CN102924356A - Preparation method for 2-substituted benzldehyde shrank hydrazine-sulfo-benzyl formate schiff base zinc and nickel complex - Google Patents
Preparation method for 2-substituted benzldehyde shrank hydrazine-sulfo-benzyl formate schiff base zinc and nickel complex Download PDFInfo
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- CN102924356A CN102924356A CN2012104462763A CN201210446276A CN102924356A CN 102924356 A CN102924356 A CN 102924356A CN 2012104462763 A CN2012104462763 A CN 2012104462763A CN 201210446276 A CN201210446276 A CN 201210446276A CN 102924356 A CN102924356 A CN 102924356A
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- benzyldithiocarbazate
- acetate
- substituted
- substituted benzaldehyde
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Abstract
The invention discloses a preparation method for2-substituted benzldehyde shrank hydrazine-sulfo-benzyl formate schiff base zinc and nickel complex, and belongs to the bio-inorganic chemistry field. The method includes M = Zn and Ni, and X= C1 and NO2. Firstly, the 2-substituted benzldehyde and hydrazine-sulfo-benzyl formate are dissolved in absolute ethyl alcohol solution for heating reflux reaction to obtain the 2-substituted benzaldehyde shrank hydrazine-sulfo-benzyl formate. Secondly, under stirring condition, acetate is added in the absolute ethyl alcohol solution. After stirring reaction, filtering and crystallizing, target compound is obtained. The preparation method is simple and practical, and raw materials are easy to obtain, and convenience is brought to industrial production. The kind of metal compound has obvious inhibition effect on cancer cells, and can be used as drugs for preparing inhibitors of the cancer cells.
Description
Technical field
The present invention relates to the preparation method of 2-substituted benzaldehyde contracting diazanyl bamic acid benzyl ester Schiff's base zinc, nickel complex, belong to the bio-inorganic chemistry field.
Background technology
Cis-platinum is one of chemicals of the treatment cancer commonly used, but its application be subject to toxic side effect (such as Toxicity of Kidney, bone marrow toxicity, ototoxicity, neurotoxicity), resistance, can not be oral etc. the restriction of factor.These shortcomings impel people to remove to research and develop the better Metal Anticancer Drug of pharmacologically active.The Metal Anticancer Drug of research and development mainly is divided into two classes at present, and a class is platinum-containing anticancer drug, and another kind of is non-platinum-containing anticancer drug.Non-platinum-containing anticancer drug mainly concentrate on have biological activity, on the teleorganic micro-metals, such as copper, zinc.Zinc plays an important role in the cell physiological activity, is the active centre of many enzymes, participates in multiple metabolic processes.For platinum complexes, the toxicity of Zn complex may be less.
Since in cress, isolating sulforaphen, it is found that dithiocarbamates compound is (such as Sulforamate, oxomate, brassinin) have good tumor prevention and anti-tumor activity, dithiocarbamates is pharmacophoric group.In recent years, S-benzyldithiocarbazate Schiff's base and title complex thereof have caused people's interest.In such Schiff's base, introduce a simple substituting group, may cause the structure of title complex and character to change a lot.In addition, this type of title complex also shows good biological activity, such as anti-microbial activity, antiviral activity and antitumour activity.Therefore, this compounds is furtherd investigate had very important theory value and using value.Closing zinc (1), 2-chlorobenzaldehyde contracting diazanyl bamic acid benzyl ester about 2-chlorobenzaldehyde contracting diazanyl bamic acid benzyl ester at present closes the preparation method that nickel (2) and 2-nitrobenzaldehyde contracting diazanyl bamic acid benzyl ester close nickel (3) title complex and has no the pertinent literature report.
Summary of the invention
The object of the present invention is to provide a kind of novel method of synthetic 2-substituted benzaldehyde contracting diazanyl bamic acid benzyl ester schiff base metal complex.
