CN105294458A - Antineoplastic small molecular compound and preparation method and application thereof - Google Patents
Antineoplastic small molecular compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides an antineoplastic small molecular compound and its preparation method and application. The compound is 3-(2-(([1,1'-biphenyl]-4-methylene)amino)ethyl)phenol; molecular formula is C21H21NO; structural formula is as shown in the specification. The preparation method comprises the following steps: 3-hydroxyphenylacetic acid and 4-bromobenzylamine hydrochloride which are used as raw materials undergo an acylation reaction to obtain N-(4-bromobenzyl)-2-(3-hydroxyphenyl)acetamide; and the N-(4-bromobenzyl)-2-(3-hydroxyphenyl)acetamide undergoes a substitution reaction, and a reduction reaction is finally carried out to obtain the compound. The compound has wide-spectrum antineoplastic activity and good permeability, can inhibit tumor cell proliferation and promote tumor cell apoptosis, has little toxic and side effect, has a simple structure, is easy to synthesize, lays a good foundation for development of new antineoplastic drugs and has an optimistic application prospect.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of anti-tumor small molecular compound and its preparation method and application.
Background technology
Malignant tumour is one of three large diseases of current harm humans health, although the mankind have developed the medicine of numerous killing tumor cell, and in the chemotherapy of tumour, played important effect, but this kind of medicine lacks selectivity to cell, while killing tumor cell, also killed and wounded normal cell, toxic side effect is very large.
Think at present, tumour is the propagation too much very few a kind of disease of apoptosis, if can the propagation of inhibition tumor cell, promotes its apoptosis, then can effective Tumor suppression process, has clear superiority compared with chemotherapy.Therefore, develop and can breed and promote the compound of its apoptosis by inhibition tumor cell, significant to the development of the treatment technology promoting malignant tumour.
Summary of the invention
The object of the present invention is to provide a kind of anti-tumor small molecular compound and its preparation method and application, this compound structure is simple, is easy to manufacture, and has good anti-tumor activity.
For achieving the above object, the technical solution used in the present invention is:
A kind of anti-tumor small molecular compound, this compound is 3-(2-(([1,1'-biphenyl]-4-methylene radical) is amino) ethyl) phenol, and molecular formula is C
21h
21nO, molecular structural formula is:
The preparation method of described anti-tumor small molecular compound, is characterized in that, comprises the following steps:
1) with a hydroxyl phenylacetic acid and 4-bromobenzylamine hydrochloride for raw material, obtain N-(4-bromobenzyl)-2-(3-hydroxyphenyl) ethanamide through acylation reaction;
2) N-(4-bromobenzyl)-2-(3-hydroxyphenyl) ethanamide and phenylo boric acid are substituted and are obtained by reacting N-([1,1'-biphenyl]-4-methylene radical)-2-(3-hydroxyphenyl) ethanamide;
3) N-([1,1'-biphenyl]-4-methylene radical)-2-(3-hydroxyphenyl) ethanamide obtains 3-(2-(([1,1'-biphenyl]-4-methylene radical) amino) ethyl through reduction reaction) phenol.
Described anti-tumor small molecular compound is preparing the application in antitumor drug.
Described antitumor drug is can breed and/or promote the medicine of apoptosis of tumor cells by inhibition tumor cell.
Described antitumor drug is the medicine that can suppress lung carcinoma cell, breast cancer cell, pancreatic cancer cell and hepatoma cell proliferation and/or promote lung carcinoma cell and Apoptosis of Breast Cancer.
Described antitumor drug is the medicine that can promote that in tumour cell, pro apoptotic protein is expressed and/or in inhibition tumor cell, inhibitor of apoptosis protein is expressed.
Described pro apoptotic protein is short apoptosis family protein Bak, and inhibitor of apoptosis protein is anti-apoptotic family protein Bcl-2 and Bcl-xl.
Described antitumor drug is the medicine that can promote that in tumour cell, DAN repair enzyme spliced body PARP expresses.
Described antitumor drug is 3-(2-(([1,1'-biphenyl]-4-methylene radical) amino) ethyl) phenol and the pharmaceutically medicine made of any one or a few auxiliary material and/or drug excipient.
The formulation of described antitumor drug comprises liquid preparation, tablet, electuary, soft capsule, soft capsule, sustained release dosage, dripping pill and injection, and its form of medication comprises oral administration and drug administration by injection.
Relative to prior art, beneficial effect of the present invention is:
The invention provides a kind of anti-tumor small molecular compound, this compound is 3-(2-(([1,1'-biphenyl]-4-methylene radical) amino) ethyl) phenol, this compound structure is simple, be easy to manufacture, and there is good anti-tumor activity, can be used in preparing antitumor drug, there is good potential applicability in clinical practice.
