CN102268046A - 9-anthracenecarboxaldehyde-4,5-dihydro-1H-imidazol-2-yl-hydrazone cisplatin complex and synthesis method and use thereof - Google Patents
9-anthracenecarboxaldehyde-4,5-dihydro-1H-imidazol-2-yl-hydrazone cisplatin complex and synthesis method and use thereof Download PDFInfo
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Abstract
The invention discloses a 9-anthracenecarboxaldehyde-4,5-dihydro-1H-imidazol-2-yl-hydrazone cisplatin complex and a synthesis method and use thereof. In the invention, the two N atoms in 9-anthracenecarboxaldehyde-4,5-dihydro-1H-imidazol-2-yl-hydrazone and a central metal ion Pt(II) are chelated and coordinated to form a chelate having a five-membered ring. Particularly, a direct complexing synthesis method or intermediate complexing synthesis method is adopted. In the technical scheme adopted by the invention, organic alkali 9-IHA having antitumor activity is used as a ligand to coordinate with the Pt(II) to form a complex; and the result of the observation of the activity of the complex for inhibiting the proliferation of human tumor cells and human normal liver cells indicates that the overall in-vitro cell toxicity of the complex is lower than that of a 9-IHA ligand and is similar to that of CDDP (cisplatin), AMSA(amsacrine) and HCPT (hydroxycamptothecine) which are clinic anticancer medicines and that the complex has high potential medical value and can be used in preparation of various antitumor medicines.
Description
Technical field
The present invention relates to the metal complex field, being specifically related to 9-miaow anthracene hydrazone is title complex and the synthetic method and the application of part.
Background technology
The anthracene nucleus antineoplastic antibiotic medicine is the common drug of a class clinical application in a line or two wires standard chemotherapy regimen, and the history in existing more than 30 year of its clinical application is occupied critical role with its determined curative effect, advantage such as cheap in cancer therapy drug market.In recent years, the domestic production enterprise that China takes as the leading factor in anthracene nucleus medicament production of raw medicine and outlet has then occupied very large portion on anthracene nucleus medicament market, and product processes and output all hold good security.
The anti-tumor activity of anthracene nucleus medicament is based on its anthracene nucleus parent nucleus: the anthracene nucleus plane is effectively between the adjacent base pair of intercalation of DNA molecule, and can combine with the dna double spiralization is reversible, and then influence the DNA transcription, finally cause dna break and cause death of neoplastic cells; Perhaps to the topoisomerase II specific combination, so anthracene nucleus medicament also belongs to embedded type topoisomerase II (topoisomerase II) inhibitor.Yet, be not that all anthracycline compounds can both be successfully applied to clinical, because anthracene nucleus itself is not optionally to the effect of DNA, this means that it has toxicity (as the cardiac toxic of Zorubicin, the leucocytotoxicity of bisantrene etc.) equally to normal cell.Therefore, anthracycline anticancer drug has the application limitation of himself, and its mechanism of action is single, easily produce resistance, to deficiencies such as the selectivity of tumour cell are low, does not meet the research and development strategy of synthetic multi-functional, the many target spots of present design, targeting antineoplastic medicine thing.
On the other hand, since Rosenberg equals unexpected cis-platinum (the cis dichloro two ammino platinum (II) of finding of the sixties in last century, cisplatin, CDDP) anti-tumor activity since, cis-platinum is the representative that the home and abroad is used for a line clinical medicine of the various malignant tumours of chemotherapy for a long time always, and is widely used in the chemotherapy combined scheme.It is pointed out that cis-platinum also is the first metal compounding material type cancer therapy drug that successfully is used for clinical chemotherapy.The success of cis-platinum has greatly promoted the metal complexes chemistry in the pharmacologically active direction especially progress of anti-tumor activity direction.At present, the Anticancer Effect and Mechanism of cis-platinum is clear and definite, it is mainly by the guanine base N Atomic coordinate of center platinum (II) ion with covalent attachment mode and tumour cell DNA, the interchain linkage or the chain that form the dna double coiled strand are interior crosslinked, thereby the normal replication of block cell DNA and expression, thereby cause necrocytosis to realize its antitumous effect.Cis-platinum is the active centre with Pt (II), and two amino molecules combine with Pt (II) by coordination, reach stablize Pt (II) make its not with other born of the same parents in ligating atom coordinate purposes such as N, S on the macromole, have the effect of delivery Pt (II) to the DNA target spot; Two chlorions are then brought into play the effect of leavings group by hydrolytic action, to the toxicity and water-soluble the playing a crucial role of cis-platinum.But clinical practice shows that cis-platinum also exists many shortcomings, and is single as action target spot and mechanism of action, makes tumour cell be easy to generate resistance, and stronger neurotoxicity and renal toxicity etc.
