CN105294458B - A kind of anti-tumor small molecular compound and its preparation method and application - Google Patents
A kind of anti-tumor small molecular compound and its preparation method and application Download PDFInfo
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- CN105294458B CN105294458B CN201510790209.7A CN201510790209A CN105294458B CN 105294458 B CN105294458 B CN 105294458B CN 201510790209 A CN201510790209 A CN 201510790209A CN 105294458 B CN105294458 B CN 105294458B
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- PYIYAMKJBMSQNO-UHFFFAOYSA-N Oc1cc(CCNCc(cc2)ccc2-c2ccccc2)ccc1 Chemical compound Oc1cc(CCNCc(cc2)ccc2-c2ccccc2)ccc1 PYIYAMKJBMSQNO-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention provides a kind of anti-tumor small molecular compound and its preparation method and application, the compound is 3 (2 (([1,1' biphenyl] 4 methylene) amino) ethyl) phenol, and molecular formula is C21H21NO, structural formula is：
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of anti-tumor small molecular compound and preparation method thereof and should
With.
Background technology
Malignant tumour is one of three big diseases of current harm human health, and it is swollen that although the mankind have been developed for numerous killings
The medicine of oncocyte, and played an important role in the chemotherapy of tumour, but this kind of medicine lacks selectivity to cell, kills
While hindering tumour cell, normal cell is also killed, toxic and side effect is very big.
It is now recognized that tumour is a kind of propagation excessively very few disease of apoptosis, if the propagation of tumour cell can be suppressed,
Promote its apoptosis, then can effectively suppress tumor progression, be had a clear superiority compared with chemotherapy.Therefore, developing can suppress swollen
Tumor cell proliferation and the compound for promoting its apoptosis, it is significant to promoting the development for the treatment of technology of malignant tumour.
The content of the invention
It is an object of the invention to provide a kind of anti-tumor small molecular compound and its preparation method and application, the compound
It is simple in construction, it is easy to prepared by production, and with good antitumor activity.
To reach above-mentioned purpose, the technical solution adopted by the present invention is：
A kind of anti-tumor small molecular compound, the compound is 3- (2- (([1,1'- biphenyl] -4- methylene) amino) second
Base) phenol, molecular formula is C21H21NO, molecular structural formula is：
The preparation method of described anti-tumor small molecular compound, it is characterised in that comprise the following steps：
1) using a hydroxyl phenylacetic acid and 4- bromobenzylamine hydrochlorides as raw material, by acylation reaction obtain N- (4- bromobenzyls)-
2- (3- hydroxyphenyls) acetamide；
2) N- (4- bromobenzyls) -2- (3- hydroxyphenyls) acetamides and phenyl boric acid are substituted reaction and obtain N- ([1,1'- connection
Benzene] -4- methylene) -2- (3- hydroxyphenyls) acetamide；
3) N- ([1,1'- biphenyl] -4- methylene) -2- (3- hydroxyphenyls) acetamides through reduction reaction obtain 3- (2- (([1,
1'- biphenyl] -4- methylene) amino) ethyl) phenol.
Application of the described anti-tumor small molecular compound in antineoplastic is prepared.
Described antineoplastic is the medicine that can suppress tumor cell proliferation and/or promote apoptosis of tumor cells.
Described antineoplastic increases for that can suppress lung carcinoma cell, breast cancer cell, pancreatic cancer cell and liver cancer cells
Grow and/or promote lung carcinoma cell and the medicine of Apoptosis of Breast Cancer.
Described antineoplastic is that pro apoptotic protein in tumour cell can be promoted to express and/or suppress in tumour cell
The medicine of anti-apoptotic proteins expression.
Described pro apoptotic protein for promote apoptosis family protein Bak, anti-apoptotic proteins be anti-apoptotic family protein Bcl-2 and
Bcl-xl。
Described antineoplastic is that can promote the medicine that DAN repair enzymes spliced body PARP is expressed in tumour cell.