Technical scheme of the present invention is as follows:
This 2-substituted benzaldehyde contracting diazanyl bamic acid benzyl ester schiff base metal complex has following structure:
M?=?Zn、Ni，X?=?Cl、NO
2。
The method for preparing above-mentioned metal complexes is comprised of the following step:
S-benzyldithiocarbazate is according to the described method preparation of document " Metal complexes of sulphur and nitrogen-containing ligands:Complexes of s-benaldithiocarbazate and a schiff base formed by its condensation with pyridine-2-carboxaldazate, M. Akbar Ali.; M.T.H. Tarafdar; J. Inorg. Nucl. Chem.; 1977; 39:1785 ~ 1791 ", productive rate 87%, m.p.123～124
oC.
The phenyl aldehyde that described 2-replaces is 2-Chlorobenzaldehyde or 2-nitrobenzaldehyde.
Described acetate is zinc acetate or nickel acetate.
The mol ratio of the S-benzyldithiocarbazate of 2-substituted benzaldehyde contracting described in above-mentioned preparation method's step 2, acetate is 2:1.
Through experimental study, the phenyl aldehyde contracting S-benzyldithiocarbazate schiff base metal complex that the present invention synthesizes has obvious restraining effect to cancer cells, the results are shown in Table 1, can be used as preparation inhibition of cancer cell agent medicine.Its raw material is easy to get cheaply, and preparation method's simple possible is convenient to suitability for industrialized production.
Description of drawings
Fig. 1 is Zn complex (1) the crystalline structure figure that embodiment 1 makes;
Fig. 2 is nickel complex (2) the crystalline structure figure that embodiment 2 makes;
Fig. 3 is Zn complex (3) the crystalline structure figure that embodiment 3 makes.
Embodiment
Embodiment one: the preparation of 2-chlorobenzaldehyde contracting S-benzyldithiocarbazate Schiff's base Zn complex
1, in the 100mL round-bottomed flask, S-benzyldithiocarbazate (1.98 g, 10.0 mmol) is dissolved in the dehydrated alcohol of 30 ml, under high degree of agitation, the ethanolic soln of the 2-chlorobenzaldehyde of the amounts such as slow dropping.Then behind the reflux 4h, be cooled to 0
oC, filtration under diminished pressure is used washing with alcohol, obtains flaxen solid, the solid that obtains is dissolved in the dehydrated alcohol recrystallization purifies, and obtains 2-chlorobenzaldehyde contracting S-benzyldithiocarbazate (H
2L).Productive rate 57%.Anal.?Calc.?for?C
15H
13ClN
2S
2:?C,?56.2;?H,?4.1;?N,?8.7，Found:?C,?55.8;?H,?4.0;?N,?8.9%.
2,2-chlorobenzaldehyde contracting S-benzyldithiocarbazate (0.32 g, 1.0mmol) is dissolved in the anhydrous ethanol solvent of 20ml, under agitation adds Zn (OAc)
22H
2The ethanol solution of O (0.11 g, 0.5 mmol),, behind the stirring reaction 4h, filter, get orange clear liquid, clear liquid is left standstill 7 days after, separate out orange crystal, productive rate 45%.Anal.?Calc.?for?C
30H
24Cl
2ZnN
4S
4:?C,?51.1;?H,?3.4;?N,?8.0.?Found:?C,?50.8;?H,?3.0;?N,?8.2%。Analyzing its result through X-ray diffraction is: C
30H
24Cl
2N
4S
4Zn.Its crystalline structure is seen Fig. 1, and crystallographic data sees Table 2, and main bond distance and bond angle see Table 3.
Embodiment two: the preparation of 2-chlorobenzaldehyde contracting S-benzyldithiocarbazate Schiff's base nickel complex
The preparation method is with embodiment one.Nickel acetate replaces zinc acetate, obtains purple crystals, productive rate 56%.Anal. Calc. for C
30H
24Cl
2N
4S
4Ni:C, 51.6; H, 3.5; N, 8.0. Found:C, 51.4; H, 3.3; N, its crystalline structure of 8.3%. is seen Fig. 2, and crystallographic data sees Table 2, and main bond distance and bond angle see Table 3.