Further, through experimental verification in the present invention, demonstrate anti-tumor small molecular compound 3-(2-(([1 provided by the invention, 1'-biphenyl]-4-methylene radical) amino) ethyl) phenol has good anti-tumor activity, to different tumor cell line, there is significant inside and outside antitumor activity and promote the ability of apoptosis of tumor cells, there is broad-spectrum anti-tumor activity and good penetrability, toxic side effect is little, breed at Tumor suppression, promote there is good potential applicability in clinical practice in tumor death, good basis and optimistic application prospect have been established in development for new antitumor drug, for vast tumour patient brings glad tidings.
Further, anti-tumor small molecular compound provided by the invention a kind ofly has that inhibition tumor cell is raw breeds and promote the compound of apoptosis of tumor cells effect, can apply preparing in the medicines such as Hepatoma therapy, lung cancer, mammary cancer, carcinoma of the pancreas.This anti-tumor small molecular compound can with pharmaceutically any one or a few auxiliary material and/or drug excipient make medicine, its preparation can be any one formulation pharmaceutically allowed, include but not limited to liquid preparation, tablet, electuary, soft capsule, soft capsule, sustained release dosage, dripping pill or injection, its form of medication mainly comprises oral administration and drug administration by injection.
Further, anti-tumor small molecular compound provided by the invention can the propagation of inhibition tumor cell, there is stronger antitumor activity, illustrate that this anti-tumor small molecular compound has stronger specificity and higher security in the anti-cancer applications in future, it all has obvious inhibition to the propagation of lung carcinoma cell, breast cancer cell, pancreatic cancer cell and liver cancer cell.The mechanism of this anti-tumor small molecular compound Tumor suppression is by promoting that apoptosis of tumor cells realizes in addition, especially obvious to the promoter action of lung carcinoma cell and breast cancer cell generation apoptosis.
Further, anti-tumor small molecular compound provided by the invention can promote the expression of short apoptosis family protein Bak and DAN repair enzyme spliced body PARP (Cleaved), and the expression of anti-apoptotic family protein Bcl-2 and Bcl-xl can be suppressed, therefore this anti-tumor small molecular compound can suppress the expression of inhibitor of apoptosis protein simultaneously by promoting that pro apoptotic protein is expressed and cause tumour cell generation apoptosis.
Accompanying drawing explanation
Fig. 1 is that flow cytometer ANNEXIN-V/PI method detects anti-tumor small molecular compound HA-08 and affects result figure for apoptosis of tumor cells ability, wherein (a) is the blank assay control group of mammary cancer born of the same parents system MDA-MB-231, b () is that the HA-08 of 20 μMs affects result to mammary cancer born of the same parents system MDA-MB-231 is apoptotic, c () is that the HA-08 of 40 μMs affects result to mammary cancer born of the same parents system MDA-MB-231 is apoptotic, d blank assay control group that () is lung cancer cell line NCI-H1299, e () is that the HA-08 of 20 μMs affects result to lung cancer cell line NCI-H1299 is apoptotic, f () is that the HA-08 of 40 μMs affects result to lung cancer cell line NCI-H1299 is apoptotic, (g) be (a), (b), the statistics comparison diagram of (c), (h) be (d), (e), the statistics comparison diagram of (f).
Fig. 2 is that flow cytometer ANNEXIN-V/PI method affects result figure on apoptosis of tumor cells ability when detecting the independent or acting in conjunction of inhibitors of apoptosis ZVAD and anti-tumor small molecular compound HA-08, wherein (a) is blank assay control group, b () is for affecting result on apoptosis of tumor cells ability during HA-08 independent role, c () is for affecting result on apoptosis of tumor cells ability during ZVAD independent role, d () is for affecting result on apoptosis of tumor cells ability during HA-08 and ZVAD acting in conjunction, (e) be (a), (b), (c), the statistics comparison diagram of (d).
Fig. 3 is that Westernblot method detects anti-tumor small molecular compound HA-08 and affects result figure to apoptosis-related protein expression level in tumour cell, wherein (a) affects result to tumour cell A549 apoptosis-related protein expression level for HA-08, and (b) affects result to tumour cell NCl-H460 apoptosis-related protein expression level for HA-08.
Embodiment
Below the present invention is described in further details.
