CN107095876A - Diphenyl joins application of the alkenyl phosphine oxide compound in treatment lung-cancer medicament is prepared - Google Patents
Diphenyl joins application of the alkenyl phosphine oxide compound in treatment lung-cancer medicament is prepared Download PDFInfo
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Abstract
The present invention discloses application of the diphenyl connection alkenyl phosphine oxide compound in treatment lung-cancer medicament is prepared, particularly application of compound (base of 11,2 allene of the phenyl 1) diphenyl phosphine oxide in adenocarcinoma of lung and lung squamous cancer medicine is prepared.This compound can suppress the growth of lung cancer tumor cell well, and mechanism is related to by promoting autophagy and activation MAPK paths to promote its apoptosis, had no toxic side effect.
Description
Technical field
The invention belongs to biomedicine field, more particularly, it is related to diphenyl connection alkenyl phosphine oxide compound and is controlled in preparation
Treat the application in lung-cancer medicament.
Background technology
Lung cancer is clinical common malignant tumour, and the lung cancer morbidity rate and the death rate of women is accounted in all malignant tumours
Second, male's morbidity and mortality hold pride of place.China is the first in the world lung cancer big country, adopts vigorous measures and prevents and treats lung cancer
As the current research emphasis of China.Although the treatment method of lung cancer is in sustained improvement, patient's prognosis is still very poor, according to stream
5 years survival rates of lung cancer only have 16% from row disease learns investigation display, self diagnosis.At present, the Main Means of lung cancer therapy have
Operation in early stage, radiation and chemotherapy.But because lung cancer is in early stage shortage typical clinical symptom, about 70%-80% patient exists
Be late period when making a definite diagnosis lung cancer, can miss operative chance, and can be performed the operation have an only 20%-30%, and up to 50% with
On patient have postoperative recurrence and transfer.Therefore most of patient, particularly Patients with Advanced Lung Cancer, still need to use based on chemotherapy
Complex treatment, but most end-stage patients are the problem of face recurrence and resistance.Therefore new chemotherapeutics is developed for lung cancer
Treatment it is significant.And inducing apoptosis of tumour cell is a key factor of chemotherapy medicine antitumor treatment, it has also become
One focus of international tumor research.
Diphenyl connection alkenyl phosphine oxide compound belongs to the category of connection vinyl compound, and connection vinyl compound contains 1,2- the third two
Alkene structure, the connection alkene of function dough generally shows extensive antibacterial, cell toxicant and enzyme inhibition activity, and the diphenyl of this research joins
Alkenyl phosphine oxide compound is exactly the allenic compound of function dough.The allenic compound of early stage is more to be extracted in natural products, is arrived
So far, people, which have been successfully separated, obtains the natural products molecule that kind more than 150 contains connection alkene structure, wherein most of displays
Go out good bioactivity.Marine organisms are the important sources for extracting allenic compound, and 1996, domestic professor Lin Yongcheng led
Research first has been carried out to sea-plant " mangrove " the endogenetic fungus XylariasP at South Sea metabolite, bag is therefrom isolated
Noval chemical compound kind more than 50 including connection alkene is included, it has been investigated that some of which allenic compound has fabulous physiologically active.
But because the amount of the allenic compound as obtained by separation method is fewer, it is difficult to carry out extensive active testing and pharmacology is ground
Study carefully, therefore it is the important directions for studying such compound that the structure for referring to natural allenic compound, which is carried out artificial synthesized,.This research makes
(1- phenyl -1,2- allene -1- bases) diphenyl phosphine oxide is by synthesizing obtained new compound, its preparation method ginseng
Examine:Hao Guo,Rong Qian,Yinlong Guo,and Shengming Ma.Neighboring Group
Participation of Phosphine Oxide Functionality in the Highly Regio-and
Stereoselective Iodohydroxylation of 1,2-Allenylic Diphenyl Phosphine
Oxides.J.Org.Chem.2008,73(20),7934-7938.2016《Oncotarget》The existing document report of magazine
This compound can suppress human epithelial ovarian carcinoma cells proliferation, and can strengthen the chemotherapy effect of cis-platinum, pass through number of ways inducing ovarian cancer
Apoptosis.But do not find research and application of the compound in terms of lung cancer by Chinese and English database retrieval, be still in
Space state.
