CN105601676B - A kind of ruthenium complex and its application - Google Patents
A kind of ruthenium complex and its application Download PDFInfo
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- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims abstract description 14
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
- C07F15/0053—Ruthenium compounds without a metal-carbon linkage
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of ruthenium complex and its applications.The cationic moiety of the ruthenium complex of the present invention is [Ru (phen)2(HIPMP)]2+, anionicsite is (ClO4)-Or Cl-.Monokaryon ruthenium complex of the present invention has good active anticancer, especially to the treatments of cancer significant effect such as human cervical carcinoma cell, liver cancer cells, lung carcinoma cell or nasopharyngeal carcinoma cell.Monokaryon ruthenium complex inducing apoptosis of tumour cell of the present invention relates generally to endogenic endoplasmic reticulum access, has important meaning for studying efficient ruthenium antitumor drug.
Description
Technical field
Present invention relates particularly to a kind of ruthenium complex and its applications.
Background technology
Cancer is one of current most important disease for threatening human health and life security.There are about 12,700,000 every year in the whole world
People is diagnosed as cancer patient, and the number that cancer is died of in the whole world every year accounts for the 13% of total death toll.There are about 150 every year in China
Ten thousand people die of cancer, and ascendant trend year by year is presented.Since cis-platinum is found to have active anticancer, Platinum Anti-tumor Drugs
Application and research rapidly developed.Wherein platinum medicine Anticancer Effect and Mechanism is destroyed mainly using DNA as major target
The effects that duplication of DNA and inhibition cell division, inhibits growth of tumour cell.But platinum medicine long-time service has poison pair
The shortcomings of effect is big, and drug resistance is strong and anticancer spectrum is narrow.Therefore, it is anti-to find efficient, high selection and the anticancer drug of Small side effects
The Main way of cancer drug exploitation.
Ruthenium complex has relatively low toxicity compared with cis-platinum, highly selective, easily absorbs and is drained quickly in vivo
And the features such as overcoming the cellular drug resistance of platinum medicine, it is considered one of most promising antitumor drug（Coord. Chem. Rev., 2002, 232, 69）.Up to the present, two kinds of ruthenium complexes NAMI and KP1019 come into phase ii clinical trial
In the stage, the former has the metastatic tumor of muroid apparent inhibitory action, and the latter has colon cancer apparent therapeutic effect, can inhibit
The inoperative tumour growth of some cis-platinums.But at present the antitumor mechanism of ruthenium complex mainly using DNA as target or
Using mitochondria as the antitumor mechanism of the inducing apoptosis of tumour cell of target spot.Such ruthenium complex there are toxic side effect greatly and low choosing
The shortcomings of selecting property.
The content of the invention
It is an object of the invention to provide the preparations and its application of a kind of ruthenium complex.
The technical solution used in the present invention is：
A kind of ruthenium complex is made of cation and anion, and the cation is [Ru (phen)2(HIPMP)]2+, knot
Structure formula is as follows：
。
Preferably, the anion is inorganic ion.
Preferably, the inorganic salt anionic is (ClO4)-Or Cl-。
The preparation method of the ruthenium complex, comprises the following steps：
1) it is abundant under inert gas shielding by 1,10- Phendiones, ammonium acetate and 5- cresotinic acid aldehyde
Intermediate product is obtained by the reactionHIPMP；
2) by step 1）Obtained intermediate productHIPMPWithcis-[Ru(phen)2Cl2]•2H2O, in inert gas shielding
Lower fully reaction, the saturated solution that anionic inorganic salt is slowly added dropwise after being cooled to room temperature generate precipitation, and precipitation is further purified
Dry ruthenium complex.
Preferably, step 1）Middle reaction added in 1,10- Phen -5,6- diketone, ammonium acetate and 5- cresotinic acids
The amount ratio of aldehyde substance is 1:20:1.
Preferably, step 1）Solvent used in middle reaction is glacial acetic acid.
Preferably, step 1）Reaction carried out in the method that is heated to reflux.
Preferably, step 1）Intermediate product obtained by the reactionHIPMPIt is further purified, comprises the following steps：With a small amount of
Ethyl alcohol dissolves, and fills column with silica gel, ethyl alcohol collects yellow color component, rotary evaporation obtains as eluentHIPMPYellow powder.
Preferably, step 2）It is middle to react what is added inHIPMP withcis-[Ru(phen)2Cl2]•2H2The amount ratio of the substance of O
For 1：1.