Embodiment three: the preparation of 2-nitrobenzaldehyde contracting S-benzyldithiocarbazate Schiff's base nickel complex
The preparation method is with embodiment one.The 2-nitrobenzaldehyde replaces the 2-chlorobenzaldehyde, and nickel acetate replaces zinc acetate, obtains purple crystals, productive rate 56%.Anal. Calc. for C
30H
24N
6O
4S
4Ni:C, 50.1; H, 3.4; N, 11.7. Found:C, 49.4; H, 3.3; N, its crystalline structure of 11.8%. is seen Fig. 3, and crystallographic data sees Table 2, and main bond distance and bond angle see Table 3.
Embodiment four: the 2-substituted benzaldehyde contracting S-benzyldithiocarbazate schiff base metal complex vitro inhibition tumor cell viability research that the present invention makes
Adopt MTT [3-(4,5)-two methyl-2-thiazole-(2,5)-phenyl bromination tetrazole is blue] method to measure title complex 1-3 to the inhibiting rate of gastric carcinoma cells (MKN45) and liver cancer cell (HEPG2), calculate IC
50(μ M).
(1) preparation of nutrient solution (every liter): RPMI-1640 cultivates one bag in powder (10.4 g), new-born calf serum 100 ml, penicillin solution (200,000 U/ml) 0.5 ml, Streptomycin sulphate solution (200,000 U/ml) 0.5 ml, after adding the tri-distilled water dissolving, the NaHCO with 5.6%
3The solution adjust pH is settled to 1000 ml at last to 7.2-7.4.Filtration sterilization.
(2) preparation of D-Hanks damping fluid (every liter): NaCl 8.00 g, KCl 0.40 g, Na
2HPO
412 H
2O 0.06 g, KH
2PO
40.06g, NaHCO
30.35 g.Autoclaving.
(3) preparation of trypsin solution: utilizing the D-Hanks damping fluid to be made into concentration is 0.5% trypsin solution.Filtration sterilization.
(4) preparation of experiment liquid: the metal complexes specimen that the embodiment of the invention is made is made into storing solution with tri-distilled water and a small amount of DMSO dissolving, general 10 times of preparation storing solutions by the experiment maximum concentration.The concentration of DMSO in nutrient solution is unsuitable excessive, and the final concentration of DMSO generally is no more than 0.05%-0.1% in the every porocyte suspension after the dosing.Storing solution is stored in-20
oFor subsequent use in the C refrigerator.
(5) cultivation of gastric carcinoma cells MKN45: cellar culture (contains 10% calf serum, 100U/ml Streptomycin sulphate) in the RPMI-1640 nutrient solution, place 37
oC, 5% CO
2Cultivate in the incubator, went down to posterity once every 3-4 days.When going down to posterity nutrient solution in the former bottle is transferred in the centrifuge tube, centrifugal 5 min of 1000 rpm discard original fluid, add the equivalent fresh medium, piping and druming evenly pipettes in right amount to the fresh culture bottle, replenishes fresh medium to original volume (nutrient solution volume be about culturing bottle capacity 1/10) again.
(6) cultivation of human liver cancer cell HEPG2: cellar culture (contains 10% calf serum, 100U/ml Streptomycin sulphate) in the RPMI-1640 nutrient solution, place 37
oC, 5% CO
2Cultivate in the incubator, went down to posterity once every 3-4 days.When going down to posterity nutrient solution in the former bottle is transferred in the centrifuge tube, centrifugal 5 min of 1000 rpm discard original fluid, add the equivalent fresh medium, piping and druming evenly pipettes in right amount to the fresh culture bottle, replenishes fresh medium to original volume (nutrient solution volume be about culturing bottle capacity 1/10) again.