The content of the invention
First purpose of the present invention is to provide diphenyl connection alkenyl phosphine oxide compound in treatment lung-cancer medicament is prepared
Application.
Second object of the present invention is that providing diphenyl connection alkenyl phosphine oxide compound is preparing induced tumor cell
LC3A/B protein expressions increase the application in medicine.
Third object of the present invention is to provide diphenyl connection alkenyl phosphine oxide compound and antineoplastic drug combination
Application in treatment antineoplastic is prepared.
To realize first purpose of the invention, the present invention discloses following technical scheme：Diphenyl joins alkenyl phosphine oxide compound
Application in treatment lung-cancer medicament is prepared.
As a preferred scheme, the structural formula of the diphenyl connection alkenyl phosphine oxide compound is as follows：
As a preferred scheme, the lung cancer is adenocarcinoma of lung and lung squamous cancer.
To realize second purpose of the invention, the present invention discloses following technical scheme：Diphenyl joins alkenyl phosphine oxide compound
Application in the autophagy factor LC3A/B protein expressions for preparing induced tumor cell increase medicine, the diphenyl joins alkenyl oxygen
The structural formula of phosphine compound is as follows：
As a preferred scheme, the tumour refers to adenocarcinoma of lung and lung squamous cancer.
To realize the 3rd purpose of the invention, the present invention discloses following technical scheme：Diphenyl joins alkenyl phosphine oxide compound
With application of the antineoplastic drug combination in treatment antineoplastic is prepared, the diphenyl joins alkenyl phosphine oxide compound
Structural formula is as follows：
As a preferred scheme, the tumour refers to adenocarcinoma of lung and lung squamous cancer.
As a preferred scheme, the antineoplastic refers to platinum class, targeted drug and taxanes.
Diphenyl connection alkenyl phosphine oxide compound of the present invention can use the such compound customary preparation methods system in this area
.CompoundBe named as：(1- phenyl -1,2- allene -1- bases) diphenyl phosphine oxide, abbreviation PHPO,
Above-claimed cpd preparation method for details, reference can be made to Hao Guo, Rong Qian, Yinlong Guo, and Shengming
Ma.Neighboring Group Participation of Phosphine Oxide Functionality in the
Highly Regio-and Stereoselective Iodohydroxylation of 1,2-Allenylic Diphenyl
Phosphine Oxides.J.Org.Chem.2008,73(20),7934-7938。
The advantage of the invention is that：This compound can suppress the growth of lung cancer tumor cell well, and mechanism is related to logical
Cross promotion autophagy and activation MAPK paths promote its apoptosis, have no toxic side effect.
Brief description of the drawings
Fig. 1 is suppression of the compound PHPO of various concentrations at each time point to the growth inhibition effect of lung cancer A549 cell
Rate figure.
Fig. 2 is the compound PHPO of various concentrations in growth inhibition effect of each time point to lung cancer NCl-H520 cells
Inhibiting rate figure
Fig. 3 is the flow cytometer showed figure for compound PHPO influence lung cancer A549 cell apoptosis of various concentrations.
Fig. 4 is the flow cytometer showed figure for compound PHPO influence lung cancer NCl-H520 Apoptosis of various concentrations.
Fig. 5 is the immunofluorescence figure that PHPO influences on lung cancer A549 cell autophagy factor LC3A/B.
Fig. 6 is the immunofluorescence figure that PHPO influences on lung cancer NCl-H520 cell autophagy factors LC3A/B.
The western blot figure that Fig. 7 PHPO influence on lung cancer A549 cell and NCl-H520 cell autophagy factors LC3A/B.
Fig. 8 is that PHPO groups and PHPO joint chloroquine groups influence the flow cytometer showed figure of lung cancer A549 cell apoptosis.
Fig. 9 is that PHPO groups and PHPO joint chloroquine groups influence the flow cytometer showed figure of lung cancer NCl-H520 Apoptosis.
Figure 10 is that the column that PHPO groups and PHPO joint chloroquine group suppression lung cancer A549 cells are bred compares figure.
Figure 11 is that the column that PHPO groups and PHPO joint chloroquine group influence suppression lung cancer NCl-H520 cells are bred compares figure.
Figure 12 is the flow cytometer showed figure that PHPO induces that lung cancer A549 cell and lung cancer NCl-H520 cell G1 phases block.
