitro and toxicity
Selectivity has good potential medical value, is expected to be used for the preparation of various anti-tumor drugs.
Claims (9)
1. compound shown in following formula (I)s or its pharmaceutically acceptable salt:
Wherein, M indicates certain divalent metal element in the periodic table of elements period 4；R indicates H or CH3, X expression H2O、
CH3OH or CH3CH2OH。
2. compound according to claim 1, it is characterised in that: the M indicates Zn (II), Co (II), Ni (II), Cu
(II) or Mn (II).
3. the synthetic method of compound described in claim 1, it is characterised in that: take shown in metal nitrate and following formula (II)s
Compound is placed in the mixed solvent, and complexation reaction is carried out under the conditions of being heated or not heated, and reactant is cooling, stands, and volatilization has
Crystal is precipitated to get target compound；Wherein, the mixed solvent is the composition or second of methanol and methylene chloride
The composition of pure and mild methylene chloride；
Wherein, R indicates H or CH3。
4. synthetic method according to claim 3, it is characterised in that: the metal nitrate is Zn (NO3)2·6H2O、
Co(NO3)2·6H2O、Ni(NO3)2·6H2O、Cu(NO3)2·3H2O or Mn (NO3)2·6H2O。
5. synthetic method according to claim 3, it is characterised in that: the in the mixed solvent, methanol or ethyl alcohol and two
The volume ratio of chloromethanes is 1-100:1-100.
6. synthetic method according to claim 3, it is characterised in that: reaction is performed under heating conditions.
7. synthetic method according to claim 6, it is characterised in that: reaction carries out under the conditions of 50-120 DEG C.
8. compound described in claim 1 or its pharmaceutically acceptable salt application in preparation of anti-tumor drugs.
9. a kind of pharmaceutical composition goes up compound described in the claim 1 of effective dose containing treatment or its is pharmaceutically acceptable
Salt.
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Non-Patent Citations (4)
| Title |
|---|
| ANDREA DEFANT ET AL: "Metal-assisted regioselectivity in n ucleophilic substitutions: a s tudy by Raman s pectroscopy and d ensity functional theory calculations", 《J. RAMAN SPECTROSC.》 * |
| BI-QUN ZOU ET AL: "Transition metal complexes with 6,7-dichloro-5,8-quinolinedione as mitochondria-targeted anticancer agents", 《POLYHEDRON》 * |
| DING, YANG ET AL: "Imaging of the nuclei of living tumor cells by novel ruthenium(II) complexes coordinated with 6-chloro-5-hydroxylpyrido[3,2-a]phenazine", 《RSC ADVANCES》 * |
| E. J. CORE ET AL: "Acylation by a Metal-ion Salt-Quinone System", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
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| CN113583028B (en) * | 2021-05-31 | 2023-05-12 | 广东石油化工学院 | High cancer cell selectivity anticancer medicine based on metal organic complex and preparation method thereof |
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