CN107095876B - Diphenyl joins application of the alkenyl phosphine oxide compound in preparation treatment lung-cancer medicament - Google Patents
Diphenyl joins application of the alkenyl phosphine oxide compound in preparation treatment lung-cancer medicament Download PDFInfo
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Abstract
The present invention discloses application of the diphenyl connection alkenyl phosphine oxide compound in preparation treatment lung-cancer medicament, especially application of compound (1- phenyl -1, the 2- allene -1- base) diphenyl phosphine oxide in preparation adenocarcinoma of lung and lung squamous cancer drug.This compound can inhibit the growth of lung cancer tumor cell well, and mechanism is related to having no toxic side effect by promoting autophagy and activation MAPK access to promote its apoptosis.
Description
Technical field
The invention belongs to biomedicine fields, more particularly, are related to diphenyl connection alkenyl phosphine oxide compound and control in preparation
Treat the application in lung-cancer medicament.
Background technique
Lung cancer is clinical common malignant tumour, and the lung cancer morbidity rate of women and the death rate account 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 in China.Although the treatment method of lung cancer is in sustained improvement, patient's prognosis is still very poor, according to stream
Row disease learns investigation display, and 5 years survival rates of lung cancer only have 16% from self diagnosis.Currently, the main means of lung cancer therapy have
Operation in early stage, radiation and chemotherapy.But since lung cancer lacks typical clinical symptom in early stage, the patient of about 70%-80% exists
Be advanced stage when making a definite diagnosis lung cancer, operative chance can be missed, and what can be performed the operation has an only 20%-30%, and up to 50% with
On patient have postoperative recurrence and transfer.Therefore most of patient, especially Patients with Advanced Lung Cancer, it still needs to use based on chemotherapy
Complex treatment, but the problem of most end-stage patients face recurrence and drug 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 hot spot of international tumor research.
Diphenyl connection alkenyl phosphine oxide compound belongs to the scope of connection vinyl compound, and connection vinyl compound contains 1,2- the third two
Alkene structure, the connection alkene of function dough usually 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 mostly extracts in natural products, arrives
So far, people have been successfully separated to obtain more than the 150 kinds of natural products molecules containing connection alkene structure, wherein most of displays
Good bioactivity out.Marine organisms are the important sources for extracting allenic compound, and 1996, domestic professor Lin Yongcheng led
Research first has been carried out to the metabolite of sea-plant " mangrove " the endogenetic fungus XylariasP at the South Sea, has therefrom isolated packet
More than 50 kinds of noval chemical compound including connection alkene are included, it has been investigated that some of them allenic compound has fabulous physiological activity.
But due to fewer by the amount of the resulting allenic compound of separation method, it is difficult to carry out extensive active testing and pharmacology is ground
The structure studied carefully, therefore refer to natural allenic compound carries out artificial synthesized being the important directions for studying such compound.This research makes
(1- phenyl -1,2- allene -1- base) diphenyl phosphine oxide is by synthesizing obtained new compound, preparation method ginseng
It examines: 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.Has document report in " Oncotarget " magazine within 2016
This compound can inhibit human epithelial ovarian carcinoma cells proliferation, and can enhance the chemotherapy effect of cis-platinum, induce oophoroma through a variety of ways
Apoptosis.But research and application of the compound in terms of lung cancer are not found by Chinese and English database retrieval, are still in
Space state.
Summary of the invention
The first purpose of this invention is to provide diphenyl connection alkenyl phosphine oxide compound in preparation treatment lung-cancer medicament
Application.
Second object of the present invention is to provide diphenyl connection alkenyl phosphine oxide compound in preparation induction tumour cell
LC3A/B protein expression increases the application in drug.
Third object of the present invention is to provide diphenyl connection alkenyl phosphine oxide compound and anti-tumor drug drug combination
Application in preparation treatment anti-tumor drug.
First purpose, the present invention disclose following technical scheme to realize the present invention: diphenyl joins alkenyl phosphine oxide compound
Application in preparation treatment lung-cancer medicament.
As a preferred embodiment, the structural formula of the diphenyl connection alkenyl phosphine oxide compound is as follows:
As a preferred embodiment, the lung cancer is adenocarcinoma of lung and lung squamous cancer.