Summary of the invention
The present invention is directed to the deficiency that anthracene nucleus medicament and cancer therapy drug exist in the prior art (single, easily produce resistance etc.) as action target spot, based on the coordination chemistry principle, providing with anthracycline anticancer drug derivative-miaow anthracene hydrazone is organic ligand and synthetic class cis-platinum type platinum (II) title complex, and the synthetic method of this title complex and anti-tumor activity thereof.
Technical purpose of the present invention is achieved by following technical proposals:
9-miaow anthracene hydrazone, i.e. 9-anthracene carboxylic aldehyde (4,5-dihydro-1H-imidazoles-2-yl) hydrazone, molecular formula-C
18H
16N
4, English name: 9-Anthracenecarboxaldehyde-4,5-dihydro-1H-imidazol-2-yl-hydrazone is abbreviated as 9-IHA, and molecular weight is 288g/mol, and chemical structural formula is as shown in the formula shown in (I):
The chemical structural formula of formula (I) 9-miaow anthracene hydrazone (9-IHA)
In this compound structure, two N atoms on the tetrahydroglyoxaline have stronger chelating coordination ability, can form N, N bidentate chelating coordination mode in coordination reaction.
Class cis-platinum type title complex based on 9-miaow anthracene hydrazone has following molecular formula:
Formula (II). based on the chemical structural formula of the class cis-platinum type title complex of 9-miaow anthracene hydrazone
Wherein, form five-ring chelating body with two atoms of N, N and the coordination of central metallic ions Pt (II) chelating of 9-IHA.Pt (II) generally takes the coordination mode of plane quadrilateral, and ligancy is 4, so part 9-IHA can be the title complex of 1: 1 type with the ratio of Pt (II) formation amount of substance.The title complex chemical formula of gained is cis-[Pt
IICl
2(9-IHA)].
Utilize formula (I) 9-miaow anthracene hydrazone (9-IHA) can adopt direct coordination synthesis method or intermediate coordination synthesis method suc as formula the method for (II) described title complex with N, N bidentate chelating mode synthetic.
Described direct coordination synthesis method, the metal-salt reaction with same mole of miaow anthracene hydrazone (9-IHA) part shown in the employing formula (I) and Pt (II).The metal-salt K of part 9-IHA and Pt (II)
2PtCl
4(or Na
2PtCl
4) ratio of amount of substance of reaction is mol ratio such as 1: 1, metal-salt and part are dissolved in respectively in water and other polar organic solvent, described polar organic solvent can be the organic solvent that ethanol, methyl alcohol, acetone, acetonitrile etc. can dissolve each other with water, also can be the mixed solvent that two or more solvent mixes with any proportional quantity among them.The proportional quantity of metal-salt, part, water and polar solvent is generally 1mmol: 1mmol: 5～50mL: 20～200mL.During concrete operations, both 9-IHA and metal-salt together can be dissolved in the mixed solvent of water and polar solvent, also can earlier metal-salt and part be dissolved in respectively in water and the polar solvent, again hybrid reaction gradually.
The solution of gained reaction system is at 30～90 ℃ temperature range internal reaction; Generally will be controlled in the reaction times 1～48 hour, also can be more than 48 hours; The productive rate of the product of gained can reach the target productive rate greater than 50%.Reaction product generally generates in a large number with the solid form; As solvent too much or solvent better to the solvability of product, reacted solution at first can be carried out evaporation concentration and remove a part of solvent, product is mainly separated out with precipitation forms.Filter this suspension then, to the solid product that filters gained wash, the means of drying carry out purifying, can obtain corresponding target product; The method of product purification can adopt water, ethanol, acetone, ether equal solvent to wash successively, wherein unreacted metal salt, 9-IHA part or other by product, Impurity removal.Drying conditions is normal temperature (for example about 25 ℃, as 20-30 ℃)～60 ℃ of vacuum-drying or forced air dryings that temperature range is interior.