Preferably, step 2）Solvent used in middle reaction is ethyl alcohol or ethylene glycol.
Preferably, step 2）Solvent used in middle reaction is ethyl alcohol.
Preferably, step 2）Reaction carried out in the method that is heated to reflux.
Preferably, step 2）In inorganic salt anionic be (ClO4)-Or Cl-。
Preferably, step 2）cis-[Ru(phen)2Cl2]·2H2O andHIPMPAmount ratio according to substance is 1:1 is added to
In ethyl alcohol, be heated to reflux under inert gas shielding 8 it is small when, obtain red clear liquid, NaClO be slowly added dropwise after being cooled to room temperature4Saturation
Solution directly rotates, and generates reddish brown precipitation.
Application of the ruthenium complex described in any of the above-described in antitumor drug.
Preferably, the cancer includes cervical carcinoma, liver cancer, lung cancer or nasopharyngeal carcinoma.
The beneficial effects of the invention are as follows：
Ruthenium complex disclosed in this patent, be it is a kind of have it is strong it is inhibition cytotoxicity, using endoplasmic reticulum as target spot
The ruthenium complex of inducing apoptosis of tumour cell has important meaning for studying efficient ruthenium antitumor drug.
The ruthenium complex of the present invention is a kind of the with antitumaous effect of structure novel, the monokaryon ruthenium of structure containing p-cresol
（II）Complex.
The monokaryon ruthenium of the present invention（II）Complex has good active anticancer, especially thin to human cervical carcinoma cell, liver cancer
The treatments of cancer significant effect such as born of the same parents, lung carcinoma cell or nasopharyngeal carcinoma cell.
The monokaryon ruthenium of the present invention（II）Complex inducing apoptosis of tumour cell relates generally to endogenic endoplasmic reticulum access.
The monokaryon ruthenium of the present invention（II）Complex has relatively low normal cell toxicity and highly selective.
Description of the drawings
Fig. 1 is complex [Ru (phen)2(HIPMP)](ClO4)2Synthetic route chart；
Fig. 2 is ruthenium complex to Cytostatic to tumor cell lab diagram；
Fig. 3 induces HeLa Apoptosis flow cytometer detection figures for ruthenium complex；
Fig. 4 for HeLa cells and ruthenium complex cultivate after 2h with ER-Tracker, Mito-Tracker and LYSO-
Cell imaging figure after Tracker contaminates altogether；
Fig. 5 is influence figure of the ruthenium complex to endoplasm Netcom road protein expression.
Specific embodiment
With reference to specific embodiment, the present invention is further illustrated, but is not limited thereto.
1 monokaryon ruthenium complex of embodiment [Ru (phen)2(HIPMP)](ClO4)2Synthesis
（1）By 1,10- Phen -5,6- diketone, ammonium acetate and 5- cresotinic acids aldehyde according to substance amount ratio be 1:20:
1, it is dissolved in appropriate glacial acetic acid, when Hybrid Heating reflux 4 is small under inert gas shielding, mixture adds in water after being cooled to room temperature,
It is neutralized with 25% ammonium hydroxide, filters, obtain yellow mercury oxide and washed with water and ether, obtain corresponding crude product.The a small amount of second of crude product
Alcohol dissolves, and uses silica gel（60-100 mesh）Column is filled, ethyl alcohol collects yellow color component, rotary evaporation obtains yellow powder as eluent
2-(1H-Imidazo- [4,5-f] [1,10] phenanthrolin-2-yl) -4-methylphenol (i.e. intermediate productsHIPMP).Yield：83%.Anal. Calcd for C20H14N4O: C, 73.61; H, 4.32; N, 17.17. Found:
C, 73.14; H, 4.61; N, 17.32%. FAB-MS: m/z = 327 (M+1)；
（2）cis-[Ru(phen)2Cl2]·2H2O andHIPMPAmount ratio according to substance is 1:1 is added in ethanol in proper amount,
Be heated to reflux under inert gas shielding 8 it is small when, obtain red clear liquid, NaClO be slowly added dropwise after being cooled to room temperature4Saturated solution, production
Raw reddish brown precipitation.It filters, it is 10 that product, which crosses column acetonitrile with ethyl alcohol volume ratio,:1 mixed liquor rinses, and is dried in vacuo to obtain production eventually
Object [Ru (phen)2(HIPMP)](ClO4)2.Synthetic route chart is shown in Fig. 1.