Second purpose, the present invention disclose following technical scheme to realize the present invention: diphenyl joins alkenyl phosphine oxide compound
Increase the application in drug in the autophagy factor LC3A/B protein expression of preparation induction tumour cell, the diphenyl joins alkenyl oxygen
The structural formula of phosphine compound is as follows:
As a preferred embodiment, the tumour refers to adenocarcinoma of lung and lung squamous cancer.
Third purpose to realize the present invention, the present invention disclose following technical scheme: diphenyl joins alkenyl phosphine oxide compound
With application of the anti-tumor drug drug combination in preparation treatment anti-tumor drug, the diphenyl joins alkenyl phosphine oxide compound
Structural formula is as follows:
As a preferred embodiment, the tumour refers to adenocarcinoma of lung and lung squamous cancer.
As a preferred embodiment, the anti-tumor drug refers to platinum class, targeted drug and taxanes.
The such compound customary preparation methods system in this field can be used in diphenyl connection alkenyl phosphine oxide compound of the present invention
.CompoundName are as follows: (1- phenyl -1,2- allene -1- base) diphenyl phosphine oxide, abbreviation PHPO,
For details, reference can be made to Hao Guo, Rong Qian, Yinlong Guo, and Shengming for above compound preparation method
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 present invention has the advantages that this compound can inhibit the growth of lung cancer tumor cell well, mechanism is related to leading to
It crosses promotion autophagy and activation MAPK access promotes its apoptosis, have no toxic side effect.
Detailed description of the invention
Fig. 1 is inhibition of the compound PHPO of various concentration at each time point to the growth inhibition effect of lung cancer A549 cell
Rate figure.
Fig. 2 is growth inhibition effect of the compound PHPO of various concentration at each time point to lung cancer NCl-H520 cell
Inhibiting rate figure
Fig. 3 is that various concentration is the flow analysis chart that compound PHPO influences lung cancer A549 cell apoptosis.
Fig. 4 is that various concentration is the flow analysis chart that compound PHPO influences lung cancer NCl-H520 Apoptosis.
Fig. 5 is the immunofluorescence that PHPO influences lung cancer A549 cell autophagy factor LC3A/B.
Fig. 6 is the immunofluorescence that PHPO influences lung cancer NCl-H520 cell autophagy factor LC3A/B.
The western blot figure that Fig. 7 PHPO influences lung cancer A549 cell and NCl-H520 cell autophagy factor LC3A/B.
Fig. 8 is the flow analysis chart that PHPO group and PHPO combine chloroquine group influence lung cancer A549 cell apoptosis.
Fig. 9 is the flow analysis chart that PHPO group and PHPO combine chloroquine group influence lung cancer NCl-H520 Apoptosis.
Figure 10 is that PHPO group and PHPO combine chloroquine group and the column of lung cancer A549 cell proliferation inhibited to compare figure.
Figure 11 is that PHPO group and PHPO combine chloroquine group and influence that the column of lung cancer NCl-H520 cell Proliferation is inhibited to compare figure.
Figure 12 is the flow analysis chart that PHPO induces lung cancer A549 cell and lung cancer NCl-H520 cell G1 phase to block.
Figure 13 is the microscope figure that PHPO influences lung cancer A549 cell and lung cancer NCl-H520 cell migration.
Figure 14 is PHPO and control group influences the column that lung cancer A549 cell migrates and compares figure.
Figure 15 is PHPO and control group influences the column that lung cancer NCl-H520 cell migrates and compares figure.
Figure 16 is to inhibit in tumor growth assay, after control group and the treatment of PHPO group, human lung cancer A549 transplanted tumor in nude mice mould
The gross tumor volume of type with treatment time variation diagram.
Figure 17 is to inhibit in tumor growth assay, after control group and the treatment of PHPO group, human lung cancer NCl-H520 nude mice model
The gross tumor volume of tumor model with treatment time variation diagram.
Figure 18 is to inhibit in subcutaneous tumor A549 and NCl-H520 growth test, and each group is small after control group, the treatment of PHPO group
Mouse in-vivo tumour volume size compares figure.