Described intermediate coordination synthesis method, it (is cis-[PtCl that the miaow anthracene hydrazone (9-IHA) shown in the employing formula (I) closes platinum (II) with cis dichloro two (dimethyl sulfoxide (DMSO))
2(DMSO)
2]) reaction with same mole.Related intermediate is that cis dichloro two (dimethyl sulfoxide (DMSO)) closes platinum (II), i.e. cis-[PtCl
2(DMSO)
2].The synthetic method of this intermediate had disclosed technology report (Al-Allaf T A K, et al.Trans.Met.Chem., 1998,23,403-406).
Suc as formula miaow anthracene hydrazone (9-IHA) part shown in (I) and Pt (II) intermediate cis-PtCl
2(DMSO)
2The ratio of the amount of substance of coordination reaction be 1: 1 etc. mol ratio.Cis-[PtCl
2(DMSO)
2] and part be dissolved in respectively in water or the ethanol isopolarity organic solvent, described polar organic solvent can be the organic solvent that ethanol, methyl alcohol, acetone, acetonitrile etc. can dissolve each other with water, also can be the mixed solvent that two or more solvent mixes with any proportional quantity among them.The proportional quantity of Pt (II) intermediate, part and polar solvent is generally 1mmol: 1mmol: 30～200mL.During concrete operations, both 9-IHA and Pt (II) intermediate together can be dissolved in the mixed solvent of water and polar solvent, also can earlier Pt (II) intermediate be dissolved in water or the above-mentioned polar solvent, part is dissolved in the above-mentioned polar solvent, again hybrid reaction gradually.
The solution of gained reaction system is at 30～90 ℃ temperature range internal reaction; Generally will be controlled in the reaction times 1～48 hour, also can be more than 48 hours; The productive rate of the product of gained can reach the target productive rate greater than 50%.Reaction product generally generates in a large number with the solid form; As solvent too much or solvent better to the solvability of product, reacted solution at first can be carried out evaporation concentration and remove a part of solvent, product is mainly separated out with precipitation forms.Filter this suspension then, to the product precipitation of filtering gained wash, the means of drying carry out purifying, can obtain corresponding target product; The method of product purification can adopt water, ethanol, acetone, ether equal solvent to wash successively, wherein unreacted Pt (II) intermediate, 9-IHA part or other by product, Impurity removal.Drying conditions is vacuum-drying or the forced air drying in 30 ℃～60 ℃ temperature ranges.
Technical scheme of the present invention is a part with the organic bases-9-IHA with anti-tumor activity, synthesized a kind of novel class cis-platinum type title complex with Pt (II) ion coordination based on anthracene nucleus class part, by investigating its proliferation inhibition activity to various human tumour cell and people's normal liver cell, the result shows that its vitro cytotoxicity totally is lower than the 9-IHA part, and it is close with clinical cancer therapy drug CDDP (cis-platinum), AMSA (amsacrine), HCPT (hydroxycamptothecine), have higher potential pharmaceutical use, can be used for various preparing anti-tumor medicine.
Description of drawings
Fig. 1 is the inhibition degree of different compounds to human tumor cells, wherein compound (9-IHA-Pt), cis-platinum (CDDP), amsacrine (AMSA), the hydroxycamptothecine (HCPT) of 9-miaow anthracene hydrazone (9-IHA), invention; BEL7404 (human hepatoma cell strain), SK-OV-3 (human oophoroma cell line), NCI-H460 (human lung carcinoma cell line).
Fig. 2 is the inhibition degree of different compounds to people's normal liver cell, wherein compound (9-IHA-Pt), cis-platinum (CDDP), amsacrine (AMSA), the hydroxycamptothecine (HCPT) of 9-miaow anthracene hydrazone (9-IHA), invention; 7702 (people's normal liver cells).
Fig. 3 is the UV spectrum of product of the present invention.
Fig. 4 is the infrared spectra of product of the present invention.
Fig. 5 is the nmr spectrum of product of the present invention.