Synthetic yield is 70%. Anal. Calcd for C44H30N8Cl2O9Ru: C, 53.56; H, 3.06; N,
11.36%; Found: C, 53.87; H, 2.92; N, 11.58%. ES-MS [CH3CN, m/z]: 788.2 ([M–
2ClO4–H]+), 394.1 ([M–2ClO4]2+). 1H NMR (400 MHz, DMSO-d6) ppm: 9.18 (d, J =
8.0 Hz, 1H), 9.03 (d, J = 6.0 Hz, 1H), 8.78 (d, J = 3.8 Hz, 2H), 8.77 (d, J =
6.0 Hz, 2H), 8.40 (s, 4H), 8.16 (d, J = 6.0 Hz, 2H), 8.12 (d, J = 6.0 Hz,
2H), 8.08 (d, J = 12.0 Hz, 2H), 8.04 (t, J = 6.0 Hz, 2H), 7.88(d, J = 8.0 Hz,
2H), 7.78 (m, 2H), 7.78 (dd, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.14
(d, J = 7.0 Hz, 1H), 2.36 (s, 3H).。
2 monokaryon ruthenium of embodiment（II）Complex makees the inhibition that tumour cell HeLa, A549, HepG2 and CNE-1 are proliferated
With
Cytotoxicity experiment：The in vitro toxicity that complex is had studied using mtt assay is tested.Experimental cell is placed in 37 first
DEG C, 5.0% CO2Logarithmic phase is grown in incubator, 0.25% collected by trypsinisation cell adjusts concentration of cell suspension, makes cell
Density is about 1 × 104A/mL is inoculated in 96 orifice plates per 100 mL of hole, and cell density is about 3-5 × 103A/hole, is placed in 37
℃、5% CO2Incubator in cultivate 24 h.Liquid to be changed, adds in the drug of various concentration gradient, each concentration does 3 Duplicate Samples,
Blank zeroing group is set（Culture medium, MTT, DMSO）, blank group（Culture medium, cell, same concentrations drug dissolving medium,
MTT、DMSO）, positive controls（Culture medium, cell, the cis-platinum of various concentration, MTT, DMSO）.It is placed in 37 DEG C, 5% CO2's
Continue to cultivate 48 h in incubator.Supernatant is sucked, 90 μ l fresh mediums are added in per hole, add 10 μ l MTT solution
（5 mg/mL, i.e. 0.5% MTT）, continue to cultivate 4 h.Culture is terminated, discards culture solution in hole, 150 μ l DMSO are added in per hole,
30 min of low-speed oscillation on shaking table is placed in, crystal is made fully to dissolve.Enzyme-linked immunosorbent assay instrument detects each hole of 490 nm wavelength
Absorbance OD.
The inhibiting rate and half-inhibition concentration of relevant cell Proliferation（IC50）It is calculated with following formula：Growth suppression
Rate processed=（ODControl-ODExperiment）/（ODControl-ODBlank）, all OD values subtract blank zeroing group OD values.By inhibiting rate and drug concentration
Mapping, draws dose-effect curve, therefrom calculates IC50Value.Monokaryon ruthenium complex [Ru (phen)2(HIPMP)](ClO4)2
(1 compound of embodiment) is to tumour cell HeLa（Human cervical carcinoma cell）、A549（Lung carcinoma cell）, HepG2 (liver cancer cells) or
CNE-1（Nasopharyngeal carcinoma cell）The IC of inhibited proliferation50Value is shown in Table 1, and inhibiting rate is shown in Fig. 2 with drug concentration graph of relation.
[the Ru (phen) of table 12(HIPMP)](ClO4)2To the IC of tumour cell50Value
The result shows that monokaryon ruthenium complex [Ru (phen)2(HIPMP)](ClO4)2To tumour cell HeLa, A549,
The IC of HepG2 and CNE-150Value is suitable with cis-platinum, and maximum to the toxicity of HeLa tumour cells.Mononuclear complex is to normal thin
The cytotoxicity of born of the same parents LO2 is all smaller to the cytotoxicity of cancer cell than it, illustrates that complex has relatively low normal cell toxicity.
3 monokaryon ruthenium of embodiment（II）Complex is using the double dye method research HeLa cell apoptosis assays of Annexin V and PI
Alexa fluor®The double dye methods of 488 annexin V/PI are a kind of sxemiquantitative being detected with flow cytometer
Apoptosis assay method (Vermes, C. Haanen, H. Steffens-Nakken and C.