Anti-tumor small molecular compound provided by the invention is 3-(2-(([1,1'-biphenyl]-4-methylene radical) is amino) ethyl) phenol, and be numbered HA-08, concrete molecular formula is C
21h
21nO, molecular weight is 303.3975, and molecular structural formula is:
The preparation method of anti-tumor small molecular compound 3-provided by the invention (2-(([1,1'-biphenyl]-4-methylene radical) is amino) ethyl) phenol specifically comprises the following steps:
1, with a hydroxyl phenylacetic acid and 4-bromobenzylamine hydrochloride for raw material, obtain N-(4-bromobenzyl)-2-(3-hydroxyphenyl) ethanamide (compound 1) through acylation reaction, its reaction equation is as follows:
By 4-bromobenzylamine hydrochloride (1.335g, 6mmol), 1-ethyl-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCI) (0.69g, 3.6mmol), I-hydroxybenzotriazole (HoBt) (0.487g, 3.6mmol) and triethylamine (1.212g, 12mmol) stirring and dissolving in methylene dichloride, then 2 batches are divided to add a hydroxyl phenylacetic acid (0.456g, 3mmol), interval 15min.After adding, stirring at room temperature reaction 8h.After reacting completely, dchloromethane is added in system, wash once with the dilute hydrochloric acid of 0.5mol/L successively, water washing 3 times, saturated sodium-chloride washs 1 time, and organic phase is through anhydrous sodium sulfate drying, filter, revolve and steam except desolventizing, obtain N-(4-bromobenzyl)-2-(3-hydroxyphenyl) ethanamide 0.96g, MS (ESI): 320.3 (M+H).
2, N-(4-bromobenzyl)-2-(3-hydroxyphenyl) ethanamide (compound 1) and phenylo boric acid are substituted and are obtained by reacting N-([1,1'-biphenyl]-4-methylene radical)-2-(3-hydroxyphenyl) ethanamide (compound 2), its reaction equation is as follows:
By N-(4-bromobenzyl)-2-(3-hydroxyphenyl) ethanamide (0.96g, 3mmol), phenylo boric acid (0.367g, 3mmol), palladium catalyst (0.049g, 0.06mmol) all add reaction flask, then add the aqueous sodium carbonate 3mL of toluene and 2mol/L, use N
2air in replacement(metathesis)reaction liquid 3 times, reaction solution return stirring reaction 2h.After having reacted, reaction mixture is cooled to room temperature, adds diluted ethyl acetate, with rare HCl adjust ph to 4 of 1mol/L, water washing 2 times, saturated NaCl washs 1 time, obtains crude product after anhydrous sodium sulfate drying evaporate to dryness.Crude product, through column chromatography (sherwood oil: acetone=4:1 ~ 3:1) purifying, obtains N-([1,1'-biphenyl]-4-methylene radical)-2-(3-hydroxyphenyl) ethanamide 0.476g.MS(ESI):318.3(M+H)。
1HNMR(400MHz,DMSO-d
6)：δ9.32(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)。
3, N-([1,1'-biphenyl]-4-methylene radical)-2-(3-hydroxyphenyl) ethanamide (compound 2) obtains 3-(2-(([1 through reduction reaction, 1'-biphenyl]-4-methylene radical) amino) ethyl) phenol (compound 3), its reaction equation is as follows:
In the two-mouth bottle of the drying containing magneton, add N-([1,1'-biphenyl]-4-methylene radical)-2-(3-hydroxyphenyl) ethanamide (0.476g, 1.5mmol) and sodium borohydride (0.143,3.75mmol), airtight, N
2replacement(metathesis)reaction bottle 3 times, injects dry tetrahydrofuran (THF) 5mL, stirs and be cooled to 10 DEG C under ice bath.Slowly drip the iodine solution (0.381g, 1.5mmol) being dissolved in dry THF with constant pressure funnel, control to drip speed and too not fast.After dropwising, be warming up to return stirring reaction 3h.After having reacted, reaction solution ice bath is cooled to 10 DEG C, regulate pH to >10 by the NaOH solution of 1mol/L, extraction into ethyl acetate, organic phase washed with water 3 times, saturated NaCl washs 1 time, and anhydrous sodium sulfate drying is spin-dried for.Crude product is through silica column purification, and eluent is sherwood oil: acetone: triethylamine=1:1:0.5% (100mL elutriant adds 0.5mL triethylamine).3-(2-(([1,1'-biphenyl]-4-methylene radical) is amino) ethyl) phenol 0.40g is obtained, productive rate 87% after purifying.MS(ESI):304.3(M+H)。
1HNMR(400MHz,DMSO-d
6)：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)；
13CNMR(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。
Also by reference to the accompanying drawings the antitumous effect of anti-tumor small molecular compound HA-08 provided by the invention is described in detail below by specific experiment.
1, anti-tumor small molecular compound HA-08 is on the impact of tumour cell competence for added value
Adopt WST-1 method to detect the impact of HA-08 on kinds of tumor cells and normal cell competence for added value, selected cell is: lung cancer cell line NCI-H460, NCI-H1299, NCI-H292; Breast cancer cell line MDA-MB-231, MCF-7; Pancreatic carcinoma MIA-PaCa-2; Hepatoma cell line Huh-7; Colon carcinoma cell line HCT-8 and Chinese hamster ovary cell CHO.All cells is all inoculated in the RPMI1640 nutrient solution containing 10% foetal calf serum, is placed in the CO that volume fraction is 5%
2, temperature is cellar culture in the incubator of 37 DEG C.
