CN110179803A - A kind of application of thioxanthene bromine class compound - Google Patents
A kind of application of thioxanthene bromine class compound Download PDFInfo
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- CN110179803A CN110179803A CN201910467327.2A CN201910467327A CN110179803A CN 110179803 A CN110179803 A CN 110179803A CN 201910467327 A CN201910467327 A CN 201910467327A CN 110179803 A CN110179803 A CN 110179803A
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- Prior art keywords
- thioxanthene
- cell
- class compound
- wwp1
- bromine class
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Abstract
The present invention relates to a kind of application of thioxanthene bromine class compound, by the WWP1 micromolecular compound inhibitor in-vitro screening system and albumen zymogram of foundation, circular dichroism spectra, in vitro from ubiquitination test experience find that the thioxanthene bromine class compound can effectively inhibit the interaction of ubiquitin ligase WWP1 Yu ubiquitin binding enzyme E2.By MTT experiment, LC3 Spot Jest, flow cytometry and cell scratch experiment the study found that cell growth, cell autophagy, Apoptosis and the cell migration ability of the thioxanthene bromine class compounds affect tumour cell.These can be used as the anti-tumor drug of targeting WWP1 the experimental results showed that the thioxanthene bromine class compound can effectively inhibit the ubiquitin ligase activity of WWP1, and then influence a variety of life process of cell.
Description
Technical field
The present invention relates to a kind of application of compound, especially a kind of application of thioxanthene bromine class compound.
Background technique
In vivo, protein participate in cell items physiological function, protein after functioning, generally require by
It removes in time.Ubiquitin-Proteasome Pathway and autophagy lysosomal pathway are two kinds of masters of the protein degradation in biological cell
Want mode, Ubiquitin-Proteasome Pathway can selectively, the protein of the degradation loss of function of specificity.Ubiquitination process is removed
It is also related to autophagy lysosomal pathway degradation pathway except the identification of mediation 26S proteasome and protein degradation matter.Egg in cell
The synthesis of white matter and a variety of vital movement phases such as degradation balance and genetic transcription, protein translation, signal transduction, growth and development
It closes, is the important mechanisms for maintaining cell homeostasis.
The disease cause of disease relevant to Ubiquitin-Proteasome Pathway is mainly the mutation of the key enzyme or substrate in the approach
(function forfeiture) leads to disease related protein accumulation or accelerated degradation.It is found by further investigation, tumorigenic generation and hair
The phenomenon that exhibition is assembled along with cell cycle exception, cancer suppressor protein excessive degradation, cancer protein, this phenomenon and uiquitin-protease
The inactivation or mutation of key enzyme or substrate are closely bound up in body approach.Therefore screening is with the key in Ubiquitin-Proteasome Pathway
Enzyme provides new strategy for the micromolecular inhibitor of target spot for the treatment of corresponding disease, becomes new research hotspot.
The ubiquitin chain type and length of ubiquitination, determine target protein by albumen in Ubiquitin-Proteasome Pathway
The different fate that other privileged sites function is degraded or be transferred to enzyme body.Ubiquitin ligase is determining protein ubiquitination
The key enzyme of type, ubiquitin chain length and structure has extremely important during the selectivity of target protein, specific recognition
Effect, therefore, ubiquitin ligase becomes the important target spot of Recent study and drug development.
WWP1 is one of numerous ubiquitin ligases in numerous human bodies, as a kind of carcinogen, a part of prostate cancer,
Overexpression in gastric cancer, breast cancer cell and leukaemia.The target protein of WWP1 reported at present have Smad2, ErbB4, KLF2,
P27, KLF5, T β RI, p63 etc..WWP1 can significantly inhibit the premature senescence of p27 induction by the p27 that degrades, and pass through the T β RI that degrades
Negative regulation TGF-β signal path promotes the occurrence and development of tumour by degradation KLF2, KLF5.The overexpression of WWP1 in a word, leads
Carcinogenic disease inhibiting factor excessive degradation, promotes the occurrence and development of cancer, this makes WWP1 become the target spot for treating associated cancer.
Summary of the invention
Technical problem to be solved by the present invention lies in provide a kind of application of thioxanthene bromine class compound.