Figure 13 is the microscope figure of PHPO influence lung cancer A549 cells and lung cancer NCl-H520 cell migrations.
Figure 14 is PHPO and the column of control group influence lung cancer A549 cell migration compares figure.
Figure 15 is PHPO and the column of control group influence lung cancer NCl-H520 cell migrations compares figure.
Figure 16 is suppresses in tumor growth assay, after control group and the treatment of PHPO groups, human lung cancer A549 transplanted tumor in nude mice moulds
The gross tumor volume of type with treatment time variation diagram.
Figure 17 is suppresses in tumor growth assay, after control group and the treatment of PHPO groups, human lung cancer NCl-H520 nude mice models
The gross tumor volume of knurl model with treatment time variation diagram.
Figure 18 is suppresses in hypodermic tumour A549 and NCl-H520 growth test, and each group is small after control group, the treatment of PHPO groups
Mouse in-vivo tumour volume size compares figure.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.Experimental method used in following embodiments for example without
Specified otherwise, is conventional method.Material, reagent used etc. in following embodiments, unless otherwise specified, can be from business way
Footpath is obtained.It should be understood that these embodiments are only illustrative of the invention and is not intended to limit the scope of the invention.
Embodiment
1. material and method
1.1st, medicine：[(1- phenyl -1,2- allene -1- bases) diphenyl phosphine oxide, abbreviation PHPO],
Preparation method for details, reference can be made to Hao Guo, Rong Qian, Yinlong Guo, and Shengming Ma.Neighboring
Group Participation of Phosphine Oxide Functionality in the Highly Regio-and
Stereoselective Iodohydroxylation of 1,2-Allenylic Diphenyl Phosphine
Oxides.J.Org.Chem.2008,73(20),7934-7938。
1.2nd, cell line：Human lung adenocarcinoma cell line A549's (article No. is HTB-77) and human lung squamous cell carcinoma cell line NCl-H520
(article No. is HTB-182) is purchased from American Type Culture Collection center (ATCC)；Cell line culture medium is RPMI1640, containing penicillin
The 100U/mL and μ g/mL of streptomysin 100,10% hyclone (GIBCO products, 10099141), condition of culture is 37 DEG C, 5%
CO2, Thermo cell culture incubator.Bibliography：1.Song L,Li D,Gu Y,Wen Zm,Jie J,Zhao D,Peng
LP.MicroRNA-126targeting PIK3R2inhibits NSCLS A549cell proliferation,
migration,and invasion by regulation of PTEN/PI3K/AKT pathway.Clinical Lung
Cancer.2016Sep；15(5):e65-e75.2.Liu C,Huang X,Hou S,et al.Silencing of
tripartite motif(TRIM)29inhibits proliferation and invasion and increases
chemosensitivity to cisplatin in human lung squamous cancer NCI-H520cells.
[J].Thoracic Cancer,2014,6(1):31-7。
1.3rd, cytotoxicity experiment：Cell determines the median lethal of cell with different pharmaceutical concentration under different action times
Amount.
1.4th, Apoptosis assay：After cell treated with medicaments, dyed with apoptosis staining kit, then use fluidic cell
Technical Analysis.
1.5th, cell autophagy is tested：Cell is thin with streaming respectively with after PHPO, PHPO joint autophagy inhibitor chloroquine processing
The situation of change of born of the same parents' instrument detection cell propagation and Apoptosis.
1.6th, immunoblot experiment：The change of related major protein in protein immunoblot detection cell primary signal pathways
Change.
1.7th, immunofluorescence experiment:Detect the change of related major protein in cell primary signal pathways.
1.8th, after cell cycle experimental cell treated with medicaments, analyzed after dyeing with Flow Cytometry.
1.9th, scratch experiment：The side of the culture medium containing PHPO is added after the adherent layer cut of 6 porocyte culture plates
Formula determines influences of the PHPO to lung carcinoma cell transfer ability.
1.10, zoopery：With effect of the mice-transplanted tumor model inspection medicine to growth and metastasis of tumours.
1.11, statistical analysis：With methods such as card side, t inspections.
