CN108635357A - A kind of application of complex of iridium in preparing mitochondria anti-tumor drugs targeting - Google Patents
A kind of application of complex of iridium in preparing mitochondria anti-tumor drugs targeting Download PDFInfo
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- CN108635357A CN108635357A CN201810510444.8A CN201810510444A CN108635357A CN 108635357 A CN108635357 A CN 108635357A CN 201810510444 A CN201810510444 A CN 201810510444A CN 108635357 A CN108635357 A CN 108635357A
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Abstract
The invention discloses a kind of application of complex of iridium in preparing mitochondria anti-tumor drugs targeting.The complex of iridium structural formula is：[Ir(ppy)2(HPIP)] ligand that Cl, wherein ppy are represented is 2 phenylpyridines, and the ligand that HPIP is represented is 3 (2 yl of 1H imidazoles [4,5 f] [1,10] Phen) phenol.Complex of iridium of the present invention has strong inhibiting effect to human tumor cells HeLa, HepG2, A 549 and cisplatin resistance strain CP/R A549, the mitochondria of tumour cell can be accumulated in and induce tumour cell that apoptosis occurs, can be used as new using tumour cell mitochondria as the antitumor drug of target spot.
Description
Technical field
The invention belongs to antitumor drug technical fields, and in particular to a kind of complex of iridium prepare it is Mitochondrially targeted anti-swollen
Application in tumor medicine.
Background technology
There are about 7,600,000 people to die of cancer every year in the whole world, accounts for the 13% of total death toll, and the annual whole world is diagnosed cancer trouble
For person up to 12,700,000, China to die of cancer there are about 1,500,000 every year, and in gradually rising trend every year.Oncotherapy includes mainly hand
Three art treatment, radiotherapy, chemotherapy aspects.Chemotherapy, i.e., the method for treating disease with chemical synthetic drug.Tradition
Chemotherapeutics due to remarkable cytotoxicity, chemotherapy being made to become the important means of current clinical treatment tumour disease, but
It is indifferent for the difference identification of normal cell and tumour cell due to it, causes to produce tumor patient in clinical application
Raw serious toxic side effect, this is the main reason for causing to interrupt treatment and treatment failure.So research and development targeting is strong, poison is secondary
Acting on low antitumor drug seems more urgent.Metal iridium complex is compared with other Metal Anticancer Drugs, is had higher
Cytotoxicity and smaller toxic side effect, show vast potential for future development, it has also become research hotspot both domestic and external.
No matter larger difference, main table all there is in structure or in function in the mitochondria of tumour cell and normal cell
Several respects such as ROS levels in present mitochondrial, film potential and permeability, mitochondria, tumour cell due to occur compared with
It is easier to be influenced by injury of mitochondria widely to make a variation, many researchs are ingenious to make Mitochondrially targeted medicine using these features
Object become antitumor drug in recent years new design direction (Nature Reviews Drug Discovery, 2010,9:447-
464.).Normal cell generally generates ATP in the way of oxidative phosphorylation, and tumour cell tends to send out due to fast breeding
Glycolysis is given birth to provide more energy.Compared with normal cell, the mitochondrial membrane potential in certain cancer cells increases extremely, chlorine
Ni Daming (Lonidamine), oblimersen (Oblimersen), the drugs such as resveratrol (Resveratrol) can be by straight
Connecing makes the film potential of mitochondria dissipate, or by adjusting the apoptosis closely related with mitochondrial membrane permeability such as bcl-2 and Bax
Protein family, the permeability for eventually leading to mitochondrial matrix expand and inducing apoptosis of tumour cell.In addition tumour cell is especially
Horizontal apparent relatively low, the menadiones (menadione) of tumor stem cell mitochondria ROS, gadolinium motexafin (motexafin
Gadolinium), lapachol (lapachone), it is by generating excessive ROS or inhibition in mitochondria to wait drugs all
The activity of SOD comes inducing apoptosis of tumour cell (Trends in Cell Biology, 2008,18 (4):165-173.).