Reutellingsperger, J. Immunol. Methods, 1995,184,39-51.), specific experiment step is such as
Under：Logarithmic phase cell is collected, adjusts concentration of cell suspension, per hole 1 × 10 in 6 orifice plates5A cell.It is placed in 37 DEG C, 5% CO2Training
It supports in case and cultivates about 24 h.Liquid is changed, adds in 1 mL various concentrations（10,20,40 μM）Drug, three parallel holes of each concentration,
The blank control wells for adding in same concentrations drug dissolving medium are set simultaneously, continue to cultivate 24 h.It is careful to suck supernatant, 0.25%
Collected by trypsinisation cell adjusts concentration of cell suspension, makes cell density about 1 × 104A/mL, 1000 rpm, 5 min
Supernatant is removed in centrifugation, adds in 100 μ l PBS and is resuspended, uses strainer filtering.1000 rpm, 5 min are centrifuged, and remove supernatant, add in 100 μ
Cell is resuspended in 1 × Binding of l Buffer, is separately added into 5 μ l Alexa fluor®488 annexin V and 1 μ l PI,
15 min are incubated at room temperature, add in 400 μ l 1 × Binding Buffer, with FACSCanto II flow cytomeries, experiment
The results are shown in Figure 3.Experimental result shows good concentration dependent.When the concentration of complex is at 10 μM, 18.3%
HeLa cells are in early apoptosis state, and 14.3% HeLa cells are in late apoptic state.When the concentration of effect reaches 40 μ
During M, a total of 88.2% cell is in apoptotic state（Early and late apoptosis）.With the raising of concentration, complex induction
The quantity of apoptotic cell rises therewith, and complex can cause HeLa Apoptosis.
4 monokaryon ruthenium of embodiment（II）Complex distributional analysis in the cell is tested
HeLa cells are cultivated in the DMEM culture mediums containing 10% hyclone, cell (5 × l08/ L) 12 orifice plates are seeded in,
Per hole about 2 × l04A cell.It is placed in 5% CO2Under 95% air conditions, 37 DEG C of cultures, when adherent growth 24 is small.Liquid is changed, is added in
1 mL monokaryon rutheniums（II）Complex (20 μM), same three parallel holes of concentration, while set and add in the dissolving of same concentrations drug
The blank control wells of medium continue to cultivate 24 h.Culture solution is suctioned out, is then washed 3-4 times with PBS buffer solution, is added respectively per hole
Enter the PBS containing 50 nM Mito-Tracker, ER-Tracker and LYSO-Tracker dyeing liquors of 1 mL, 37 DEG C of incubations,
Be incubated 30 min, picture observed and shoot by Olympus IX71 inverted fluorescence microscopes, exciting light using feux rouges with it is green
Light binary channels excites.
Experimental result is shown in Fig. 4, from the figure, it can be seen that monokaryon ruthenium complex is under laser excitation, after complex coloring
Cell is all that bright red is presented, and is distributed in endoplasmic reticulum, is coincide well with commercial endoplasmic reticulum dyestuff.Complex with
There is no coincide well for commercial mitochondrial dye and lysosome dyestuff.Illustrate that complex is located in endoplasmic reticulum.
5 monokaryon ruthenium of embodiment（II）The signal path research of complex inducing apoptosis of tumour cell effect
（1）Prepared by protein sample, collect in logarithmic phase HeLa cells, adjustment concentration of cell suspension, 6 orifice plates per hole 1
×105A cell is placed in overnight incubation in incubator.
（2）Liquid is changed, adds ruthenium complex, 10,20,40 μM of concentration co-cultures 24 h with cell.
（3）At the end of incubation, cell is collected, extracts albumen.Suitable protein is taken, by 4:1 ratio adds in loading and delays
Fliud flushing, 100 DEG C of metal baths, which heat 5 min, makes albuminous degeneration, and 20,000 rpm centrifugations take supernatant for use.
（4）SDS-PAGE electrophoresis, installs vertical electrophoresis apparatus, prepares the separation gel of required concentration, encapsulating.
（5）After treating PAGE glue solidification completely, glass plate is removed, by flag sequence in electrophoresis tank, pulls out comb.With
5 × electrophoretic buffer that ultra-pure water dilution has prepared, mixing add in electrophoresis tank.
（6）Loading plugs sample injector, is loaded with special loading pipette tips, and general 3 μ l of marker provide sample loading for oneself
Measure 25 μ l（The comb of 1 mm thickness）, the applied sample amount of sample can be adjusted as needed.