Fig. 6 is the electrospray ionization mass spectrum spectrogram of product of the present invention.
Embodiment
Further specify technical scheme of the present invention below in conjunction with specific embodiment.
At first by the preparation of embodiment formula (II) based on the class cis-platinum type title complex of miaow anthracene hydrazone.
Embodiment 1: the directly synthetic cis-[Pt of normal pressure solution method
IICl
2(9-IHA)]
With K
2PtCl
4(1.0mmol, 0.415g) and 9-IHA (1.0mmol 0.290g) is dissolved in respectively in new distillatory oxygen-free water of 5mL and the 50mL methyl alcohol, will be dissolved with K then
2PtCl
4The aqueous solution dropwise be added drop-wise in the methanol solution of 9-IHA, reacted 48 hours under 30 ℃ of following lucifuges, the nitrogen protection, have a large amount of dark-browns precipitations to generate, be target product.Cold filtration, water, methyl alcohol, ether repeatedly wash on a small quantity successively, place vacuum drier, and 30 ℃ are dried to constant weight.
Embodiment 2: the normal pressure solution method is synthesized cis-[Pt
IICl
2(9-IHA)]
With Na
2PtCl
4(1.0mmol, 0.400g) and 9-IHA (1.0mmol 0.290g) is dissolved in 20mL H respectively
2In O and the 100mL ethanol, the ethanolic soln that is dissolved with 9-IHA is added drop-wise to Na gradually
2PtCl
4In the aqueous solution, under lucifuge, nitrogen protection, in 80 ℃ of back flow reaction 2 hours, most of solvent was removed in evaporation, had a large amount of dark-browns precipitations to generate after the cooling, was target product.Cold filtration, water, ethanol, acetone repeatedly wash on a small quantity successively, place blast drier, are dried to constant weight under 60 ℃.
Embodiment 3: the normal pressure solution method is by the synthetic cis-[Pt of intermediate
IICl
2(9-IHA)]
With Pt (II) intermediate cis-[PtCl
2(DMSO)
2] (1.0mmol; 0.422g) heating be dissolved in the 30mL methyl alcohol; (1.0mmol 0.290g) is dissolved in the 50mL methyl alcohol 9-IHA, and the methanol solution that will be dissolved with Pt (II) intermediate then is added drop-wise in the methanol solution of 9-IHA gradually; under 65 ℃ of following lucifuges, the nitrogen protection; back flow reaction 1 hour after most of methyl alcohol is removed in evaporation, is cooled to room temperature; there are a large amount of dark-brown precipitations to generate, are target product.Cold filtration, water, methyl alcohol, ether repeatedly wash on a small quantity successively, place vacuum drier, are dried to constant weight under 40 ℃.
Embodiment 4: the normal pressure solution method is by the synthetic cis-[Pt of intermediate
IICl
2(9-IHA)]
With Pt (II) intermediate cis-[PtCl
2(DMSO)
2] (1.0mmol; 0.422g) heating be dissolved in the 10mL ethanol/water mixed solvent (volume ratio of ethanol/water=1/1); 9-IHA (1.0mmol; 0.290g) heating be dissolved in the 20mL ethanol; the ethanolic soln that will be dissolved with 9-IHA then dropwise is added drop-wise in the solution that is dissolved with Pt (II) intermediate, under lucifuge, the nitrogen protection, in 80 ℃ of following back flow reaction 2 hours; have a large amount of dark-brown precipitations to generate after being cooled to room temperature, this is target product.Cold filtration, water, ethanol, acetone repeatedly wash on a small quantity successively, place vacuum drier, are dried to constant weight under 40 ℃.