2. result
2.1st, PHPO suppresses cell propagation
CCK-8 experiments are made of lung cancer cell line A549 and NCl-H520, PHPO antiproliferative effect is detected.Use various concentrations
After the PHPO of (being shown in Table 1) is handled 24 hours, 48 hours and 72 hours, cytoactive is detected using CCK-8 experiments respectively, as a result table
Bright PHPO successfully suppresses the propagation of cell in the way of concentration dependant.And growth over time, ICs of the PHPO to A549 cells50
Value also decline therewith.It is specifically shown in Fig. 1 and Fig. 2.Fig. 1-2 be respectively various concentrations compound PHPO at each time point to lung cancer
The inhibiting rate figure of the growth inhibition effect of A549 cells and NCl-H520 cell sums.ICs of the PHPO to two kinds of cell line50Numerical value is shown in
Table 1
Table 1.PHPO processing cell different times measure median lethal dose (IC50)
2.2nd, PHPO inducing apoptosis of tumour cell
In order to confirm apoptosis-promoting effects of the PHPO to lung carcinoma cell, to A549 and NCl-H520 cells with after the double dyes of AV/PI
Do flow cytometer showed.(after handling 48 hours, control group and dosing group are examined for double dye detections after using DMSO and PHPO processing respectively 24 hours
Survey and show that the ratio of mechanical damage is higher, detected within 24 hours so making processing into).PHPO groups apoptosis and the toatl proportion of necrosis are obvious
Higher than control group, wherein being become apparent to the apoptosis-promoting effect of NCl-H520 cells.As a result show that PHPO has promotion lung carcinoma cell
Effect (the P of apoptosis<, and effect is strong and weak related to dosage 0.05).It is specifically shown in Fig. 3 and Fig. 4.Fig. 3-4 be various concentrations for change
Compound PHPO influences the flow cytometer showed figure of lung cancer A549 and NCl-H520 Apoptosis.
2.3rd, PHPO can be with induced tumor cell autophagy
After being handled 24 hours with DMSO and PHPO respectively, Western Blot and the related egg of Immunofluorescence test autophagy are utilized
White LC3A/B.As a result show, PHPO can induce A549 cells and NCl-H520 LC3A/B protein expressions to increase (P<0.05),
And in dose-dependant, illustrate that PHPO can induce the LC3A/B protein expressions of A549 and NCl-H520 cells to increase to promote hair
It is born from and bites.It is specifically shown in Fig. 5-7.Fig. 5-6 is to detect lung cancer A549 cell and NCl-H520 LC3A/B using immunofluorescence experiment
Variation diagram.Fig. 7 is to detect lung cancer A549 cell and NCl-H520 LC3A/B variation diagrams using Western blot.
2.4th, PHPO suppresses proliferation of lung cancer cells by autophagy
In order to verify effect of the autophagy in PHPO suppresses proliferation of lung cancer cells, suppressed respectively with PHPO (40 μM) and autophagy
Agent chloroquine (Chloroquine, CQ, 5 μM) processing A549 cells 24 hours, with (5 μM) processing NCl- of PHPO (25 μM) and CQ
H520 cells 24 hours.Apoptosis and cell propagation are detected using Annexin V/PI and CCK-8 method, as a result finds that CQ can be with
The Apoptosis of PHPO inductions is significantly inhibited, weakens the ability of its Inhibit proliferaton.It is specifically shown in Fig. 8-11.Fig. 8-9 is fluidic cell
The analysis chart that instrument detection PHPO influences on lung carcinoma cell autophagy, Figure 10-11 is that CCK-8 methods detect PHPO groups and PHPO joint chloroquines
Group compares figure to the column of lung cancer A549 and NCl-H520 cell proliferative effect.
2.5th, the PHPO induced tumors cell G1 phases block
In order to confirm that PHPO can induce the lung carcinoma cell G1 phases to block, by A549 cells and NCl-H520 cells RPMI1640
Complete culture solution and PHPO (being respectively 40 μm of ol/L and 25 μm of ol/L) are handled after 24h, by the cell of experimental group and control group point
Be not collected, fixed with ice-cold ethanol after cell pellet overnight, centrifugation 5min abandon upper strata ethanol, be resuspended respectively with PBS, with containing
Cell is resuspended in 0.1%Triton X-100 and RNAse PBS mixed liquors, adds PI lucifuges and is incubated 30 minutes, uses flow cytometer
Tested and analyzed, specific experiment result is shown in Figure 12.As a result show that PHPO has induction lung carcinoma cell G1Effect (the P of phase retardance<
0.05).Figure 12 is the flow cytometer showed figure that PHPO induces that lung cancer A549 cell and lung cancer NCl-H520 cell G1 phases block.