（7）Electrophoresis plugs in, and sets 80 V of constant pressure, and sample reaches 120 V after concentration glue separation gel interface, can root
According to needing adjustment time length.
（8）Transferring film, pvdf membrane are steeped 30 minutes with absolute methanol, storing order（Hei-white）：Sponge-filter paper-glue-
Pvdf membrane-filter paper-sponge.According to black to black (cathode), white is to red（Anode）Order transferring film clip is placed on
In electrophoresis tank, while ice chest is put into, fills it up with fresh transferring film liquid（It is stored in 4 DEG C）, 250 mA/h of constant current is set.
（9）Immuning hybridization takes out film after transferring film, is rinsed one time with TBST, is immersed in confining liquid, at room temperature shaking table
It is upper slowly to shake, close 1 h.Film in confining liquid is taken out, is rinsed one time, is immersed in the primary antibody solution prepared with TBST,
It is placed in 4 DEG C of overnight incubations.After primary antibody is incubated, film is washed 3 times with TBST, every time 6 min.It is corresponding according to the selection of the source of primary antibody
Secondary antibody, secondary antibody dilution is with confining liquid, general 1:2000 dilutions, room temperature shaker are incubated 1 h.
（10）Exposure imaging after secondary antibody is incubated, washes film 3 times, every time 5 min with TBST.After TBST being blotted with paper handkerchief,
ECL is dropped evenly into pvdf membrane, preservative film in covering is placed in post-exposure in exposure box.According to the power of destination protein signal
Select the time for exposure.According to the destination protein Band signal strong and weak adjustment time for exposure to obtain optimum efficiency, film is scanned, is preserved
Analysis result.
Western bolt laboratory test results are shown in Fig. 5, p-PERK, and p-eIF2 α and CHOP protein expression increase,
Caspase-7 and PARP albumen is broken.The result shows that monokaryon ruthenium complex can inducing protein kinase β sample endoplasmic reticulum swash
Phosphorylation occurs for enzyme (PERK), then activates downstream signaling molecule Eukaryotic Initiation Factor 42（enkaryoticinitiation
2α, eIF2α）, while er stress specific transcription factor CHOP is raised, so as to active cell apoptotic signal access.In CHOP
Induction under, Caspase-7 is sheared activation, and then the mark of cutter activation its substrate molecule PARP, PARP Apoptosis point
Son, Activation markers cell and irreversible apoptosis occur.In conclusion the monokaryon ruthenium complex can pass through er stress apoptosis
Apoptosis occurs for access induction tumour cell.
Above-described embodiment is the preferable embodiment of the present invention, but embodiments of the present invention and from above-described embodiment
Limitation, other any Spirit Essences without departing from the present invention with made under principle change, modification, replacement, combine, simplification,
Equivalent substitute mode is should be, is included within protection scope of the present invention.
Claims (7)
1. a kind of ruthenium complex is made of cation and anion, it is characterised in that：The cation is [Ru (phen)2
(HIPMP)]2+, structural formula is as follows：
The anion is inorganic ion.
2. ruthenium complex according to claim 1, it is characterised in that：The inorganic salt anionic is (ClO4)-Or Cl-。
3. the preparation method of ruthenium complex described in claim 1, which is characterized in that comprise the following steps：
1) by 1,10- Phendiones, ammonium acetate and 5- cresotinic acid aldehyde, fully reacted under inert gas shielding
Obtain intermediate product HIPMP；
2) the intermediate product HIPMP for obtaining step 1) and cis- [Ru (phen)2Cl2]·2H2O according to substance amount ratio be 1
: 1 is added in ethanol in proper amount or ethylene glycol, is fully reacted under inert gas shielding, be slowly added dropwise after being cooled to room temperature it is cloudy from
The saturated solutions of sub- inorganic salts generates precipitation, and dry ruthenium complex is further purified in precipitation.
4. preparation method according to claim 3, it is characterised in that：Added in 1, the 10- neighbour's Féraud of reaction in step 1)
The amount ratio of quinoline -5,6- diketone, ammonium acetate and 5- cresotinic acid aldehyde substances is 1: 20: 1.
5. preparation method according to claim 3, it is characterised in that：Reaction solvent used is glacial acetic acid in step 1).
6. application of any one of the claim 1-2 ruthenium complexes in antitumor drug is prepared.
7. application according to claim 6, it is characterised in that：The tumour includes cervical carcinoma, liver cancer, lung cancer or nasopharynx
Cancer.
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