In conclusion the antitumor drug for acting directly on mitochondria, which has, avoids the latent of traditional chemotherapy resistance mechanisms
Power can be used for the treatment of drug-resistant tumor；And utilize the difference of tumour cell and normal cell mitochondria but also mitochondria target
Be substantially reduced to the toxic side effect of drug, to reach Synergy and attenuation antitumor drug clinical application demand.
Invention content
The preparation and the application in antitumor drug that the goal of the invention of the present invention is to provide a kind of complex of iridium.
The above-mentioned purpose of the present invention is achieved by following technical solution：
A kind of application of complex of iridium in preparing mitochondria anti-tumor drugs targeting, wherein the sun of the complex of iridium
Ionic structure formula isAnion is Cl-。
The complex of iridium synthetic method reference：Dalton Trans.,2014,43,17463–17474.The iridium is matched
Closing object structural formula is：The complex of iridium structural formula is：[Ir(ppy)2(HPIP)] ligand that Cl, wherein ppy are represented is 2-
Phenylpyridine, the ligand that HPIP is represented are 3- (1H- imidazoles [4,5-f] [1,10] Phen -2-yl) phenol.It is of the present invention
Tumour cell HeLa, A-549, HepG2, the MCF- of complex of iridium to people's (ovarian neoplasm, tumor of breast, liver tumour or lung neoplasm)
7 and cisplatin resistance strain CP/R-A549 has strong inhibiting effect, and to human normal liver cell L 02 toxicity very little.The iridium is matched
Close object have green fluorescence, into cell after by organelle common location research discovery the complex energy special target be accumulated in it is swollen
Oncocyte mitochondria.It can induce tumour cell that apoptosis occurs.It can be used as new using tumour cell mitochondria as the anti-swollen of target spot
Tumor medicine.
Description of the drawings
Fig. 1 is organelle common location experimental result picture of the complex of iridium in HeLa cells；
Fig. 2 is the flow cytometry results figure that complex of iridium induces HeLa apoptosis；
Specific implementation mode
The present invention is further explained with reference to specific embodiment, but specific embodiment is not to the present invention
It is limited in any way.Unless stated otherwise, reagent involved in embodiment, method are reagent and method commonly used in the art.
The complex of iridium synthetic method reference：Dalton Trans.,2014,43,17463–17474.The iridium is matched
Closing object structural formula is：[Ir(ppy)2(HPIP)] ligand that Cl, wherein ppy are represented is 2- phenylpyridines, the ligand that HPIP is represented
For 3- (1H- imidazoles [4,5-f] [1,10] Phen -2-yl) phenol.
1 complex of iridium in vitro antitumor activity assay of embodiment
The cell strain of screening has：Tumour cell HeLa, A-549, HepG2, MCF-7 and cisplatin resistance strain CP/R-A549,
Control cell uses normal Fetal hepatocyte L02.Positive control medicine uses cis-platinum.It measures blue (MTT) using bromination tetrazole
Method, principle are：Bromination tetrazole indigo plant [MTT, 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl-
Tetrazolium bromide] be a kind of dyestuff that can receive hydrogen atom, in living cells mitochondria with the relevant dehydrogenases of NADP
The MTT of yellow can be converted to insoluble bluish violet Jia Za in the cell, and dead cell is then without this function.With dimethyl Asia
After sulfone (DMSO) Rong Xie Jia Za, OD value is measured with microplate reader, you can quantitatively measure the survival of cell under certain wavelength
Rate.Experimental procedure：The tumour cell of logarithmic growth phase is inoculated in 96 well culture plates, 200 holes μ L/.Testing each sample is
5 concentration, each concentration set 6 multiple holes.After drug is added, cell is placed in 37 DEG C, 5%C02Continue culture 48 in incubator
Hour, then add MTT, be cultivated for 4 hours, suck supernatant, adds 150 μ L DMSO per hole, with microplate reader in 49Onm waves
It is long to survey each hole absorbance, cell proliferation inhibition rate is calculated according to the following formula.The inhibiting rate and cell quantity of relevant cell Proliferation
The death rate calculated with following formula：Inhibiting rate (%)=(control group mean OD value-administration group mean OD value)/control
Group mean OD value × 100%；Half inhibiting rate (the IC provided according to China Medicine University's new medicament screen center50) software for calculation asks
Go out IC50Value, experimental result are shown in Table 1.