With above-mentioned product through infrared spectra (Perkin Elmer Spectrum One FT-IR Spectrometer, KBr), UV spectrum (Perkin Elmer Lambda45UV-Vis Spectrophotometer), electrospray ionization mass spectrum (Thermo-Finngan LCQ/AD Quadrupole Ion Trap ESI-MS),
1H nuclear magnetic resonance spectrum (Bruker DRX-500NMR spectrometer, 500MHz) and ultimate analysis (PerkinElmer SeriesII CHNS/O Analyzer 2400) test, above-mentioned four embodiment show essentially identical infrared absorption spectrum feature, show that tentatively four kinds of products should be same compound, can determine that through above-mentioned test analysis product is formula (II) class cis-platinum type title complex cis-[Pt
IICl
2(9-IHA)].Characterization data result following (Ar represents phenyl ring):
(1) according to the peak value shown in the infrared spectra as can be known (IR) (KBr), above-mentioned product has following absorption peak and structure: 3379cm
-1(v
N-H), 3044cm
-1(v
Ar-H), 1630cm
-1(v
C=N), 1517cm
-1And 1482cm
-1(v
C=C), 1060cm
-1(v
C-N), 505cm
-1(v
Pt-N)
(2) UV spectrum (UV-Vis) (aqueous solution that contains 1wt%DMSO): it is 1.623 that the whole piece UV spectrum produces maximum absorbance A at wavelength 254nm place, and the concentration that experiment is adopted is 0.00002 mol, ε
Max81150L.mol
-1.cm
-1
(3) ultimate analysis (Anal.Calcd.for C
18H
16N
4Cl
2Pt, wt%) result shows: the analytical results of Theoretical Calculation is: C, 29.32; H, 2.19; N, 7.60; S, 0.00, the results of elemental analyses of measuring is: C, 28.92; H, 2.10; N, 7.22; S, 0.28 since instrument to the error of element sulphur content in 0.8, so the element sulphur result in the above-mentioned analytical results can not consider, the measured value of experiment of C, H, N and the difference of calculated value are all within limit of error.
(4) electrospray ionization mass spectrum (ESI-MS) (ms+, the methanol solution of 1wt%DMSO) result shows, the peak value correspondence at 641.12 places [Pt (DMSO)
2(9-IHA)+H]
+, the peak value correspondence at 597.12 places [PtCl (DMSO) (9-IHA)]
+
Above-mentioned analysis as can be known, product has kept the structure of miaow anthracene hydrazone (9-IHA) basically, and and Pt form title complex.
Further adopt
1H nuclear magnetic resonance spectrum (Bruker DRX-500NMR spectrometer, 500MHz, d
6-DMSO) characterize, according to the label of H in the following molecular formula (III), (δ) is as follows in chemical shift:
(1)8.66(s，1H，9-H)
(2)8.45(d，2H，1-H，8-H)
(3)8.28(s，1H，Ar-CH＝N)
(4)8.14(d，2H，4-H，5-H)
(5)7.58(t，4H，2-H，3-H，6-H，7-H)
(6) 3.66 (d, 4H, the CH on the side chain imidazole ring
2CH
2)
Formula (III)
This shows, the result of nucleus magnetic resonance has further verified based on infrared spectra, UV spectrum, ultimate analysis and mass spectroscopy the chemical structure of class cis-platinum type title complex of the present invention has been inferred, proved that product of the present invention is defined as formula (II) class cis-platinum type title complex cis-[Pt
IICl
2(9-IHA)].
Utilize class cis-platinum type title complex cis-[Pt of the present invention
IICl
2(9-IHA)] carry out the anti tumor activity in vitro test, adopt conventional mtt assay (being tetramethyl-azo azoles salt colorimetry) to finish, its experimental procedure is:
1, cell strain and cell cultures
The anti tumor activity in vitro of BEL7404 (human hepatoma cell strain), SK-OV-3 (human oophoroma cell line), three kinds of tumor line test compounds of NCI-H460 (human lung carcinoma cell line) is selected in this experiment for use, and with 7702 (people's normal liver cells) in contrast cell strain test its vitro cytotoxicity.
The all cells strain is all cultivated in the RPMI-1640 nutrient solution that contains the little ox blood of 10wt%, 100U/mL penicillin, 100U/mL Streptomycin sulphate, puts 37 ℃ and contains in the volumetric concentration 5%CO2 incubator and cultivate.
2, primary dcreening operation
This research compound used therefor (purity all 〉=95%) is mixed with 20 μ mol/L with all compounds, and solubility promoter DMSO final concentration≤1% is tested under this concentration compound to the inhibition degree of growth of tumour cell.Every growth of tumour cell is produced obviously suppressed effect, and meets the metamorphosis that cell under the light microscopic is subjected to press down (as cell shrinkage, fragmentation, floating etc.), and it is effective then to be judged to be primary dcreening operation.
