CN103588687B - A kind of monovalence copper metal complex and its production and use - Google Patents
A kind of monovalence copper metal complex and its production and use Download PDFInfo
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- CN103588687B CN103588687B CN201210476610.XA CN201210476610A CN103588687B CN 103588687 B CN103588687 B CN 103588687B CN 201210476610 A CN201210476610 A CN 201210476610A CN 103588687 B CN103588687 B CN 103588687B
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Abstract
The invention belongs to chemical medicine field, relate to metal complex kind anti-cancer drugs thing, it is specifically related to monovalence copper metal complex and its production and use, the univalent copper complex two [diethyldithiocar bamic acid closes copper (I)] of the present invention, through cell and animal anti-tumor experiment, as a result, it was confirmed that tumor cell SW1990, BXPC3, PANC-1 are all had significant inhibitory action by described univalent copper complex；Results of animal confirms, described univalent copper complex can effectively suppress the growth of animal-transplanted tumor in safe-dosaging limits.The univalent copper complex good water solubility of the present invention, has higher anti-tumor activity.Clinical cancer therapy medicine can be prepared further, especially prepare treatment malignant tumor medicine.
Description
Technical field
The invention belongs to chemical medicine field, relate to metal complex kind anti-cancer drugs thing, be specifically related to monovalence copper metal complex and its production and use, especially this monovalence copper metal complex purposes in preparation treatment malignant tumor medicine.
Background technology
The Drug therapy of tumor is one of three big basic skills treating malignant tumor at present.Prior art discloses metal complex cisplatin (abbreviation cisplatin) to be determined by experiment from Luxembourg in 1969 there is anti-tumor activity, within 1978, go through to be applied to clinical treatment tumor of testis and ovarian cancer, now become one for the treatment of most commonly used 3 kinds of medicines of cancer applications in the world.The successful Application of cisplatin causes the numerous scientists very big concern to platinum metals coordination compound kind anti-cancer drugs thing, and research obtains a series of achievements in research, as, successively develop the medicines such as carboplatin, oxaliplatin, lobaplatin, and nearly 30 various metals platinum complexes are in clinical trial.Practice display, cisplatin series antineoplastic medicament is applied successfully to clinic, particularly to the solid tumor accounting for the overwhelming majority and therapeutic effect and poor prognosis clinically, has good curative effect such as ovarian cancer, carcinoma of testis, pulmonary carcinoma, gastric cancer etc..Research shows, metallic copper is widely present in life system, and it has special biological activity, due to serious toxicity and the drug resistance of platinum complexes, and the good anti-tumor activity of copper complex, metal copper complexes gradually becomes the research emphasis of anti-tumor complex.Research finds, 1-Phenylethanone. thiosemicarbazones and metallic copper (II) form two tooth coordination compounds, and the growth of mice transplanted tumor S180 ascites cells is had good inhibitory action；When epirubicin, ametycin and copper complex synergy, the growth of HeLa-S3 human cervical carcinoma cell there is significant coordinate repression；The growth of human breast carcinoma and cervical cancer cell is also had obvious coordinate repression by the coordination compound of copper and malonate derivative and epirubicin, Cisplatin.
It is reported, U.S. FDA approval is for the medicine disulfiram (Disulfiram of alleviating alcohol addiction, DSF), the coordination compound with Graft Versus Tumor can be formed with bivalent cupric ion, its mechanism of action be disulfiram copper (II) coordination compound can protease inhibition body activity, stop the degraded of proteasome, thus stoping tumor cell proliferation.Research also shows, tumor cell is very sensitive to proteasome inhibitor, and normal cell is then insensitive to this, and the inhibitory action of tumor cell is had selectivity by proteasome inhibitor.Although copper and disulfiram protease inhibition body activity can cause apoptosis of tumor cells directly in conjunction with the coordination compound formed, but the defect such as it still suffers from poorly water-soluble, and biological value is low.Sodium diethyldithiocarbamate (DDTC) has the chemical group similar with disulfiram, can also with copper ion generation complex reaction, this just industrial circle DDTC is used as detection copper content and clinical medicine DDTC is used as to drive the chemical fundamentals of copper agent, but DDTC-Cu (II) water solublity is still very poor, so far, there is not yet the report using it for clinical therapy of tumor research.
Summary of the invention
It is an object of the invention to provide a kind of monovalence copper dual-nuclei structure model that can be used for clinical cancer therapy and preparation method thereof.The monovalence copper dual-nuclei structure model of the present invention, forms stable aqueous solution in Valid concentration after being dissolved in water, its bioavailability is high, and Graft Versus Tumor is strong, can prepare antitumor drug further.
