CN103483388A - Norharman-ruthenium (II) polypyridine complex with antitumour activity - Google Patents
Norharman-ruthenium (II) polypyridine complex with antitumour activity Download PDFInfo
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Abstract
The invention discloses a preparation method for a Norharman-ruthenium (II) polypyridine complex and the antitumour activity thereof. The chemical formula of the Norharman-ruthenium (II) polypyridine complex disclosed by the invention is [Ru(tpy)(Norharman)3]<2+>(tpy=2,2':6',2''- terpyridyl, Norharman=9H-pyridino-[3,4-b] indol), and prepared by taking ruthenium trichloride and Norharman as raw materials, and performing the steps of heating reflux reaction, cooling and filtering, washing, drying and the like. The influence of the complex on tumour cells is researched in in-vitro antitumour activity test, and the complex is found to be strong in an inhibition effect on the growth of tumour cells HeLa, HepG2, A549, MCF-7, NCI-H460, Bel-7402 and HCT-116. The complex is indicated to be good in a tumour inhibition effect by animal test data, and expected to be a novel antitumour medicinal member, and wide in application prospect.
Description
Technical field
The present invention relates to antitumor novel micromolecular compound field, be specifically related to a kind of new Norharman-ruthenium (II) multi-pyridine ligand, and its preparation method and application.
Background technology
Cancer is as the second largest cause of death in disease, and the mankind's health in serious threat, and the whole world approximately has 7,000,000 people to die from cancer every year, and wherein annual 1500000 people of China die from cancer, and cancer has become the No.1 killer of all kinds of causes of the death of China.Therefore, development of new, can optionally act on tumour cell and not have virose antitumor drug to seem particularly urgent to normal cell.Chemotherapy is one of 3 large means of current clinical anticancer, but for a long time, if for the drug main organic compound of oncotherapy; There is anti-tumor activity until the biophysicist Barnett Rosenberg of the state university of Michigan, United States in 1969 chances on cis-platinum, just excite the concern of people to Metal Drugs.Cis-platinum and carboplatin are to use clinically at present one of the widest cancer therapy drug, are the choice drugs of the many tumours for the treatment of.But at present, the problem of clinical application platinum kind anti-cancer drugs maximum is resistance, many patients are congenital or the day after tomorrow platinum-containing anticancer drug is produced to resistance, curative effect and the anticancer spectrum (H.Sakurai thereof of medicine have seriously been reduced, Y.Yoshikawa, H.Yasui.Chem.Soc.Rev., 2008,37,2383-2392).Ruthenium complexe has caused people's attention as new cancer therapy drug in recent years.In non-platinum group medicine, ruthenium complex is one of the most promising cancer therapy drug.
These researchs with ruthenium complex of anti-tumor activity tentatively start, and in the work of having reported, have multiple ruthenium complexe to show good anti-tumor activity, and wherein some ruthenium complexe has entered I phase or II phase clinical stage at present.It is [HL] [trans-Ru (III) L that Keppler working group has synthesized a series of general structures
2cl
4] ruthenium complexe, wherein L is Nitrogen-Containing Heterocyclic Ligand, finds that they have obvious result for the treatment of to colorectal carcinoma.The KP1019 that the indoles of take is main part has completed the first phase clinical experiment in 2006, it can pass through the mitochondria pathway cell death inducing, can suppress the growth of the inoperative tumour of some cis-platinums, and in vivo with experiment in vitro in, all do not produce resistance, there is no very severe side effect (O.Domotor, C.G.Hartinger yet, A.K.Bytzek, T.Kiss, B.K.Keppler and E.A.Enyedy.J.Biol.Inorg.Chem., 2013,18,9-17).Alessio etc. modify KP1019, synthesize and obtain NAMI-A, entered the I phase in 1999 clinical, within 2003, enter the II phase clinical, that first enters clinical ruthenium complexe (G.Mestroni, E.Alessio, G.Sava, S.Pacor, M.Coluccia and A.Boccarelli.Metal-Based Drugs, 1994, Isosorbide-5-Nitrae 1-63).Although they find that this class title complex is aobvious active in testing in vitro, the metastatic tumor of muroid is but had to restraining effect clearly.The designs such as Sadler have been synthesized and have been had [(η
6-arene) Ru (X) (Y) (Z)] the ruthenium-aromatic hydrocarbons title complex of general structure.Such title complex provides 3 approach that can regulate its structure: the type that bitooth ligand can be regulated the stability of title complex and ligand exchange speed, aromatic ring can affect the effect of the absorption of cell and title complex and possible drug targets and leavings group X(is generally Cl-) can determine the time (Y.K.Yan that medicine is activated, M.Melchart, A.Habtemariam and P.J.Sadler.Chem.Commun, 2005,4764 – 4776).