2.6th, PHPO can suppress the migration of lung carcinoma cell
The control group and medicine PHPO groups of lung cancer A549, NCl-H520 are after 6 porocyte culture plates culture 24h, in patch
Parietal cell layer vertically draws even width with 10 μ L sample-adding pipette tips, consistent cell wound model, then respectively adds PHPO and contains
The RPMI1640 culture mediums (final concentration is respectively 35uM and 20uM) of 1% hyclone, the isometric of not drug containing is added to group
Nutrient solution (containing the DMSO with medicine same dose), is incubated after 48h in cell culture incubator respectively, in measuring and calculating under light microscope
The width of each cut.As a result show, migrations of the PHPO to lung carcinoma cell has inhibitory action (P<0.05).Specific experiment result is shown in figure
13-15.Figure 13 is that PHPO influences lung cancer A549 cell and lung cancer NCl-H520 cell migration microscope figures.Figure 14-15 is PHPO
Influence lung cancer A549 cell and the column of lung cancer NCl-H520 cell migrations compare figure.
2.7PHPO suppresses external lung cancer tumor growth
Gross tumor volume reaches 50mm after subcutaneous vaccination tumour cell quantity 5,000,000,1-2 weeks3When start administration, respectively
To DMSO, PHPO (30mg/kg), intraperitoneal injection is administered every other day.Use vernier caliper measurement diameter of tumor, gross tumor volume within every two days
Calculation formula：Gross tumor volume (mm3)=0.5 × major diameter (mm) × minor axis2(mm3).Weigh mouse weight to evaluate PHPO within every two days
Toxicity.After experiment terminates, all nude mice euthanasia, and measurement of tumor is divested as early as possible.As a result show, PHPO can significantly inhibit transplanting
The growth of knurl mouse tumor, and without overt toxicity.It is different time tumour after injection medicine and DMSO to see Figure 16-18, Figure 16-17
The variation diagram of tissue.Figure 18 is to suppressing in hypodermic tumour A549 and NCl-H520 growth test, after control group, the treatment of PHPO groups
Gross tumor volume compares figure.
Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
Member, under the premise without departing from the principles of the invention, can also make some improvements and modifications, these improvements and modifications also should be regarded as
Protection scope of the present invention.
Claims (8)
1. diphenyl joins application of the alkenyl phosphine oxide compound in treatment lung-cancer medicament is prepared.
2. application of the diphenyl connection alkenyl phosphine oxide compound in treatment lung-cancer medicament is prepared according to claim 1, it is special
Levy and be, the structural formula of the diphenyl connection alkenyl phosphine oxide compound is as follows：
3. application of the diphenyl connection alkenyl phosphine oxide compound according to claim 1 or claim 2 in treatment lung-cancer medicament is prepared, its
It is characterised by, the lung cancer is adenocarcinoma of lung and lung squamous cancer.
4. diphenyl connection alkenyl phosphine oxide compound increases medicine in the autophagy factor LC3A/B protein expressions for preparing induced tumor cell
Application in thing, the structural formula of the diphenyl connection alkenyl phosphine oxide compound is as follows：
5. diphenyl connection alkenyl phosphine oxide compound according to claim 4 is preparing the autophagy factor of induced tumor cell
LC3A/B protein expressions increase the application in medicine, it is characterised in that the tumour refers to adenocarcinoma of lung and lung squamous cancer.
6. diphenyl joins application of the alkenyl phosphine oxide compound with antineoplastic drug combination in treatment antineoplastic is prepared,
The structural formula of the diphenyl connection alkenyl phosphine oxide compound is as follows：
7. diphenyl connection alkenyl phosphine oxide compound according to claim 6 is preparing treatment with antineoplastic drug combination
Application in antineoplastic, it is characterised in that the tumour refers to adenocarcinoma of lung and lung squamous cancer.
8. diphenyl connection alkenyl phosphine oxide compound according to claim 7 is preparing treatment with antineoplastic drug combination
Application in antineoplastic, it is characterised in that the antineoplastic refers to platinum class, targeted drug and taxanes.
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Cited By (1)
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