Specific embodiment
Present invention will be further explained below with reference to specific examples.Experimental method used in following embodiments for example without
Specified otherwise is conventional method.The materials, reagents and the like used in the following examples unless otherwise specified can be from business way
Diameter obtains.It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
Embodiment
1. material and method
1.1, drug:[(1- phenyl -1,2- allene -1- base) diphenyl phosphine oxide, abbreviation PHPO],
For details, reference can be made to Hao Guo, Rong Qian, Yinlong Guo, and Shengming Ma.Neighboring for preparation method
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。
1.2, cell line: human lung adenocarcinoma cell line A549 (article No. HTB-77) and human lung squamous cell carcinoma cell line NCl-H520
(article No. HTB-182) is purchased from American Type Culture Collection Center (ATCC)；Cell line culture medium is RPMI1640, contains penicillin
100 μ g/mL of 100U/mL and streptomysin, 10% fetal calf serum (GIBCO product, 10099141), condition of culture be 37 DEG C, 5%
CO2, Thermo cell 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。
1.3, cytotoxicity experiment: cell measures the median lethal of cell with different pharmaceutical concentration under the different role time
Amount.
1.4, it Apoptosis assay: after cell treated with medicaments, is dyed with apoptosis staining kit, then uses fluidic cell
Technology analysis.
1.5, cell autophagy is tested: thin with streaming after cell uses PHPO, PHPO joint autophagy inhibitor chloroquine processing respectively
The situation of change of born of the same parents' instrument detection cell Proliferation and Apoptosis.
1.6, immunoblot experiment: protein immunoblot detects the change of related major protein in cell primary signal pathways
Change.
1.7, immunofluorescence experiment: the variation of related major protein in detection cell primary signal pathways.
1.8, it after cell cycle experimental cell treated with medicaments, is analyzed after dyeing with Flow Cytometry.
1.9, the side of the culture medium containing PHPO scratch experiment: is added after the adherent layer scratch of 6 porocyte culture plates
Formula measures influence of the PHPO to lung carcinoma cell transfer ability.
1.10, zoopery: with mice-transplanted tumor model inspection drug to the effect of growth and metastasis of tumours.
1.11, it statisticallys analyze: with the methods of card side, t inspection.
2. result
2.1, PHPO inhibits cell Proliferation
CCK-8 experiment is done with lung cancer cell line A549 and NCl-H520, detects the antiproliferative effect of PHPO.Use various concentration
After the PHPO of (being shown in Table 1) is handled 24 hours, 48 hours and 72 hours, cell activity is detected using CCK-8 experiment respectively, as a result table
Bright PHPO successfully inhibits the proliferation of cell in a manner of concentration dependant.And with the growth of time, IC of the PHPO to A549 cell50
Value also decline therewith.It is specifically shown in Fig. 1 and Fig. 2.Fig. 1-2 be respectively various concentration compound PHPO at each time point to lung cancer
The inhibiting rate figure of the growth inhibition effect of A549 cell and NCl-H520 cell sum.IC of the PHPO to two kinds of cell line50Numerical value is shown in
Table 1
Table 1.PHPO processing cell different time measures median lethal dose (IC50)
2.2, PHPO inducing apoptosis of tumour cell
In order to confirm PHPO to the apoptosis-promoting effect of lung carcinoma cell, after A549 the and NCl-H520 cell bis- 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
The ratio for surveying display mechanical damage is higher, detects so being changed to processing 24 hours).PHPO group 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 cell.The result shows that PHPO has promotion lung carcinoma cell
The effect (P < 0.05) of apoptosis, and act on strong and weak related to dosage.It is specifically shown in Fig. 3 and Fig. 4.Fig. 3-4 is being of various concentration
Closing object PHPO influences the flow analysis chart of lung cancer A549 and NCl-H520 Apoptosis.
2.3, PHPO can induce tumour cell autophagy
After being handled 24 hours with DMSO and PHPO respectively, Western Blot and Immunofluorescence test autophagy correlation egg are utilized
White LC3A/B.The results show that PHPO can induce the LC3A/B protein expression of A549 cell and NCl-H520 to increase (P < 0.05),
And be in dose-dependant, illustrate that PHPO can induce the LC3A/B protein expression of A549 and NCl-H520 cell to increase to promote to send out
It is born from and bites.It is specifically shown in Fig. 5-7.Fig. 5-6 is the LC3A/B that lung cancer A549 cell and NCl-H520 are detected using immunofluorescence experiment
Variation diagram.Fig. 7 is the LC3A/B variation diagram that lung cancer A549 cell and NCl-H520 are detected using Western blot.