Half-inhibition concentration of 1 complex of iridium of table to various cells
aIC50Unit with μM indicating, data are indicated with mean ± standard deviation,bCP/R:For cisplatin resistance strain,cL02:For just
Ordinary person liver cell.
The experimental results showed that complex of iridium is suitable significantly lower than classical chemotherapeutics to the half inhibiting rate of kinds of tumor cells
Platinum, but have significant inhibiting effect for cisplatin resistance strain, and cis-platinum is significantly less than to the toxicity of Human normal hepatocyte.This
Illustrate that the complex of iridium of meaning of the invention may be used as anticancer drug application.
2 Mitochondrially targeted positioning of embodiment
The HeLa cells of logarithmic growth phase, adjustment a concentration of 1 × 104/ mL is inoculated into 35mm Tissue Culture Dish, waits for thin
Complex of iridium and mitochondria specificity fluorescent probe Mito-Tracker is added to 60% degree of converging in intracellular growth, is incubated 30 minutes,
It is positioned in the cell with laser confocal microscope (Zeiss Axio Observer D1) detection complex of iridium, experimental result is such as
(A is complex of iridium (green fluorescence), and B is mitochondria specificity fluorescent probe (red fluorescence), and C is nucleus dyestuff shown in Fig. 1
DAPI images (blue-fluorescence), D are to scheme being superimposed for A, B and C).Experiment show Fig. 1-D show sent out by complex of iridium it is green
Orange fluorescence is presented after the red fluorescence superposition that color fluorescence and mitochondria specificity fluorescent probe are sent out, it was demonstrated that signified iridium cooperation
Object can be targeted and is located in the mitochondria of cell.
3 complex of iridium of embodiment induces tumour cell that apoptosis occurs
It measures using flow cytometry Annexin-V decoration methods, principle is：Phosphatidylserine
(Phosphatidylserine, PS) is normally at the inside of cell membrane, but early stage Apoptosis, and PS can be from cell membrane
The surface for turning inside out cell membrane, is exposed in extracellular environment.Annexin-V is a kind of Ca2+Dependence phosphatide combination egg
In vain, it can be specifically bound with PS high-affinities.Annexin-V is carried out fluorescein (FITC) to mark, with what is be marked
Annexin-V can detect the generation of Apoptosis using flow cytometer as fluorescence probe.Experimental procedure：It is given birth in logarithm
Long-term HeLa cells are with 5x 104The cell density of a/mL is inoculated in 6 orifice plates, per hole 2mL, is placed in 37 DEG C, 5%CO2Saturation
After being cultivated 24 hours in humidified incubator, the complex of iridium of various concentration is then added, isometric PBS is added in control group.Training
It supports 24 hours, 3000r/min collects cell, and PBS is washed three times, each 5min.It is resuspended in 100 μ L binding buffer
(10mM HEPES,140mM,2.5mM CaCl2, pH 7.4) add 5 μ L Annexin V-FITC (Invitrogen, USA,
CA), it is protected from light 15 minutes in room temperature.Then 400 μ L combination buffers are added, with FACSCanto II (BD Biosciences,
USA) flow cytometer is analyzed, and is as a result shown in Fig. 2.
The experimental results showed that complex of iridium is added after 24 hours, a large amount of apoptosis, and apoptosis rate is with complex of iridium
The increase of dosage and increase, illustrate complex of iridium can effectively induce tumour cell occur apoptosis.