In recent years, using and there is the development of bioactive molecule as the metal complexes of part, efficient for pursuing, provide more wide space for the new drug design of target activity.Beta-carboline alkaloid is the compound of a class natural origin and synthetic, has the calmness of comprising, anxiety, and hypnosis, anticonvulsion, antitumor, antiviral, parasiticide and the broad-spectrum biological pharmacological activity such as antibiotic.Beta-carboline alkaloid can be brought into play by number of mechanisms the activity of antitumor action, as inserted DNA, suppresses topoisomerase I and II, suppress CDK and I kappa b kinase (R.H.Cao, W.L.Peng, Z.H.Wang and A.L.Xu.Curr.Med.Chem., 2007,14,479-500).In our previous work, find that there is anti-tumor activity beta-carboline ruthenium (Xu Anlong, Peng Wenlie, Tan Caiping, king's Min Acquaintance, Zhu Yiping, Wu Shouhai, rely dense, Lian Wu, Chinese invention patent, CN201010173100.6).For improving the anti-tumor capacity of title complex, we design and have prepared a kind of Norharman-ruthenium (II) multi-pyridine ligand [Ru (tpy) (Norharman)
3]
2+, find that it has higher anti-tumor activity.
Summary of the invention
The object of the present invention is to provide a kind of new antitumor Norharman-ruthenium (II) multi-pyridine ligand and its preparation method and application.
The present invention is achieved through the following technical solutions above-mentioned purpose:
A kind of Norharman-ruthenium (II) multi-pyridine ligand, [Ru (tpy) (Norharman) for chemical formula
3]
2+(tpy=2,2 ': 6 ', 2 ' '-terpyridyl, Norharman=9H-pyrido [3,4-b] indoles 2,2-dipyridyl), structural formula is as shown in the formula I:
The preparation method of above-mentioned Norharman-ruthenium (II) multi-pyridine ligand, is characterized in that first synthesizing Ru (tpy) Cl
3, join in ethanol the lower 76 ℃ of reflux 24h of argon shield together with silver triflate; be cooled to room temperature; remove by filter insolubles, add Norharman in filtrate, the lower 76 ℃ of reflux 48h of argon shield; be cooled to room temperature; remove by filter insolubles, the filtrate rotary evaporated to dryness, cross neutral alumina column; the toluene that is 1:1 by volume ratio and the drip washing of acetonitrile mixed solution, vacuum-drying obtain described Norharman-ruthenium (II) multi-pyridine ligand
The preparation method of described Norharman-ruthenium (II) multi-pyridine ligand, [Ru (tpy) Cl
3] with the mol ratio of Norharman be 1:3.3.
Show after deliberation the above-mentioned title complex that contains the Norharman part of the present invention [Ru (tpy) (Norharman)]
2+, can cross over cytolemma in the short period of time and enter cell.Can induce the kinds of tumor cells apoptosis such as HeLa, HepG2, A549, MCF-7, NCI-H460, Bel-7402, HCT-116 in vitro, the anti-tumor in vivo experiment shows that title complex can suppress the propagation of mouse MCF-7, HepG2 tumour.Thereby the above-mentioned title complex that contains the Norharman part [Ru (tpy) (Norharman)]
2+can be used as novel antitumor drug.
Compared with prior art, the present invention has following beneficial effect:
Ru-polypyridine complex molecular structure stabilized of the present invention, synthetic method is simple.The introducing of beta-carboline alkaloid Norharman in this ruthenium (II) title complex, strengthened the cell transmembrane ability of title complex greatly.Anti-tumor experiment shows, this title complex can successfully be induced the kinds of tumor cells apoptosis, suppresses mouse tumor propagation.Its ability of inhibition to HeLa cell proliferation is cis-platinum 29 times, be the most efficient known Ru-polypyridine complex at present, will there is great application potential aspect antitumor drug.
The accompanying drawing explanation
[Ru (tpy) (Norharman) for Fig. 1
3]
2+the complex molecule structural formula.
The route of synthesis of Fig. 2 Norharman part.