(7) cell is hatched: 2 kinds of tumour cells in the vegetative period of taking the logarithm, the accent concentration of cell suspension is 1-1.5 * 10
5Individual ml
-1Every hole adds cell suspension 100 μ l in 96 well culture plates, puts 37
oC, 5% CO
2Cultivate 24 h in the incubator.After cultivating 24 h, add liquid by design respectively.
(8) dosing: the metal complexes test liquid that the embodiment of the invention is made joins respectively in each hole according to the concentration gradient of ultimate density, and each concentration is established 6 parallel holes.Experiment is divided into drug test group (the test medicine that adds respectively different concns), control group (only add nutrient solution and cell, do not add the test medicine) and blank group (only add nutrient solution, do not add cell and test medicine).96 orifice plates after the dosing are placed 37
oC, 5% CO
2Cultivate 24,48,72 h in the incubator.The positive control drug of 5 FU 5 fluorouracil (5-FU), active method according to specimen is measured.
(9) mensuration of survivaling cell: cultivated 24,48, in 96 orifice plates behind the 72h, every hole adds respectively MTT 40 μ l(and is made into 4 mg/ml with the D-Hanks damping fluid).37
oC removes supernatant liquor after placing 4 h.Every hole adds 150 μ l DMSO, and 5 min that vibrate make the formazan dissolving crystallized.At last, utilize automatic microplate reader to detect the optical density(OD) (OD value) in each hole at 570 nm wavelength places.
The calculating of inhibiting rate: the inhibiting rate of Growth of Cells calculates according to following formula:
Growth inhibition ratio=(1-survival rate) * 100%=[1-(OD
Experiment-OD
Blank)/(OD
Contrast-OD
Blank)] * 100%(OD
ExperimentThe average optical of the metal complexes testing drug group that the expression embodiment of the invention makes, OD
ContrastThe average optical of expression control group, OD
BlankThe average optical of expression control group).
Half-inhibition concentration (IC
50) be defined as the drug level when the survival of 50% tumour cell.According to the optical density(OD) (OD value) of measuring, make the typical curve of inhibitory rate of cell growth, try to achieve its corresponding drug level at typical curve.
The IC that records
50Be shown in Table 1:
The inhibition IC of the cancer cells of the listed title complex 1-3 of table 1 the present invention
50Value (μ M)
The crystallographic data of table 2 title complex 1-3 of the present invention
| Compound | 1 | 2 | 3 |
| Empirical Formula | C 30H 24Cl 2N 4S 4Zn | C 30H 24Cl 2N 4S 4Ni | C 30H 24N 6O 4S 4Ni |
| Formula weight | 705.04 | 698.38 | 719.50 |
| T/ K | 296(2) | 296(2) | 293(2) |
| Wavelength / ? | 0.71073 | 0.71073 | 0.71073 |
| Crystal shape/color | Block / orange | rod / purple | rod / purple |
| Crystal size / mm | 0.32 x 0.27 x 0.21 | 0.38 x 0.21 x 0.15 | 0.36 x 0.15 x 0.12 |
| Crystal system | Triclinic | Monoclinic | Triclinic |
| Space group | Pī | P2 1/c | Pī |
| a (?) | 9.249(4) | 5.1377(9) | 7.584(2) |
| b (?) | 12.975(5) | 25.116(4) | 9.972(3) |
| c (?) | 3.844(6) | 12.092(2) | 11.730(3) |
| α ( o) | 75.789(7) | 90 | 78.624(5) |
| β ( o) | 88.522(7) | 99.235(3) | 74.409(4) |
| γ ( o) | 78.467(7) | 90 | 70.867(5) |
| V / ? 3 | 1577.6(11) | 1540.1(5) | 801.4(4) |
| |
2 | 2 | 1 |
| D / g·cm -3 | 1.484 | 1.506 | 1.491 |
| μ(Mo Kα) / mm -1 | 1.240 | 1.103 | 0.912 |
| F(000) | 720 | 716 | 370 |
| θ range ( o) | 1.95 to 26.00 | 1.89 to 26.00 | 1.82 to 26.00 |