The technical solution adopted by the present invention is that:
A kind of thioxanthene bromine class compound, it is characterised in that: be 1-Hexadecanaminium, N- [2- [[(4-
Methoxyphenyl) methyl] -2-pyrimidinylamino] ethyl]-N, N-dimethyl-, bromide (1:1), tool
There is structure shown in formula (I):
The screening technique of above-mentioned thioxanthene bromine class compound, the specific steps are as follows:
(1) it is coated with ubiquitin binding enzyme: buffer will be coated with carbonate to coating protein and be diluted to 80ng/100 μ L, and mixed
It is added in 96 orifice plates according to every 100 μ L of hole afterwards, 37 DEG C are incubated for 2h or 4 DEG C and are incubated overnight, and albumen is made to be attached to orifice plate bottom；
The closing of (2) 5% skim milks: milk in 96 orifice plates is outwelled, and 200 μ LPBST washing buffers are added, and level is shaken
Bed oscillation 5min, outwells and claps the liquid in clear opening, washed repeatedly 4 times with PBST；The every hole 80ng/100 μ L is added 150 μ L and uses
5% skim milk that PBS buffer solution is prepared, 37 DEG C of closing 2h；
(3) WWP1 is incubated for altogether with ubiquitin binding enzyme: milk in 96 orifice plates is outwelled, 200 μ LPBST washing buffers are added,
Horizontal shaker vibrates 5min, outwells and clap the liquid in clear opening, is washed repeatedly 4 times with PBST；With PBS buffer solution by WWP1 albumen
It is diluted to 364ng/100 μ L mixing, takes 300 μ L protein liquids that small molecule compound is diluted to 5 μm of ol/L, is pressed after being incubated for 10min
It is added in 96 orifice plates according to every 100 μ L of hole, 37 DEG C of incubation 2h；
(4) primary antibody is incubated for: liquid in 96 orifice plates being outwelled, 120 μ L PBST washing buffers, horizontal shaker oscillation is added
5min outwells and claps the liquid in clear opening, is washed repeatedly 4 times with PBST；It will be added with the diluted primary antibody of PBS according to every 100 μ L of hole
Enter in 96 orifice plates, 37 DEG C of incubation 2h；
(5) secondary antibody is incubated for: the primary antibody in 96 orifice plates being outwelled, 120 μ L PBST washing buffers, horizontal shaker vibration is added
5min is swung, the liquid in clear opening is outwelled and clap, is washed repeatedly 4 times with PBST；By the HRP secondary antibody diluted with PBS according to every hole
100 μ L are added in 96 orifice plates, and 37 DEG C are protected from light incubation 30min-1h；
(6) it develops the color: the secondary antibody in 96 orifice plates is outwelled, 120 μ L PBST washing buffers, horizontal shaker oscillation is added
5min, outwells and claps the liquid in clear opening, and PBST uses PBS instead after washing 3 times and washed once；By the A liquid and B liquid of TMB developing solution
After isometric mixing (matching while using), it is added in 96 orifice plates by every 100 μ L of hole；
(7) terminate: when liquid blue difference maximum in enzyme mark hole, the sulfuric acid that 100 μ L2mol/L are added terminates reaction；
(8) it detects: detecting the OD450 value in each hole with microplate reader.
Application of the above-mentioned thioxanthene bromine class compound in terms of preparing WWP1 inhibitor.
The thioxanthene bromine class compound can effectively inhibit the interaction of WWP1 and ubiquitin binding enzyme, WWP1 is inhibited to mediate
Ubiquitination process.
Application of the above-mentioned thioxanthene bromine class compound in terms of preparing the drug of related disease of WWP1 induction.
Preferably, the application of above-mentioned thioxanthene bromine class compound, the disease are tumor disease.
Preferably, the application of above-mentioned thioxanthene bromine class compound, the disease are breast cancer.
The thioxanthene bromine class compound can effectively inhibit the growth and migration of cancer cell.
The thioxanthene bromine class compound can effectively inhibit autophagy degradation pathway, can effectively accumulate autophagy correlation egg in cancer cell
White LC3.
The thioxanthene bromine class compound being capable of effective cancer cell specific induction of apoptosis.