More specifically, the invention provides a kind of monovalence copper dual-nuclei structure model that can be used for clinical cancer therapy, it is characterized in that, univalent copper complex two [diethyldithiocar bamic acid closes copper (I)] its molecular formula that described metal complex is formula (I) structure is [C4H10NS2Cu]2。
The present invention adopts and is chemically synthesized new univalent copper complex, and uses physical means to determine the structure of coordination compound.Through this coordination compound impact on tumor cell of cell and animal active Immunotherapy of Cancer Induced, cell experiment is as a result, it was confirmed that tumor cell SW1990, BXPC3, ME180 are all had significant inhibitory action by described univalent copper complex；Results of animal confirms, described univalent copper complex can effectively suppress the growth of animal-transplanted tumor in safe-dosaging limits.The univalent copper complex good water solubility of the present invention, has higher anti-tumor activity.
The present invention prepares above-mentioned univalent copper complex by following method: by part sodium diethyldithiocarbamate (DDTC) and water soluble bivalent nantokite such as copper chloride (CuCl2) or copper sulfate (CuSO4), reducing agent is sodium sulfite (Na such as2SO3) or sodium sulfite (NaHSO3) (mol ratio, such as DDTC:Na in proportion2SO3:CuCl2=2:1:2, reducing agent can be excessive) be added to the water, synthesizing two [diethyldithiocar bamic acid closes copper (I)] metal complex in aqueous, chemical reaction process is as shown in Equation 2.
Formula 2
The univalent copper complex good water solubility of the present invention, has higher anti-tumor activity.Clinical cancer therapy medicine can be prepared further.
Figure of description
Fig. 1 is the mass spectrum-1 of coordination compound of the present invention.
Fig. 2 is the mass spectrum-2 of coordination compound of the present invention.
Fig. 3 is the infrared absorpting light spectra-1 of coordination compound of the present invention.
Fig. 4 is the infrared absorpting light spectra-2 of coordination compound of the present invention.
Fig. 5 is each group of medicine inhibitory action comparison diagram to cell viability.
Fig. 6 is transplanted tumor in nude mice growth curve.
Fig. 7 zoopery tumor entity figure.
Detailed description of the invention
The present invention tests reagent and the raw material of employing:
RPMI1640 culture medium (RPMI1640+10% hyclone)；CCK-8(is purchased from colleague chemical company product).
Embodiment 1 synthesizes univalent copper complex
Deionized water preparation sodium diethyldithiocarbamate (DDTC), copper chloride (CuCl2), sodium sulfite (Na2SO3) three kinds of solution 50ml, concentration is 200mM, airtight, 4 DEG C of storages, takes 500ml indigo plant lid bottle, is separately added into 200ml deionized water and 200ml chloroform methanol mixed solvent, sequentially adds DDTC, the Na of preparation2SO3,CuCl2Solution, fully mixes, and is the product of visible brown color in lower floor's chloroformic solution, after deionized water cyclic washing, separatory funnel separates, and rotary evaporator 50 DEG C removes chloroform and methanol, obtaining dark brown crystalline powder, normal hexane cleans three times, inserts exsiccator inner drying.
Its molecular weight of mass spectral analysis is 422.22, ir data: 2981,2929,2869,1506,1436,1377,1353,1301,1274,1208,1148,1097,1073,997,914,847,778,572.
The 2-in-1 one-tenth univalent copper complex of embodiment
Deionized water preparation sodium diethyldithiocarbamate (DDTC), copper chloride (CuCl2), sodium sulfite (Na2SO3) three kinds of solution 50ml, concentration is 200mM, airtight, 4 DEG C of storages, takes 500ml indigo plant lid bottle, adds 200ml deionized water, is sequentially added into DDTC, the Na of above preparation2SO3,CuCl2Solution, fully mixes, and namely generates brown coordination compound, natural subsidence 1 hour, suck the supernatant, take off a layer suspension 3000rpm centrifugal sedimentation, supernatant discarded, take sedimentation part, 0.45uM filter membrane+2 metafiltration paper vacuum pump negative pressure leaching, deionized water rinses repeatedly, removes salinity, obtain coordination compound blocks of solid, normal temperature drying in exsiccator.
Its molecular weight of mass spectral analysis is 444.82, adding the molecular ion peak after unification sodium for it, theoretical value is 444.90, and the molecular weight recorded with embodiment 1 after deducting a sodium atom is consistent, the above-mentioned coordination compound data of infrared absorption spectroscopy data and gained also meet, elementary analysis: C28.34%, H4.86%, N6.59%, with theoretical value (C28.35%, H4.76%, N6.61%) also consistent, it was demonstrated that and the chemical structural formula of coordination compound is reliable with synthetic method.
Embodiment 3 antitumor cytolytic activity
Medicine is prepared
Sterilizing deionized water preparation sodium diethyldithiocarbamate (DDTC), copper chloride (CuCl2), sodium sulfite (Na2SO3) three kinds of solution, concentration is 200mM, airtight, 4 DEG C of storages, standby.