| h min / h max | -10 / 11 | -6 / 6 | -9 / 9 |
| k min / k max | -15 / 11 | -26 / 30 | -12 / 10 |
| l min / l max | -17 / 15 | -13 / 14 | -14 / 14 |
| Data collected | 8774 | 8499 | 4389 |
Unique data
 |
6099 | 3028 | 3108 |
| Maximum and minimum transmission | 0.7807 and 0.6923 | 0.8520 and 0.6793 | 0.8985 and 0.7350 |
| parameters | 370 | 187 | 205 |
| restraints | 0 | 0 | 0 |
| Goodness-of-fit on F 2 | 1.057 | 1.043 | 0.997 |
R
1, wR
2  |
0.0300, 0.0743 | 0.0329, 0.0752 | 0.0480, 0.0746 |
| R 1, wR 2? (all data) | 0.0388, 0.0776 | 0.0498, 0.0812 | 0.0945, 0.0803 |
| Largest difference peak and hole / (e? -3) | 0.311 and -0.303 | 0.309 and -0.215 | 0.441 and -0.458 |
Important bond distance and the bond angle of table 3 title complex 1-3 of the present invention
Claims (2)
1. one kind prepares the 2-substituted benzaldehyde contracting S-benzyldithiocarbazate Schiff's base zinc with following structure, the method for nickel metal complexes, it is characterized in that, realizes through the following steps:
(1) phenyl aldehyde and the S-benzyldithiocarbazate that 2-are replaced are dissolved in the anhydrous ethanol solvent, and then heating reflux reaction is cooled to 0
oC washs respectively with dehydrated alcohol, and filtration under diminished pressure obtains solid chemical compound, and the solid chemical compound recrystallization that obtains is purified, and obtains 2-substituted benzaldehyde contracting S-benzyldithiocarbazate;
(2) the 2-substituted benzaldehyde contracting S-benzyldithiocarbazate that step 1 is obtained is dissolved in the alcohol solvent, under agitation adds the ethanol solution of acetate, and stirring reaction filters, and gets clear liquid; After clear liquid left standstill a couple of days, crystallize out was 2-substituted benzaldehyde contracting S-benzyldithiocarbazate schiff base metal complex;
The phenyl aldehyde that described 2-replaces is 2-Chlorobenzaldehyde or 2-nitrobenzaldehyde;
Described acetate is zinc acetate or nickel acetate;
M?=?Zn、Ni，X?=?Cl、NO
2。
2. the method for preparing 2-substituted benzaldehyde contracting S-benzyldithiocarbazate Schiff's base zinc, nickel metal complexes as claimed in claim 1 is characterized in that, the mol ratio of described 2-substituted benzaldehyde contracting S-benzyldithiocarbazate, acetate is 2:1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107936044A (en) * | 2017-11-22 | 2018-04-20 | 广西师范大学 | It is a kind of using pyridyl ketone contracting thiocarbohydrazone as the copper complex and its synthetic method of ligand and application |
-
2012
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| Title |
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| SNEHIKA SHRIVASTAVA, ANIL KUMAR等: "Synthesis, Characterization and Biological Activity of Mn(II), Ni(II), Cu(II) and Zn(II) Complexes of Schiff Base Ligand", 《ASIAN JOURNAL OF CHEMISTRY》 * |
| ZHU XU-HUI，CHEN XIAO-FENG: "Unambiguous cis-coordination of mono- and bi-dentate Lewis bases to Ni(SN) Schiff-base complexes derived from S-alkyl dithiocarbazate", 《POLYHEDRON》 * |
| 仇晓阳，刘起峰等: "二齿肼基硫代甲酸苄酯席夫碱锌配合物的合成、晶体结构和抗肿瘤活性", 《无机化学学报》 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107936044A (en) * | 2017-11-22 | 2018-04-20 | 广西师范大学 | It is a kind of using pyridyl ketone contracting thiocarbohydrazone as the copper complex and its synthetic method of ligand and application |
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Application publication date: 20130213 |