The beneficial effects of the present invention are:
Above-mentioned thioxanthene bromine class compound can effectively inhibit the interaction of WWP1 and ubiquitin binding enzyme, and WWP1 is inhibited to mediate
Ubiquitination process.By MTT experiment, LC3 Spot Jest, flow cytometry and cell scratch experiment the study found that above-mentioned
Thioxanthene bromine class compound can influence growth, autophagy, apoptosis and the transfer ability of cancer cell.Above-mentioned thioxanthene bromine class compound can have
The protein degradation process that effect inhibits WWP1 to mediate, and then a variety of life process of cell are influenced, it can be used as the complete of targeting WWP1
Novel anti-tumor drug.
Detailed description of the invention
Fig. 1 is that WWP1 micromolecular inhibitor of the present invention screening System For Screening obtains thioxanthene bromine class compound of the present invention
As a result.As a result illustrate, the compound that number is S4355 is that thioxanthene bromine class compound of the present invention can effectively inhibit WWP1
With the interaction of ubiquitin binding enzyme.
Fig. 2 is that the present invention influences WWP1 from ubiquitination from ubiquitination experiment detection thioxanthene bromine class compound of the present invention
Result.As a result illustrate, the compound that number is S4355 is that thioxanthene bromine class compound of the present invention can effectively inhibit WWP1
From ubiquitination.
Fig. 3 is that MTT experiment of the present invention detects the result that thioxanthene bromine class compound of the present invention influences growth of cancer cells.
As a result illustrate, the compound that number is S4355 is that thioxanthene bromine class compound of the present invention can effectively inhibit cancer cell living
Power；
Fig. 4 is that cell scratch experiment of the present invention detects what thioxanthene bromine class compound of the present invention influenced cancer cell migration
As a result.As a result illustrate, the compound that number is S4355 is that thioxanthene bromine class compound of the present invention can effectively inhibit cancer thin
Born of the same parents' migration.
Fig. 5 is that GFP-LC3 Spot Jest of the present invention detects thioxanthene bromine class compound of the present invention to cancer cell autophagy shadow
Loud result.As a result illustrate, the compound that number is S4355 is that thioxanthene bromine class compound of the present invention can inhibit autophagy
Degradation pathway；
Fig. 6 is the knot that Flow cytometry of the present invention thioxanthene bromine class compound of the present invention influences cancer cell-apoptosis
Fruit.As a result illustrate, the compound that number is S4355 is that thioxanthene bromine class compound of the present invention can induce cancer cell and wither
It dies.
Specific embodiment
Below with reference to embodiment, the present invention is further described, but embodiment does not limit the scope of the invention.
Embodiment 1
(1) screening of thioxanthene bromine class compound
1. being coated with ubiquitin binding enzyme: buffer will be coated with carbonate to coating protein His-HA-UbcH7 and be diluted to
80ng/100 μ L is added in 96 orifice plates after mixing according to every 100 μ L of hole, and 37 DEG C are incubated for 2h or 4 DEG C and are incubated overnight, and keeps albumen attached
Arrive orifice plate bottom；
2. 5% skim milk is closed: milk in 96 orifice plates being outwelled, 200 μ L PBST washing buffers are added, level is shaken
Bed oscillation 5min, outwells and claps the liquid in clear opening, washed repeatedly 4 times with PBST；Every hole is added 150 μ L and is matched with PBS buffer solution
5% skim milk of system, 37 DEG C of closing 2h；
3. WWP1 is incubated for altogether with ubiquitin binding enzyme: milk in 96 orifice plates is outwelled, 200 μ L PBST washing buffers are added,
Horizontal shaker vibrates 5min, outwells and clap the liquid in clear opening, is washed repeatedly 4 times with PBST；WWP1 is truncated with PBS buffer solution
Body protein (GST-WW4-end) albumen is diluted to 364ng/100 μ L mixing, and 300 μ L protein liquids is taken to dilute small molecule compound
To 5 μm of ol/L, it is added in 96 orifice plates after being incubated for 10min according to every 100 μ L of hole, 37 DEG C of incubation 2h；
4. primary antibody is incubated for: liquid in 96 orifice plates being outwelled, 120 μ L PBST washing buffers, horizontal shaker oscillation is added