3, cell growth inhibition test
With test-compound to be measured with the DMSO hydrotropy after, use perfect medium to be diluted to the working fluid that final concentration is 20 μ mol/L, use the filtering with microporous membrane degerming of diameter d=0.22 μ m again, place 4 ℃ to preserve down.
The serial tumor cell line that will be in logarithmic phase respectively is inoculated in 96 orifice plates respectively with every hole 190 μ L, and cell concn is about 0.5 * 10
4/ hole, cultivated 12 hours, after treating cell attachment, add the test-compound working fluid, each compound is parallel establishes 4 multiple holes, wherein the DMSO final concentration is not higher than 1%, establish corresponding negative control group (having only cell and equivalent DMSO in the nutrient solution, no medicine) and blank group (having only the medicine of equivalent in the nutrient solution, acellular) simultaneously, each organizes also parallel 4 the multiple holes of establishing, and drug treating time is 48 hours.Cultivate preceding 4 hours every holes of end and add 10 μ LMTT (5mg/mL PBS), continue to cultivate after 4 hours, nutrient solution inclines, add DMSO 150 μ L/ holes, dull and stereotyped oscillator vibration 5min fully dissolves crystallisate, the zeroing of blank group, measure to remove absorbancy (A) value after the bias light absorption value with microplate reader with the 570nm/630nm dual wavelength, record inhibiting rate.According to inhibiting rate measured under the different gradient concentrations, go out the half growth inhibitory concentration value of compound to different cell strains, i.e. IC again by the Bliss computed in software
50Value.The active testing result is shown in following table and accompanying drawing 1.
By last table and accompanying drawing 1 as can be seen, title complex cis-[Pt of the present invention
IICl
2(9-IHA)] three kinds of typical human tumor cell lines are all shown certain proliferation inhibition activity, but its activity is selectively: to the highest (IC of inhibition activity of SK-OV-3 ovarian cancer cell
50=4.52 ± 0.079 μ M), to the also higher (IC of the inhibition activity of BEL7404 liver cancer cell
50=15.73 ± 0.059 μ M), to the then very low (IC of inhibition activity of NCI-H460 lung carcinoma cell
50＞100 μ M).But compare with miaow anthracene hydrazone (9-IHA), title complex has all reduced the inhibition activity of 3 kinds of tumor lines, and the cytotoxicity of this explanation miaow anthracene hydrazone (9-IHA) is than higher, and title complex is then lower.On the other hand, title complex of the present invention is active to have comparability with three kinds of clinical activity with cancer therapy drug-cis-platinum (CDDP), amsacrine (AMSA), hydroxycamptothecine (HCPT), to different tumor lines, activity is had nothing in common with each other, but title complex of the present invention generally is higher than three kinds of cancer therapy drugs to the activity of SK-OV-3 and two kinds of tumor lines of BEL7404.
Can find target title complex cis-[Pt by last table and 2 in accompanying drawing
IICl
2(9-IHA)] cytotoxicity to people's normal liver cell 7702 is lower, is starkly lower than part 9-IHA, also is lower than two kinds of clinical cancer therapy drug AMSA and HCPT, and CDDP then is minimum to 7702 cytotoxicity.
All in all, the cytotoxicity of 9-IHA part is the highest, does not also show the significant cytotoxicity selectivity, and whole toxicity is significantly higher than two kinds of clinical cancer therapy drug CDDP and AMSA; And target title complex cis-[Pt
IICl
2Cytotoxicity (9-IHA)] is moderate, and shows certain cytotoxicity selectivity, has potential preferably pharmaceutical use, is expected to be applied to the preparation of various cancer therapy drugs.
More than the present invention has been done exemplary description; should be noted that; under the situation that does not break away from core of the present invention, the replacement that is equal to that any simple distortion, modification or other those skilled in the art can not spend creative work all falls into protection scope of the present invention.
Claims (9)
1. based on the class cis-platinum type title complex of 9-miaow anthracene hydrazone, it is characterized in that having following molecular formula:
Wherein with two atoms of N, N and the coordination of central metallic ions Pt (II) chelating of 9-miaow anthracene hydrazone, form five-ring chelating body, Pt (II) takes the coordination mode of plane quadrilateral, and ligancy is 4, and the ratio of the amount of substance of 9-miaow anthracene hydrazone and Pt (II) is 1: 1.