[Ru (tpy) (Norharman) for Fig. 3
3] (CF
3sO
3)
2the route of synthesis of title complex.
Fig. 4 HeLa cell and 5 μ M [Ru (tpy) (Norharman)
3] (CF
3sO
3)
2cultivate 0.5h, 1.0h, cell imaging result after 1.5h and 2.0h.
Fig. 5 HeLa cell and 5 μ M [Ru (tpy) (Norharman)
3] (CF
3sO
3)
2cultivate 0.5h, 1.0h, after 1.5h and 2.0h, ICP-MS detects cell whole (Total Cell), the content of metal Ru in tenuigenin (Cytoplasmic) and nucleus (Nuclear).
[Ru (tpy) (Norharman) for Fig. 6
3] (CF
3sO
3)
2tumor proliferation on tumor-bearing mice (MCF-7 and HepG2) suppresses and the impact of body weight only.
Embodiment
Embodiment 1
[Ru (tpy) (Norharman) for title complex
3] (CF
3sO
3)
2synthetic method:
(1) Ru (tpy) Cl
3synthetic
Can prepare with reference to existing document (B.P.Sullivan, D.J.Salmn and T.J.Meyer, Inorg.Chem., 1978,17,3334) by the synthetic of this compound.Take RuCl
3nH
2the about 10mmol of O2.62g(), 2,2 ': 6 ', 2 ' '-terpyridyl 2.33g(10mmol), in 250cm
3in dehydrated alcohol, reflux approximately 3 hours.After being chilled to room temperature, suction filtration, after for precipitation, frozen water, cold acetone are cleaned, vacuum-drying, obtain the atropurpureus crystallite.Average yield 80%.
(2) Norharman's is synthetic
The synthetic of this compound can be with reference to existing document (H.R.Snyder, H.G.Walker and F.X.Werber.J.Am.Soc.Chem., 1949,71,527-529) preparation.Take the about 49mmol of L-Trp 10.0g(), the about 100mmol of sodium hydroxide 4.0g() in 500cm
3in ultrapure water, be stirred to fully and dissolve.Add subsequently 40% methyl alcohol 5.6cm
3(about 70mmol), 3 hours post-heating of stirring at room reflux 3 hours.After being cooled to room temperature, add 4cm
3glacial acetic acid and 2.0L ultrapure water, reflux.Dripped 500cm in 45 minutes
310% potassium dichromate aqueous solution and 100cm
3the mixing solutions of Glacial acetic acid, continue to reflux 2 minutes.Be cooled to room temperature, add sodium bisulfite to remove unreacted potassium bichromate, add anhydrous sodium bicarbonate to pH value of solution=9.Extracted with diethyl ether, merge organic phase, and the anhydrous sodium sulfate drying rear filtration of spending the night, by the filtrate rotary evaporated to dryness.Methyl alcohol and water (volume ratio 3:1) recrystallization for crude product, obtain white or brown transparent crystals, average yield 52%.
(3) [Ru (tpy) (Norharman) for title complex
3] (CF
3sO
3)
2synthetic.
By Ru (tpy) Cl3 (0.44g; 1mmol) and silver triflate (0.85g; 3.3mmol) join in the 200mL dehydrated alcohol; argon shield, 76 ℃ of reflux 12 hours; after filtered while hot is removed insolubles, add Norharman (0.55g, 3.3mmol) in filtrate; argon shield, 76 ℃ of reflux 24 hours, obtain the reddish black clear liquid.Be cooled to room temperature, solution rotating be evaporated to dry, obtain a large amount of black solids.Solid 15cm after the ether washing
3acetonitrile dissolves, neutral alumina column, V (toluene): V (acetonitrile)=1:1 drip washing purifying.Vacuum-drying, obtain dark red solid 0.60g, productive rate 53%.Anal.Calcd.forC
50H
35F
6N
9O
6RuS
2(%):C,52.81;H,3.10;N,11.09.Found(%):C,52.75;H,3.18;N,11.02.ES-MS(CH
3OH)m/z:419.2[M-2SO
3CF
3]
2+。
Embodiment 2
[Ru (tpy) (Norharman)
3] (CF
3sO
3)
2laser co-focusing experiment, this example take HeLa cell and title complex Laser Scanning Confocal Microscope-cell imaging is tested is example.