Described antineoplastic is for 3- (2- (([1,1'- biphenyl] -4- methylene) amino) ethyl) phenol and pharmaceutically
The medicine that any one or a few auxiliary material and/or drug excipient are made.
The formulation of described antineoplastic includes liquid preparation, tablet, electuary, soft capsule, soft capsule, sustained release agent, drop
Ball and injection, its form of medication include being administered orally and drug administration by injection.
Relative to prior art, beneficial effects of the present invention are：
The invention provides a kind of anti-tumor small molecular compound, the compound is that ((([1,1'- biphenyl] -4- is sub- by 2- by 3-
Methyl) amino) ethyl) phenol, the compound structure is simple, it is easy to prepared by production, and with good antitumor activity, can
For preparing antineoplastic, with good potential applicability in clinical practice.
Further, experimental verification is passed through in the present invention, it was demonstrated that the anti-tumor small molecular compound 3- of the invention provided
(2- (([1,1'- biphenyl] -4- methylene) amino) ethyl) phenol has good antitumor activity, to different tumor cell lines
Ability with significant inside and outside antitumor activity and promotion apoptosis of tumor cells, with broad-spectrum anti-tumor activity and permeability
Good, toxic and side effect is small, is suppressing tumor proliferation, is promoting have good potential applicability in clinical practice in tumor death, is new antitumor
Good basis and optimistic application prospect have been established in the development of medicine, are that vast tumor patient brings glad tidings.
Further, the anti-tumor small molecular compound that the present invention is provided is that one kind has suppression tumour cell life propagation simultaneously
Promote the compound of apoptosis of tumor cells effect, can be answered in the medicines such as treatment liver cancer, lung cancer, breast cancer, cancer of pancreas are prepared
With.Medicine can be made with pharmaceutically any one or a few auxiliary material and/or drug excipient in the anti-tumor small molecular compound,
Its preparation can be any one formulation pharmaceutically allowed, including but not limited to liquid preparation, tablet, electuary, soft capsule, soft
Capsule, sustained release agent, dripping pill or injection, its form of medication mainly include being administered orally and drug administration by injection.
Further, the anti-tumor small molecular compound that provides of the present invention can suppress the propagation of tumour cell, with compared with
Strong antitumor activity, illustrates that the anti-tumor small molecular compound has in following anti-cancer applications stronger specific and higher
Security, its propagation to lung carcinoma cell, breast cancer cell, pancreatic cancer cell and liver cancer cells, which all has, obvious suppresses effect
Really.The mechanism that the other anti-tumor small molecular compound suppresses tumour is realized by promoting apoptosis of tumor cells, to lung cancer
The facilitation that apoptosis occurs for cell and breast cancer cell is especially apparent.
Further, the anti-tumor small molecular compound that the present invention is provided can promote apoptosis family protein Bak and DAN
Repair enzyme spliced body PARP (Cleaved) expression, and can suppress anti-apoptotic family protein Bcl-2 and Bcl-xl expression,
Therefore the anti-tumor small molecular compound can by promote pro apoptotic protein expression and meanwhile suppress anti-apoptotic proteins expression and
Tumour cell is caused to occur apoptosis.
Brief description of the drawings
Fig. 1 is that flow cytometer ANNEXIN-V/PI methods detect anti-tumor small molecular compound HA-08 for tumour cell
The influence result figure of apoptosis capacity, wherein (a) is breast cancer born of the same parents system MDA-MB-231 blank assay control group, (b) is 20 μM
HA-08 to the influence result of breast cancer born of the same parents system MDA-MB-231 Apoptosis, (c) is to breast cancer born of the same parents for 40 μM of HA-08
The influence result of MDA-MB-231 Apoptosis, (d) is lung cancer cell line NCI-H1299 blank assay control group, and (e) is 20
μM HA-08 to the influence result of lung cancer cell line NCI-H1299 Apoptosis, (f) is 40 μM of HA-08 to lung cancer cell line
The influence result of NCI-H1299 Apoptosis, (g) is (a), (b), the statistics comparison diagram of (c), and (h) is (d), (e), (f)
Statistics comparison diagram.