Claims (4)
1. a kind of application of complex of iridium in preparing mitochondria anti-tumor drugs targeting, which is characterized in that the complex of iridium
Cationic structural beAnion is Cl-.
2. complex of iridium application in preparation of anti-tumor drugs according to claim 1, which is characterized in that the tumour
For ovarian neoplasm, tumor of breast, liver tumour or lung neoplasm.
3. complex of iridium application in preparation of anti-tumor drugs according to claim 2, which is characterized in that the tumour
Cell strain be HeLa, MCF-7, HepG2, A-549.
4. complex of iridium application in preparation of anti-tumor drugs according to claim 1, which is characterized in that described anti-swollen
Tumor mechanism is that apoptosis occurs for induction tumour cell.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110423260A (en) * | 2019-07-12 | 2019-11-08 | 中山大学 | A kind of Cyclometalated iridium photosensitizer of glucose modified and its preparation method and application |
| CN113583057A (en) * | 2021-09-07 | 2021-11-02 | 中山大学 | Efficient metal iridium complex and preparation method and application thereof |
| CN114057777A (en) * | 2021-11-18 | 2022-02-18 | 南方海洋科学与工程广东省实验室(湛江) | Beta-carboline derivative and preparation method and application thereof |
| CN116063372A (en) * | 2023-01-17 | 2023-05-05 | 齐齐哈尔医学院 | Mitochondria-targeted antitumor compound, and preparation method and application thereof |
| CN116425804A (en) * | 2023-04-04 | 2023-07-14 | 东莞市人民医院 | Cyclometalated iridium complex with anti-inflammatory and anti-tumor activities and preparation method and application thereof |
-
2018
- 2018-05-24 CN CN201810510444.8A patent/CN108635357A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| JIN-QUANWANG等: "A cyclometalated iridium(III) complex that induces apoptosis in cisplatin-resistant cancer cells", 《INORGANIC CHEMISTRY COMMUNICATIONS》 * |
| QIANG ZHAO等: "Tuning Photophysical and Electrochemical Properties of Cationic Iridium(III) Complex Salts with Imidazolyl Substituents by Proton and Anions", 《ORGANOMETALLICS》 * |
| SOUMIK MANDAL等: "Development of a cyclometalated iridium complex with specific intramolecular hydrogen-bonding that acts as a fluorescent marker for the endoplasmic reticulum and causes photoinduced cell death", 《DALTON TRANSACTIONS》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110423260A (en) * | 2019-07-12 | 2019-11-08 | 中山大学 | A kind of Cyclometalated iridium photosensitizer of glucose modified and its preparation method and application |
| CN110423260B (en) * | 2019-07-12 | 2022-08-02 | 中山大学 | Glucose-modified cyclometalated iridium photosensitizer and preparation method and application thereof |
| CN113583057A (en) * | 2021-09-07 | 2021-11-02 | 中山大学 | Efficient metal iridium complex and preparation method and application thereof |
| CN113583057B (en) * | 2021-09-07 | 2023-04-14 | 中山大学 | Efficient metal iridium complex and preparation method and application thereof |
| CN114057777A (en) * | 2021-11-18 | 2022-02-18 | 南方海洋科学与工程广东省实验室(湛江) | Beta-carboline derivative and preparation method and application thereof |
| CN116063372A (en) * | 2023-01-17 | 2023-05-05 | 齐齐哈尔医学院 | Mitochondria-targeted antitumor compound, and preparation method and application thereof |
| CN116425804A (en) * | 2023-04-04 | 2023-07-14 | 东莞市人民医院 | Cyclometalated iridium complex with anti-inflammatory and anti-tumor activities and preparation method and application thereof |
| CN116425804B (en) * | 2023-04-04 | 2023-09-29 | 东莞市人民医院 | Cyclometalated iridium complex with anti-inflammatory and anti-tumor activities and preparation method and application thereof |
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