2.4, PHPO inhibits proliferation of lung cancer cells by autophagy
Inhibit the effect in proliferation of lung cancer cells to verify autophagy in PHPO, is inhibited respectively with PHPO (40 μM) and autophagy
Agent chloroquine (Chloroquine, CQ, 5 μM) is handled A549 cell 24 hours, with (5 μM) processing NCl- of PHPO (25 μM) and CQ
H520 cell 24 hours.Apoptosis and cell Proliferation are detected using Annexin V/PI and CCK-8 method, as a result, it has been found that CQ can be with
The Apoptosis for significantly inhibiting PHPO induction, 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 lung carcinoma cell autophagy, Figure 10-11 are that CCK-8 method detects PHPO group and PHPO combines chloroquine
The column that group influences lung cancer A549 and NCl-H520 cell Proliferation compares figure.
2.5, PHPO induces the tumour cell G1 phase to block
Block to confirm that PHPO can induce the lung carcinoma cell G1 phase, by A549 cell and NCl-H520 cell RPMI1640
After complete culture solution and PHPO (respectively 40 μm of ol/L and 25 μm of ol/L) processing for 24 hours, by the cell of experimental group and control group point
It is not collected, after fixing cell pellet overnight with ice-cold ethanol, centrifugation 5min abandons upper layer ethyl alcohol, is resuspended respectively with PBS, with containing
Cell is resuspended in the PBS mixed liquor of 0.1%Triton X-100 and RNAse, and PI is added and is protected from light incubation 30 minutes, uses flow cytometer
It is tested and analyzed, specific experiment the result is shown in Figure 12.The result shows that PHPO has induction lung carcinoma cell G1Phase retardance effect (P <
0.05).Figure 12 is the flow analysis chart that PHPO induces lung cancer A549 cell and lung cancer NCl-H520 cell G1 phase to block.
2.6, PHPO can inhibit the migration of lung carcinoma cell
The control group and drug PHPO group of lung cancer A549, NCl-H520 are pasting after 6 porocyte culture plates cultures for 24 hours
Parietal cell layer vertically draws even width, consistent cell wound model with 10 μ L sample-adding pipette tips, then respectively contains PHPO addition
The isometric of not drug containing is added to group in the RPMI1640 culture medium (final concentration is respectively 35uM and 20uM) of 1% fetal calf serum
Culture solution (containing the DMSO with drug same dose) is calculated under optical microscopy after being incubated for 48h in cell incubator respectively
The width of each scratch.The result shows that PHPO has inhibiting effect (P < 0.05) to the migration of lung carcinoma cell.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 figure.Figure 14-15 is PHPO
The column for influencing lung cancer A549 cell and lung cancer NCl-H520 cell migration compares figure.
2.7PHPO inhibits external lung cancer tumor growth
Tumour cell quantity 5,000,000 is inoculated, gross tumor volume reaches 50mm after 1-2 weeks3When start to be administered, respectively
To DMSO, PHPO (30mg/kg), intraperitoneal injection is administered every other day.Every two days with vernier caliper measurement diameter of tumor, gross tumor volume
Calculation formula: gross tumor volume (mm3)=0.5 × major diameter (mm) × minor axis2(mm3).Weighing mouse weight is to evaluate PHPO within every two days
Toxicity.After experiment, all nude mice euthanasia, and measurement of tumor is stripped as early as possible.The results show that PHPO can significantly inhibit transplanting
The growth of tumor mouse tumor, and without overt toxicity.See that Figure 16-18, Figure 16-17 are different time tumour after injection drug and DMSO
The variation diagram of tissue.Figure 18 be to inhibit subcutaneous tumor A549 and NCl-H520 growth test in, control group, PHPO group treat after
Gross tumor volume compares figure.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
Member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications also should be regarded as
Protection scope of the present invention.
Claims (1)
1. diphenyl joins application of the alkenyl phosphine oxide compound in preparation treatment lung-cancer medicament, which is characterized in that the diphenyl
The structural formula for joining alkenyl phosphine oxide compound is as follows:The lung cancer is adenocarcinoma of lung and lung squamous cancer.
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