Fig. 2 is that flow cytometer ANNEXIN-V/PI methods detect inhibitors of apoptosis ZVAD and anti-tumor small molecular compound
Influence result figure when HA-08 is separately or cooperatively acted on to apoptosis of tumor cells ability, wherein (a) is blank assay control group,
(b) influence result when for HA-08 independent roles to apoptosis of tumor cells ability, (c) is thin to tumour when being ZVAD independent roles
The influence result of born of the same parents' apoptosis capacity, influence result when (d) is HA-08 and ZVAD collective effects to apoptosis of tumor cells ability,
(e) it is (a), (b), (c), the statistics comparison diagram of (d).
Fig. 3 is that Western blot methods detect anti-tumor small molecular compound HA-08 to apoptosis correlation egg in tumour cell
The influence result figure of white expression, wherein (a) is influences of the HA-08 to tumour cell A549 apoptosis-related protein expressions
As a result, (b) is influence results of the HA-08 to tumour cell NCl-H460 apoptosis-related protein expressions.
Embodiment
The present invention is described in further details below.
The anti-tumor small molecular compound that the present invention is provided is 3- (2- (([1,1'- biphenyl] -4- methylene) amino) second
Base) phenol, numbering is HA-08, and specific molecular formula is C21H21NO, molecular weight is 303.3975, and molecular structural formula is：
The anti-tumor small molecular compound 3- (2- (([1,1'- biphenyl] -4- methylene) amino) ethyl) that the present invention is provided
The preparation method of phenol specifically includes following steps：
1st, using a hydroxyl phenylacetic acid and 4- bromobenzylamine hydrochlorides as raw material, by acylation reaction obtain N- (4- bromobenzyls)-
2- (3- hydroxyphenyls) acetamide (compound 1), its reaction equation is as follows：
By 4- bromobenzylamine hydrochlorides (1.335g, 6mmol), 1- ethyls-(3- dimethylaminopropyls)-carbodiimide hydrochloride
Salt (EDCI) (0.69g, 3.6mmol), I-hydroxybenzotriazole (HoBt) (0.487g, 3.6mmol) and triethylamine (1.212g,
12mmol) the stirring and dissolving in dichloromethane, then divides hydroxyl phenylacetic acid (0.456g, 3mmol) between 2 batches of additions, interval
15min.After adding, reaction 8h is stirred at room temperature.After reaction completely, dchloromethane is added into system, 0.5mol/ is used successively
L watery hydrochloric acid be washed once, water washing 3 times, and saturated sodium-chloride is washed 1 time, and organic phase is filtered through anhydrous sodium sulfate drying, rotation
Solvent is evaporated off, N- (4- bromobenzyls) -2- (3- hydroxyphenyls) acetamide 0.96g, MS (ESI) is obtained:320.3(M+H).
2nd, N- (4- bromobenzyls) -2- (3- hydroxyphenyls) acetamide (compound 1) and phenyl boric acid are substituted reaction and obtain N-
([1,1'- biphenyl] -4- methylene) -2- (3- hydroxyphenyls) acetamide (compound 2), its reaction equation is as follows：
By N- (4- bromobenzyls) -2- (3- hydroxyphenyls) acetamide (0.96g, 3mmol), phenyl boric acid (0.367g, 3mmol),
Palladium catalyst (0.049g, 0.06mmol) all adds reaction bulb, adds toluene and 2mol/L aqueous sodium carbonate 3mL,
Use N2Air in displacement reaction solution 3 times, reaction solution return stirring reaction 2h.Reactant mixture is cooled to room after having reacted
Temperature, adds ethyl acetate dilution, adjusts pH value to 4 with 1mol/L dilute HCl, water washing 2 times, saturation NaCl is washed 1 time, anhydrous
Sodium sulphate drying obtains crude product after being evaporated.Crude product is through column chromatography (petroleum ether：Acetone=4:1~3:1) purify, obtain N- ([1,1'- connection
Benzene] -4- methylene) -2- (3- hydroxyphenyls) acetamide 0.476g.MS(ESI):318.3(M+H).