Cell cultures: the HeLa cell is being cultivated containing in the DMEM substratum of 10% foetal calf serum, cell (5 * l0
8/ L) be seeded at the bottom of the Laser Scanning Confocal Microscope special glass in culture dish culture dish diameter 35mm, cover-glass thickness 0.085～0.13mm wherein, culture dish center micro-pore diameter 10mm, 5%CO
2under 95% air conditions, 37 ℃ of cultivations, adherent growth 24 hours.
Laser Scanning Confocal Microscope-cell imaging: the HeLa cell is with [Ru (tpy) (Norharman)
3] (CF
3sO
3)
2(5 μ M) cultivates 30min, 1h, 1.5h and 2h, and the sucking-off nutrient solution, then with PBS damping fluid washing 3～4 times, imaging on Leica TCS SP5 laser scanning co-focusing microscope, use 63 */1.4 oily mirrors, with 350nm light, as excitation light source, collect the fluorescence in 440～460nm scope.Experimental result is shown in Fig. 4.From Fig. 4, can observe, title complex is by diffusing into cell.Cultivate 30min and 1h, title complex mainly concentrates in tenuigenin, and between the prolongation cultivation, to 1.5h and 2h, title complex diffuses to nucleus from tenuigenin, is full of whole cell.
Embodiment 3
[Ru (tpy) (Norharman)
3] (CF
3sO
3)
2cellular uptake, it is example that this example be take the inductivity coupled plasma mass spectrometry experiment of HeLa cell and title complex.
Cell cultures: the HeLa cell is being cultivated containing in the DMEM substratum of 10% foetal calf serum, cell (5 * l0
8/ L) be seeded in Tissue Culture Dish culture dish diameter 100mm, 5%CO
2under 95% air conditions, 37 ℃ of cultivations, adherent growth 24 hours.
Inductivity coupled plasma mass spectrometry (ICP-MS): the HeLa cell is with [Ru (tpy) (Norharman)
3] (CF
3sO
3)
2(5 μ M) cultivates 30min, 1h, 1.5h and 2h, and the sucking-off nutrient solution, then with PBS damping fluid washing 3～4 times.Become unicellular with 0.25% trysinization, cell is divided into to 4 parts.First part for cell counting, second part of tenuigenin separating kit isolated cell matter of using Thermo, the 3rd part of nucleus separating kit separating nucleus that uses Thermo.Tenuigenin, nucleus that the 4th part of cell and separation are obtained are scattered in 60% nitric acid, under room temperature, place 24 hours.With ultrapure water, every duplicate samples being diluted to concentration of nitric acid subsequently is 2%.Agilent (ICP-MS) 7700x inductivity coupled plasma mass spectrometry detects the content of metal Ru.Experimental result is shown in Fig. 5.The experiment acquired results is consistent with embodiment 2, and [Ru (tpy) (Norharman) for the title complex of cellular uptake
3] (CF
3sO
3)
2amount increase and increase along with the time.Cultivate 30min and 1h, title complex mainly concentrates in tenuigenin, and between the prolongation cultivation, to 1.5h and 2h, title complex diffuses to nucleus from tenuigenin, is full of whole cell.
Embodiment 4
MTT vitro cytotoxicity analysis experiment
Select human cervical carcinoma cell (Hela), human liver cancer cell (HepG-2, Bel-7402), lung carcinoma cell (A549, NCI-H460), tumour cell and people's normal breast epithelial cell (MCF-10A) such as colon cancer cell (HCT-116), breast cancer cell (MCF-7), liver cell (L-02) carries out this research.Select above-mentioned well-grown cell to become single cell suspension with 0.25% tryptic digestion, adopt blood counting chamber to carry out viable count, adjusting viable cell concentrations is 5 * 10
4/ mL is inoculated in 96 well culture plates, every hole 160 μ L, after cultivating 24 hours, then add respectively different concns [Ru (tpy) (Norharman)
3] (CF
3sO
3)
2, positive control is cis-platinum, is placed in 37 ℃, is containing 5%CO
2incubator in hatch 48 hours, in finishing to add in first 4 hours MTT20 μ L/ hole, abandoning supernatant after 4 hours, add DMSO100 μ L/ hole, vibrate about 10 minutes, be placed in multi-functional microplate reader, for avoiding the inhalation effects of Ru-polypyridine complex itself, measure 570nm and the 607nm wavelength OD of place value, by following formula, calculate survival rate:
The average OD value of the average OD value/control wells of survival rate %=medicine feeding hole * 100%
Half casualty-producing concentrations (IC is tried to achieve in mapping simultaneously
50), estimate vitro Drug antitumor cell activity with this, and contrasted with the effect of the existing medicines such as cis-platinum.Experimental result is in Table 1.