5min outwells and claps the liquid in clear opening, is washed repeatedly 4 times with PBST；After GST primary antibody is diluted by 1:10000 with PBS is dilute,
Every 100 μ L of hole is added in 96 orifice plates, 37 DEG C of incubation 2h；
5. secondary antibody is incubated for: the primary antibody in 96 orifice plates being outwelled, 120 μ L PBST washing buffers, horizontal shaker oscillation is added
5min outwells and claps the liquid in clear opening, is washed repeatedly 4 times with PBST；After HRP secondary antibody is pressed 1:20000 with PBS, every hole 100
μ L is added in 96 orifice plates, and 37 DEG C are protected from light incubation 30min-1h；
6. colour developing: the secondary antibody in 96 orifice plates being outwelled, 120 μ L PBST washing buffers, horizontal shaker oscillation is added
5min, outwells and claps the liquid in clear opening, and PBST uses PBS instead after washing 3 times and washed once；By the A liquid and B liquid of TMB developing solution
After isometric mixing (matching while using), it is added in 96 orifice plates by every 100 μ L of hole；
7. terminating: when liquid blue difference maximum in enzyme mark hole, the sulfuric acid that 100 μ L 2mol/L are added terminates reaction；
8. detection: detecting the OD in each hole with microplate reader450Value.Fig. 1 is the results show that number the compound for being S4355, as
After thioxanthene bromine class compound processing of the present invention, the Degree of interaction of WWP1 and ubiquitin binding enzyme weakens, and illustrates the present invention
The thioxanthene bromine class compound can effectively inhibit WWP1 with ubiquitin binding enzyme interaction.
(2) thioxanthene bromine class compound is to WWP1 from the influence of ubiquitination
GST-WW4-end from ubiquitination reaction system, as shown in table 1.
Table 1 is in vitro from ubiquitination experimental system
By table 1 by from each component in ubiquitination system it is ice bath melted after be added in EP pipe；EP pipe is set after mixing centrifugation
In 30 DEG C of water-bath 1h；7.5 μ L 5 × SDS albumen sample-loading buffers are added, 95 DEG C are boiled mixing centrifugation after 5min；Carry out Western
Blot detection.Fig. 2 the results show that after the processing of the compound that number is S4355, as thioxanthene bromine class compound of the present invention,
WWP1's dies down from ubiquitination band, illustrate effectively to inhibit Ji Wei thioxanthene bromine class compound of the present invention WWP1 from ubiquitin
Change.
(3) influence of the thioxanthene bromine class compound to cancer cell vigor
1. 96 orifice plate bed boards: collecting logarithmic phase MDA-MB-231 cell, adjust the concentration of cell suspension, 100 μ are added in every hole
L DMEM culture medium, bed board make 5000/hole of cell density to be measured.
2. the compound or DMSO that are utilized respectively various concentration (0,5,10,20,40 μM) handle cell 48 and 72h.
Continue to cultivate 4h 3. 20 μ L MTT (matching while using is configured to the MTT solution of 5mg/mL with PBS) is added in every hole.
4. terminating culture, the culture medium in hole is carefully sucked, is careful not to siphon away precipitating.
5. 200 μ L DMSO dissolution precipitating is added in every hole, low-speed oscillation 10min makes to crystallize abundant dissolution.
6. utilizing the absorbance (A in each hole under microplate reader detection 490nm wavelength490)。
7. cell viability=experimental group light absorption value/control group light absorption value.Fig. 3's the results show that the chemical combination that number is S4355
Object, thioxanthene bromine class compound as of the present invention can effectively inhibit cancer cell vigor.
(4) influence of the thioxanthene bromine class compound to cancer cell migration
1. appropriate MDA-MB-231 cell is inoculated in 6 orifice plates, 37 DEG C, be incubated overnight in 5%CO2 incubator；
2. when cell it is long to 60%-70% when, crossed along ruler perpendicular to culture dish with 200 μ L pipette tips, every 0.5-
1cm is in " well " font together；
Lower cell is drawn 3. being cleaned with DPBS, the fresh DMEM containing small molecule compound is added according to experimental design and cultivates
Base.It is placed in 37 DEG C, cultivates in 5%CO2 incubator；
It is tied 4. observing in drug-treated 0,12,24,48h and being tested in same position photographic analysis under the microscope respectively
Fruit.Fig. 4 is the results show that thioxanthene bromine class compound of the present invention can effectively inhibit cancer cell migration.