1H NMR(400MHz,DMSO-d6)：δ 9.32 (d, J=2.1Hz, 1H), 8.55 (t, J=6.0Hz, 1H), 7.67-
7.57(m,4H),7.50–7.41(m,2H),7.39–7.28(m,3H),7.13–7.04(m,1H),6.74–6.59(m,3H),
4.34–4.25(m,2H),3.41–3.37(m,2H)。
3rd, N- ([1,1'- biphenyl] -4- methylene) -2- (3- hydroxyphenyls) acetamides (compound 2) are obtained through reduction reaction
3- (2- (([1,1'- biphenyl] -4- methylene) amino) ethyl) phenol (compound 3), its reaction equation is as follows：
In the two-mouth bottle of the drying containing magneton, N- ([1,1'- biphenyl] -4- methylene) -2- (3- hydroxyphenyls) is added
Acetamide (0.476g, 1.5mmol) and sodium borohydride (0.143,3.75mmol), closed, N2Replace reaction bulb 3 times, injection is dry
Stirring is cooled to 10 DEG C under dry tetrahydrofuran (THF) 5mL, ice bath.The iodine for being dissolved in dry THF is slowly added dropwise with constant pressure funnel
Solution (0.381g, 1.5mmol), control drop speed should not be too fast.After completion of dropping, return stirring reaction 3h is warming up to.React
Reaction solution ice bath is cooled to 10 DEG C afterwards, with 1mol/L NaOH solution adjust pH to>10, ethyl acetate extraction, organic phase is used
Water washing 3 times, saturation NaCl is washed 1 time, and anhydrous sodium sulfate drying is spin-dried for.Crude product is purified through silicagel column, and eluant, eluent is oil
Ether：Acetone：Triethylamine=1：1：0.5% (100mL eluents add 0.5mL triethylamines).Obtaining 3- after purification, ((([1,1'- joins 2-
Benzene] -4- methylene) amino) ethyl) phenol 0.40g, yield 87%.MS(ESI):304.3(M+H).
1H NMR(400MHz,DMSO-d6)：δ9.23(s,1H),7.69–7.55(m,5H),7.49–7.31(m,5H),
7.04 (t, J=7.7Hz, 1H), 6.65-6.52 (m, 3H), 3.74 (s, 2H), 2.67 (dd, J=15.5,6.3Hz, 4H)；
13C NMR(101MHz,DMSO)：δ157.66,142.27,140.66,140.51,138.81,129.56,
129.31,128.92,127.63,126.95,126.82,119.63,115.85,113.20,52.92,50.84,36.33。
The anti-tumor small molecular compound HA-08's provided below by specific experiment and with reference to accompanying drawing the present invention is anti-swollen
Knurl effect is described in detail.
1st, influences of the anti-tumor small molecular compound HA-08 to tumour cell competence for added value
Influences of the HA-08 to kinds of tumor cells and normal cell competence for added value, selected cell line are detected using WST-1 methods
For：Lung cancer cell line NCI-H460, NCI-H1299, NCI-H292；Breast cancer cell line MDA-MB-231, MCF-7；Cancer of pancreas
Cell line MIA-PaCa-2；Liver cancer cell lines Huh-7；Colon carcinoma cell line HCT-8 and Chinese hamster ovary cell CHO.Institute
There is cell to be inoculated in the RPMI1640 nutrient solutions containing 10% hyclone, be placed in the CO that volume fraction is 5%2, temperature
For cellar culture in 37 DEG C of incubators.