Table 1MTT method is analyzed the cytotoxicity of title complex to various kinds of cell
From list data, can see: the IC of title complex of the present invention to tumour cell
50value is starkly lower than cis-platinum, to Normocellular IC
50value is far above the IC to tumour cell
50value, show that the external antitumor cell activity of matching object of the present invention is high, is better than the cis-platinum of present wide clinical application, great exploitation potential for its.
Embodiment 5
Title complex is tested in the body tumor suppression
To inoculate respectively the mouse of people MCF-7 and HepG2 tumour, the mouse of every kind of tumour is divided into 4 groups at random, and 10 every group, intraperitoneal injection.Model control group (brief note is control, physiological saline), cis-platinum group (brief note is cisplatin, 10mg/kg), [Ru (tpy) is (Norharman) for title complex
3] (CF
3sO
3)
2group (brief note is Ru1,10mg/kg), part group (brief note is Norharman, 40mg/kg), the injection volume of every mouse is 0.4ml, every 24 hours once, continuous 14 days.The inhibiting rate of tumor proliferation calculates according to following formula:
(C–T)/C×100
Wherein, the weight in average that C is control group (control group) tumour knurl piece, the weight in average that T is other group tumour knurl pieces.Data are shown in Fig. 6.[Ru (tpy) (Norharman) for title complex
3] (CF
3sO
3)
2inhibiting rate to mouse MCF-7 and HepG2 tumour is respectively 52.1% and 58.2%, higher than existing antitumor drug cis-platinum (cisplatin).In addition, part Norharman is less than 15% to the inhibiting rate of mouse MCF-7 and HepG2 tumour.Above data show, part Norharman is combined with the metal Ru center, can effectively improve the antitumous effect of Norharman, and [Ru (tpy) (Norharman) for the title complex obtained
3] (CF
3sO
3)
2the antitumor drug aspect has very wide application prospect.
Claims (4)
1. Norharman-ruthenium (II) multi-pyridine ligand with anti-tumor activity, its structural formula is as shown in the formula I:
2. the preparation method of Norharman-ruthenium claimed in claim 1 (II) multi-pyridine ligand, is characterized in that first synthesizing Ru (tpy) Cl
3, join in ethanol the lower 76 ℃ of reflux 24h of argon shield together with silver triflate, be cooled to room temperature, remove by filter insolubles, add Norharman in filtrate, the lower 76 ℃ of reflux 48h of argon shield, be cooled to room temperature, remove by filter insolubles, the filtrate rotary evaporated to dryness, cross neutral alumina column, the toluene that is 1:1 by volume ratio and the drip washing of acetonitrile mixed solution, vacuum-drying obtain described Norharman-ruthenium (II) multi-pyridine ligand;
Wherein tpy is 2,2 ': 6 ', 2 ' '-terpyridyl, Norharman is 9H-pyrido [3,4-b] indoles 2, the 2-dipyridyl.
3. the application of the described Norharman-ruthenium of claim 1 (II) multi-pyridine ligand in the preparation anti-tumor activity medicine.
4. an antitumor drug, contain Norharman-ruthenium claimed in claim 1 (II) multi-pyridine ligand as effective constituent and pharmaceutically acceptable auxiliary.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103951610A (en) * | 2014-05-20 | 2014-07-30 | 武汉理工大学 | Simple preparation method of ruthenium polypyridine complex |
| CN110857310A (en) * | 2018-08-12 | 2020-03-03 | 南京大学 | Polyamphidine ruthenium complex with photoactivity and application thereof |
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| CN101845060A (en) * | 2010-05-05 | 2010-09-29 | 中山大学 | Beta-carboline ruthenium compound as well as preparation method and application thereof |
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| CN101845060A (en) * | 2010-05-05 | 2010-09-29 | 中山大学 | Beta-carboline ruthenium compound as well as preparation method and application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103951610A (en) * | 2014-05-20 | 2014-07-30 | 武汉理工大学 | Simple preparation method of ruthenium polypyridine complex |
| CN103951610B (en) * | 2014-05-20 | 2016-07-06 | 武汉理工大学 | A kind of preparation method of Ru-polypyridine complex |
| CN110857310A (en) * | 2018-08-12 | 2020-03-03 | 南京大学 | Polyamphidine ruthenium complex with photoactivity and application thereof |
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