2. a method for preparing class cis-platinum type title complex as claimed in claim 1 is characterized in that, utilizes the 9-miaow anthracene hydrazone shown in the following formula with N, the synthetic class cis-platinum type title complex of N bidentate chelating mode, adopts direct coordination synthesis method or intermediate coordination synthesis method.
3. a kind of method for preparing class cis-platinum type title complex as claimed in claim 1 according to claim 2 is characterized in that, described direct coordination synthesis method, the metal-salt reaction with same mole of employing 9-miaow anthracene hydrazone and Pt (II).
4. a kind of method for preparing class cis-platinum type title complex as claimed in claim 1 according to claim 3, it is characterized in that, in the described direct coordination synthesis method, the ratio of the amount of substance of the metal-salt of 9-miaow anthracene hydrazone and Pt (II) is 1: 1, and the metal-salt of described Pt (II) is K
2PtCl
4Or Na
2PtCl
4The metal-salt of described Pt (II) and 9-miaow anthracene hydrazone are dissolved in respectively in water or the polar organic solvent, described polar organic solvent can be the organic solvent that ethanol, methyl alcohol, acetone, acetonitrile etc. can dissolve each other with water, also can be the mixed solvent that two or more solvent mixes with any proportional quantity among them.
5. a kind of method for preparing class cis-platinum type title complex as claimed in claim 1 according to claim 3, it is characterized in that, in the described direct coordination synthesis method, the proportional quantity of the metal-salt of Pt (II), 9-miaow anthracene hydrazone, water and polar solvent is 1mmol: 1mmol: 5～50mL: 20～200mL, the solution of gained reaction system is at 30～90 ℃ temperature range internal reaction, and the reaction times is controlled at more than 1～48 hour or 48 hours.
6. a kind of method for preparing class cis-platinum type title complex as claimed in claim 1 according to claim 2 is characterized in that, described intermediate coordination synthesis method adopts 9-miaow anthracene hydrazone and cis dichloro two (dimethyl sulfoxide (DMSO)) to close platinum (II) reaction with same mole.
7. a kind of method for preparing class cis-platinum type title complex as claimed in claim 1 according to claim 6, it is characterized in that, in the described intermediate coordination synthesis method, the ratio that 9-miaow anthracene hydrazone and cis dichloro two (dimethyl sulfoxide (DMSO)) close the amount of substance of platinum (II) is 1: 1, described 9-miaow anthracene hydrazone and cis dichloro two (dimethyl sulfoxide (DMSO)) close platinum (II) and are dissolved in respectively in water or the polar organic solvent, described polar organic solvent can be ethanol, methyl alcohol, acetone, the organic solvent that acetonitrile etc. can dissolve each other with water also can be the mixed solvent that two or more solvent mixes with any proportional quantity among them.
8. a kind of method for preparing class cis-platinum type title complex as claimed in claim 1 according to claim 6, it is characterized in that, in the described intermediate coordination synthesis method, the proportional quantity that cis dichloro two (dimethyl sulfoxide (DMSO)) closes platinum (II), 9-miaow anthracene hydrazone and polar solvent is 1mmol: 1mmol: 30～200mL, the solution of gained reaction system is at 30～90 ℃ temperature range internal reaction, and the reaction times is controlled at more than 1～48 hour or 48 hours.