Take the logarithm each cell line in growth period, cell is inoculated in the training of 96 orifice plates with the density of 5000 cells/wells respectively
Support overnight.After after cell attachment, by micromolecular compound HA-08 with various concentrations (0,10,20,40,60 μm of ol/L) add hole
In.After 48 hours, WST-110 μ L are added per hole, incubator are put into, 2 as a child took out, be placed at ELIASA, detection 450nm
Light absorption value (OD).Inhibiting rate computing formula is [1-OD (drug-treated group)/OD (control group)] × 100%.HA-08 is calculated respectively
To the half-inhibition concentration IC of each cell line50。
As a result as shown in table 1, analysis result is shown：(1) (the IC compared with normal cell system CHO50>100), small molecule chemical combination
Thing HA-08 has stronger antitumor activity (average IC to tumour cell50=40.3), HA-08 is pointed out in following anti-cancer applications,
There is stronger specific and higher security.(2) HA-08 is most sensitive to HA-08 to different tumour-specific all differences
Be lung carcinoma cell and breast cancer cell, least sensitive is colon cancer cell, the result can for HA-08 from now on concrete application
Good foundation is provided.
Influences of the HA-08 of table 1 to different tumor cell line multiplication capacities
IC50(μM):Half-inhibition concentration, unit：μM.
2nd, HA-08 promotes the experiment of apoptosis of tumor cells
Using the double dye experiment detection micromolecular compound HA-08 of flow cytometer Annexin V-PI to apoptosis of tumor cells
The influence of ability：Take the logarithm the breast cancer and lung cancer cell line (MDA-MB-231, NCI-H1299) about 1 × 10 in growth period6Individual point
It is not incubated 24h jointly with the HA-08 of various concentrations, collected by trypsinisation cell, PBS twice, delay by the combination for adding 300 μ L
Fliud flushing suspension cell, adds after 5 μ L Annexin V-FITC mixings, adds 5 μ L PI reagents, mix, room temperature, lucifuge, instead
15min is answered, flow cytometry analysis result is used.In Apoptosis in early days, in cell membrane phosphatidylserine (PS) is by adipose membrane
Laterally, Annexin V can be in connection, and the cell membrane of apoptotic cell still keeps complete, and dyestuff PI can not enter for interior rollover
Cell is dyed.In Apoptosis late period, permeability of cell membrane is changed, and dyestuff PI is combined dye with nucleus into cell
Color.Therefore it can be tested by the double dyes of Annexin V-PI, Annexin V positive rate counts the percentage of apoptotic cell.
As a result as shown in figure 1, display HA-08 can remarkably promote lung cancer, breast cancer cell occur apoptosis and in concentration according to
Lai Xing, i.e., with HA-08 concentration increase, apoptosis of tumor cells ratio also increases.The drug-treated group and control group of each concentration
Compare, its apoptosis ratio has significant difference, p<0.001.
3rd, inhibitors of apoptosis ZVAD can effectively weaken apoptosis-promoting effects of the HA-08 to tumour cell.
Can be effective using the double dye experiments of flow cytometer Annexin V and WST-1 testing inspection inhibitors of apoptosis ZVAD
Weaken HA-08 Hepetoma.Specific test method is the same as those described above, and drug-treated group is respectively HA-08 treatment groups, ZVAD processing
Group and HA-08+ZVAD treatment groups.
As a result as shown in Fig. 2 display inhibitors of apoptosis ZVAD can significantly inhibit the ability of HA-08 killing tumor cells,
ZVAD is in itself to tumour cell without obvious lethal effect.
Complex chart 1 and Fig. 2 result prompting, HA-08 can significantly inhibit the propagation of tumour, and it suppresses the mechanism of tumour very
It may be by promoting what apoptosis of tumor cells was realized.
4th, influences of the Western blot methods detection HA-08 to apoptosis-related protein expression in tumour cell.