Take the clean sterile centrifugation tube of 15ml, be initially charged 9ml sterilizing deionized water, by DDTC:CuCl2:Na2SO3=2:2:1 is separately added into the reagent solution of the 200mM concentration of 50ul, 50ul, 25ul tri-kinds preparation, shakes up, obtains the stable drug solution of brown color；The drug solution taking preparation carries out cell experiment and zoopery.
By complex structure monomer, namely DDTC-Cu equivalent concentration is that 1mM. is airtight, 4 DEG C of storages, standby.
Cell experiment
Human pancreas cancer SW1990, BXPC3, PANC-1 cell is incubated at 1640+10%FBS culture fluid, 5%CO, 37 DEG C of cellar cultures.96 well culture plates, 5000 cells are implanted in every hole, after preculture 24 hours, adopt above-mentioned containing (the comparison employing 2.5 μMs between different pharmaceutical of different pharmaceutical concentration,, the detection of IC50 value adopts 0-100 μM of concentration range) 1640+10%FBS culture fluid cellar culture after 24 hours, adopt CCK-8 reagent, microplate reader 450nm wavelength detecting every hole absorbance (OD), calculates growth of tumour cell suppression ratio and cell viability as follows.
Growth of tumour cell suppression ratio=(ODBlank-ODExperiment)/ODBlank×100%
Cell viability=ODExperiment/ODBlank×100%
Result shows, by sodium diethyldithiocarbamate and copper chloride with under reducing agent sodium sulfite or bisulfite combined effect, DDTC-Cu (I) coordination compound formed can effectively suppress SW1990, PANC-1, the propagation of BXPC-3 three-type-person's pancreas cancer cell strain, the IC50 value of 24 hours respectively 0.48,0.46,0.47uM. under 2.5uM concentration conditions, DDTC, CuCl2、Na2SO3Or DDTC+Na2SO3, CuCl2+Na2SO3Described cell strain is not had effective Inhibit proliferaton effect.
Zoopery
5 week old Female nude mice (purchased from Chinese science academy), SPF environment is raised, and first takes 5 nude mices, and right side omoplate is subcutaneously injected into SW1990 cell 1 × 107/ only, after 3 weeks, tumor growth is to～500mm3, conventional treatment nude mice, take tumor block, choose eugonic two tumor blocks, be cut into the square fragment of 1mm × 1mm × 1mm, implant other 20 nude mices. when nude mice lotus tumor grows to～200mm3During size (2 weeks), it is randomly divided into DDTC-Cu group (n=10) and matched group (n=10)；
Carry out pharmaceutical intervention: (1) matched group: lumbar injection and treatment group medication equal-volume normal saline；(2) DDTC-Cu group: 10nmol/gDDTC-Cu, lumbar injection, the next day once；Within every three days, measure gross tumor volume by following formula,
Gross tumor volume computing formula: V=(L × W2)×0.5
In formula, L is tumor major diameter, and W is tumor minor axis.
After nude mice treats three weeks, all processed routinely at the 22nd day, take out tumor block, take pictures, retain tumor tissues.
Gross tumor volume measurement result according to the 21st day, compared with matched group, result shows, the suppression ratio of tumor growth is 52.9% (P=0.007) by DDTC-Cu treatment.In medication process, medicine shows becomes thin, diarrhoea and certain untoward reaction such as hemafecia.
Claims (4)
1. the univalent copper complex two [diethyldithiocar bamic acid closes copper (I)] of formula (I) structure, its structural formula is as follows:
2. the univalent copper complex two [diethyldithiocar bamic acid closes copper (I)] of claim 1 purposes in preparation tumor.
3. by the purposes described in claim 2, it is characterised in that described tumor is malignant tumor.
4. by the purposes described in claim 2, it is characterised in that described tumor is human pancreas cancer.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4842753A (en) * | 1987-05-07 | 1989-06-27 | Shin-Etsu Chemical Co., Ltd. | Silicone grease composition |
| US20010016600A1 (en) * | 1998-09-08 | 2001-08-23 | Kennedy Thomas Preston | Method of treating cancer using dithiocarbamate derivatives |
| WO2004067505A2 (en) * | 2003-01-29 | 2004-08-12 | National University Of Singapore | Bismuth dithiocarbamate compounds and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4842753A (en) * | 1987-05-07 | 1989-06-27 | Shin-Etsu Chemical Co., Ltd. | Silicone grease composition |
| US20010016600A1 (en) * | 1998-09-08 | 2001-08-23 | Kennedy Thomas Preston | Method of treating cancer using dithiocarbamate derivatives |
| WO2004067505A2 (en) * | 2003-01-29 | 2004-08-12 | National University Of Singapore | Bismuth dithiocarbamate compounds and uses thereof |
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