(5) influence of the thioxanthene bromine class compound to cancer cell autophagy
1. HeLa (GFP-LC3) cell and MDA-MB-231 cell of logarithmic phase are collected in digestion respectively；
2. adjusting concentration of cell suspension after being counted respectively with tally, HeLa (GFP-LC3) (includes by every 100 μ L of hole
5000-8000 cell) it is added in 96 orifice plates, MDA-MB-231 is by 500,000, every hole cell inoculation into 6 orifice plates；
3. filling 96 orifice plate rims holes with DPBS, two orifice plates are placed in 37 DEG C, 5%CO2It is incubated overnight in incubator；
4. old culture medium is replaced with the culture medium containing above compound or DMSO according to experimental design, in 37 DEG C, 5%
CO2Continue to cultivate in incubator；
HeLa 5. (GFP-LC3) cell respectively drug-treated 0,12, for 24 hours when utilize fluorescence microscope GFP-LC3
The formational situation of spot, and preservation of taking pictures；The albumen in MDA-MB-231 cell is extracted, is then detected using protein immunoblot
Autophagy GAP-associated protein GAP LC3 and p62 protein level.Fig. 5 is as of the present invention the results show that the compound that number is S4355
After the processing of thioxanthene bromine class compound,
GFP-LC3 assembles to form spot, and LC3, P62 increase, and illustrates that thioxanthene bromine class compound of the present invention can inhibit
Autophagy degradation pathway；
(6) Annexin V/PI detects influence of the thioxanthene bromine class compound to cancer cell-apoptosis
1. being inoculated with appropriate MDA-MB-231 cell in 6 orifice plates, orifice plate is placed in 37 DEG C, cultivates under the conditions of 5%CO2.
2. after cell is completely adherent, respectively for 24 hours with compound or the DMSO of equivalent processing cell.
3. collecting cell.Every hole adds 200 μ L without 0.25% trypsin digestion cell of EDTA.After the completion of digestion, every hole adds
1mL culture medium terminates digestion, is blown and beaten repeatedly with pipettor, is suspended in cell in culture medium.Then cell suspension is transferred to
In 1.5mL EP pipe.
4. 3000r/min is centrifuged 3min, discards upper layer culture medium, cell is resuspended with 1mL PBS.
5. 3000r/min is centrifuged 3min, cell, pipettor supernatant cleared as far as possible are collected.
6. cell is resuspended with 500 μ L binding buffer, pressure-vaccum for several times, becomes unicellular outstanding pipettor repeatedly
Liquid.It is separately added into 2 μ L Annexin V and PI dye liquors into EP pipe, is protected from light dyeing 15min.The blank control that dye liquor is not added is set
Only plus single sun of 2 μ L Annexin V or 2 μ L PI compares.
7. flow cytomery Apoptosis.Fig. 6 is the results show that the compound that number is S4355, institute as of the present invention
Stating thioxanthene bromine class compound can induce cancer cell-apoptosis.
The detailed description that above-described embodiment carries out a kind of application of the thioxanthene bromine class compound, be it is illustrative rather than
Limited, several embodiments, therefore the change in the case where not departing from present general inventive concept can be enumerated according to limited range
Change and modify, should belong within protection scope of the present invention.
Claims (4)
1. a kind of application of thioxanthene bromine class compound in terms of preparing WWP1 inhibitor, the thioxanthene bromine class compound has formula
(I) structure shown in:
2. application of the thioxanthene bromine class compound described in claim 1 in terms of preparing the drug of related disease of WWP1 induction.
3. the application of thioxanthene bromine class compound according to claim 2, it is characterised in that: the disease is tumor disease.
4. the application of thioxanthene bromine class compound according to claim 3, it is characterised in that: the disease is breast cancer.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170304387A1 (en) * | 2014-10-24 | 2017-10-26 | Launx Biomedical Co., Ltd. | New indication of antibiotic drugs for preparation of cancer inhibition pharmaceutical composition |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170304387A1 (en) * | 2014-10-24 | 2017-10-26 | Launx Biomedical Co., Ltd. | New indication of antibiotic drugs for preparation of cancer inhibition pharmaceutical composition |
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