9. the class cis-platinum type title complex based on 9-miaow anthracene hydrazone as claimed in claim 1 is characterized in that, the application in the preparation antitumor drug.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103086975A (en) * | 2013-02-05 | 2013-05-08 | 广西师范大学 | 9-hydroxymethyl-10-imidazolanthracenehydrazone, and synthetic method and application thereof |
| CN104387423A (en) * | 2014-11-07 | 2015-03-04 | 广西师范大学 | Platinum (II) complex by taking chiral compound as ligand as well as synthetic method and application of platinum (II) complex |
| CN105440085A (en) * | 2015-12-30 | 2016-03-30 | 广西师范大学 | 9-benzothianthrene hydrazine-ruthenium (II) complex as well as synthetic method and application thereof |
| CN107746418A (en) * | 2017-09-27 | 2018-03-02 | 玉林师范学院 | A kind of synthesis and its application of 9 chlorine 1,2,3,4 tetrahydro acridine platinum (II) complex for targeting liver cancer |
| 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 |
| CN108774270A (en) * | 2018-07-20 | 2018-11-09 | 玉林师范学院 | Target Sorafenib anti-tumor platinum (II) complex and the preparation method and application thereof of human lung cancer mdr cell |
| CN108774269A (en) * | 2018-07-20 | 2018-11-09 | 玉林师范学院 | Novel targeted benzimidazoles derivative anti-tumor platinum (II) and ruthenium (II) complex and the preparation method and application thereof |
| CN108997436A (en) * | 2018-07-20 | 2018-12-14 | 玉林师范学院 | A kind of novel Rui Gefeini anti-tumor platinum (II) complex and the preparation method and application thereof |
| CN110903307A (en) * | 2019-10-28 | 2020-03-24 | 广西师范大学 | Dinuclear metal complex with 9-aldehyde-10-mianthracene hydrazone as ligand and synthetic method and application thereof |
| CN110938035A (en) * | 2019-10-28 | 2020-03-31 | 广西师范大学 | 9-benzenesulfonic acid-10-mianthracene hydrazone and synthesis method and application thereof |
| CN110950913A (en) * | 2019-10-28 | 2020-04-03 | 广西师范大学 | Ionic metal complex with 9-aldehyde-10-pyrimidinehydrazone as ligand and synthetic method and application thereof |
| CN110950896A (en) * | 2019-10-28 | 2020-04-03 | 广西师范大学 | Copper (II) complex with 9-aldehyde-10-pyrimidinehydrazone as ligand and synthetic method and application thereof |
| CN110950895A (en) * | 2019-10-28 | 2020-04-03 | 广西师范大学 | Binuclear copper complex with 9-aldehyde-10-benzothiazole anthracene hydrazone as ligand and synthetic method and application thereof |
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Cited By (19)
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| CN103086975A (en) * | 2013-02-05 | 2013-05-08 | 广西师范大学 | 9-hydroxymethyl-10-imidazolanthracenehydrazone, and synthetic method and application thereof |
| CN104387423A (en) * | 2014-11-07 | 2015-03-04 | 广西师范大学 | Platinum (II) complex by taking chiral compound as ligand as well as synthetic method and application of platinum (II) complex |
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| CN108774270B (en) * | 2018-07-20 | 2020-06-12 | 玉林师范学院 | Sorafenib antitumor platinum (II) complex targeting drug-resistant cells of human lung cancer and preparation method and application thereof |
| CN108997436B (en) * | 2018-07-20 | 2020-06-12 | 玉林师范学院 | Rueglini antitumor platinum (II) complex and preparation method and application thereof |
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| CN110903307A (en) * | 2019-10-28 | 2020-03-24 | 广西师范大学 | Dinuclear metal complex with 9-aldehyde-10-mianthracene hydrazone as ligand and synthetic method and application thereof |
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| CN110950896A (en) * | 2019-10-28 | 2020-04-03 | 广西师范大学 | Copper (II) complex with 9-aldehyde-10-pyrimidinehydrazone as ligand and synthetic method and application thereof |
| CN110950913A (en) * | 2019-10-28 | 2020-04-03 | 广西师范大学 | Ionic metal complex with 9-aldehyde-10-pyrimidinehydrazone as ligand and synthetic method and application thereof |
| CN110938035A (en) * | 2019-10-28 | 2020-03-31 | 广西师范大学 | 9-benzenesulfonic acid-10-mianthracene hydrazone and synthesis method and application thereof |
| CN110950896B (en) * | 2019-10-28 | 2021-05-14 | 广西师范大学 | Copper (II) complex with 9-aldehyde-10-pyrimidinehydrazone as ligand and synthetic method and application thereof |
| CN110950895B (en) * | 2019-10-28 | 2021-05-14 | 广西师范大学 | Binuclear copper complex with 9-aldehyde-10-benzothiazole anthracene hydrazone as ligand and synthetic method and application thereof |
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