Detect that HA-08 is believed apoptosis of tumor cells correlation using classical protein immunoblotting method (Western Blot)
The influence of number path.The HA-08 (0,5,10,20 μM) of various concentrations is respectively acting on tumour cell A549 and NCI-H460 cell
After 24h, abundant cell lysis makes protein sample and carries out protein immunoblotting reaction.Internal reference in two kinds of cell lines is detected respectively
Albumen Tubulin, promotees apoptosis family protein Bak, anti-apoptotic family protein Bcl-2, Bcl-xl and DAN repair enzyme spliced body
PARP (Cleaved) situation of change.
As a result as shown in figure 3, the HA-08 of various concentrations does not cause the expression water of Tubulin albumen in two kinds of cell lines
It is flat to change；Anti-apoptotic family member Bcl-2, Bcl-xl expression can be raised and reduced with HA-08 concentration；Promote apoptosis
Family member Bak and PARP (Cleaved) expression can be raised and increased with HA-08 concentration.Result above points out HA-
08 can be by promoting pro apoptotic protein expression while suppressing the expression of anti-apoptotic proteins and causing tumour cell to occur apoptosis.
Claims (10)
1. a kind of anti-tumor small molecular compound, it is characterised in that the compound is 3- (2- (([1,1'- biphenyl] -4- methylenes
Base) amino) ethyl) phenol, molecular formula is C21H21NO, molecular structural formula is：
2. the preparation method of the anti-tumor small molecular compound described in claim 1, it is characterised in that comprise the following steps：
1) using a hydroxyl phenylacetic acid and 4- bromobenzylamine hydrochlorides as raw material, N- (4- bromobenzyls) -2- (3- are obtained by acylation reaction
Hydroxyphenyl) acetamide；
2) N- (4- bromobenzyls) -2- (3- hydroxyphenyls) acetamides and phenyl boric acid are substituted reaction and obtain N- ([1,1'- biphenyl] -4-
Methylene) -2- (3- hydroxyphenyls) acetamide；
3) N- ([1,1'- biphenyl] -4- methylene) -2- (3- hydroxyphenyls) acetamides obtain 3- (2- (([1,1'- through reduction reaction
Biphenyl] -4- methylene) amino) ethyl) phenol.
3. application of the anti-tumor small molecular compound described in claim 1 in antineoplastic is prepared.
4. application as claimed in claim 3, it is characterised in that described antineoplastic is that can suppress tumor cell proliferation
And/or promote the medicine of apoptosis of tumor cells.
5. application as claimed in claim 4, it is characterised in that described antineoplastic is that can suppress lung carcinoma cell, breast
Adenocarcinoma cell, pancreatic cancer cell and hepatoma cell proliferation and/or the medicine for promoting lung carcinoma cell and Apoptosis of Breast Cancer.
6. the application as described in any one in claim 3-5, it is characterised in that described antineoplastic is to promote
The medicine of pro apoptotic protein expression and/or suppression tumour cell moderate resistance expression of apoptosis protein in tumour cell.
7. application as claimed in claim 6, it is characterised in that described pro apoptotic protein resists to promote apoptosis family protein Bak
Apoptotic proteins are anti-apoptotic family protein Bcl-2 and Bcl-xl.
8. the application as described in any one in claim 3-5, it is characterised in that described antineoplastic is to promote
The medicine that DAN repair enzymes spliced body PARP is expressed in tumour cell.
9. the application as described in any one in claim 3-5, it is characterised in that described antineoplastic is 3- (2-
(([1,1'- biphenyl] -4- methylene) amino) ethyl) phenol and medicine that pharmaceutically any one or a few auxiliary material is made.
10. application as claimed in claim 9, it is characterised in that the formulation of described antineoplastic include tablet, electuary,
Soft capsule, soft capsule, sustained release agent, dripping pill and injection, its form of medication include being administered orally and drug administration by injection.
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