Each clone of taking the logarithm vegetative period, is inoculated in 96 orifice plate overnight incubation by cell with the density of 5000 cells/well respectively.After cell attachment, micromolecular compound HA-08 is added in hand-hole with different concns (0,10,20,40,60 μm of ol/L).After 48 hours, every hole adds WST-110 μ L, puts into incubator, and 2 as a child took out, and were placed in microplate reader, detects the light absorption value (OD) at 450nm place.Inhibiting rate calculation formula is [1-OD (drug treating group)/OD (control group)] × 100%.Calculate HA-08 respectively to the half-inhibition concentration IC of each clone
50.
Result is as shown in table 1, and analytical results shows: (1) is (IC compared with normal cell system CHO
50>100), micromolecular compound HA-08 has stronger antitumor activity (average IC to tumour cell
50=40.3), HA-08 is in the anti-cancer applications in future in prompting, has stronger specificity and higher security.(2) HA-08 is to different tumour-specific all differences, to HA-08 the most responsive be lung carcinoma cell and breast cancer cell, the most insensitive is colon cancer cell, and the embody rule that this result can be HA-08 from now on provides good foundation.
Table 1HA-08 is on the impact of different tumor cell line multiplication capacity
IC
50(μM): half-inhibition concentration, unit: μM.
2, HA-08 promotes the experiment of apoptosis of tumor cells
The two dye experiment of application flow cytometer AnnexinV-PI detects micromolecular compound HA-08 to the impact of apoptosis of tumor cells ability: the mammary cancer in vegetative period of taking the logarithm and lung cancer cell line (MDA-MB-231, NCI-H1299) about 1 × 10
6individually jointly hatch 24h with the HA-08 of different concns respectively, collected by trypsinisation cell, PBS cleaning twice, adds the binding buffer liquid suspension cell of 300 μ L, after adding 5 μ LAnnexinV-FITC mixings, add 5 μ LPI reagent again, mixing, room temperature, lucifuge, reaction 15min, uses flow cytometry analysis result.Early stage at apoptosis, the phosphatidylserine (PS) in cytolemma by turning on one's side laterally in adipose membrane, AnnexinV can with its combination, and the cytolemma of apoptotic cell still keeps complete, and dyestuff PI can not enter cell and dye.In apoptosis late period, permeability of cell membrane changes, and dyestuff PI enters cell and is combined with nucleus and dyes.Therefore by the two dye experiment of AnnexinV-PI, the positive rate of AnnexinV adds up the percentage of apoptotic cell.
As shown in Figure 1, display HA-08 significantly can promote lung cancer, breast cancer cell generation apoptosis and in concentration dependent, namely along with the concentration of HA-08 increases, apoptosis of tumor cells ratio also increases to result.The drug treating group of each concentration is compared with control group, and its apoptosis ratio all has significant difference, p<0.001.
3, inhibitors of apoptosis ZVAD effectively can weaken the apoptosis-promoting effect of HA-08 to tumour cell.
Can the two dye test of application flow cytometer AnnexinV and WST-1 testing inspection inhibitors of apoptosis ZVAD effectively weaken the Hepetoma of HA-08.Concrete test method ditto described in, drug treating group is respectively HA-08 treatment group, ZVAD treatment group and HA-08+ZVAD treatment group.
As shown in Figure 2, display inhibitors of apoptosis ZVAD significantly can suppress the ability of HA-08 killing tumor cell to result, ZVAD itself to tumour cell without obvious lethal effect.
The result prompting of synthesizing map 1 and Fig. 2, HA-08 can the propagation of remarkable Tumor suppression, and the mechanism of its Tumor suppression is possibly via promoting apoptosis of tumor cells realization.
4, Westernblot method detects HA-08 to the impact of apoptosis-related protein expression level in tumour cell.
Classical protein immunoblotting method (WesternBlot) is adopted to detect the impact of HA-08 on apoptosis of tumor cells associated signal paths.After the HA-08 (0,5,10,20 μMs) of different concns acts on tumour cell A549 and NCI-H460 cell 24h respectively, abundant lysing cell makes protein sample and carries out protein immunoblotting reaction.Detect internal reference albumen Tubulin in two kinds of clones respectively, short apoptosis family protein Bak, the changing conditions of anti-apoptotic family protein Bcl-2, Bcl-xl and DAN repair enzyme spliced body PARP (Cleaved).
As shown in Figure 3, in two kinds of clones, the HA-08 of different concns does not all cause the expression level of Tubulin albumen to change to result; The expression level of anti-apoptotic family member Bcl-2, Bcl-xl can raise with HA-08 concentration and reduce; The expression level of short apoptosis family member Bak and PARP (Cleaved) can raise with HA-08 concentration and increase.Above result prompting HA-08 can suppress the expression of inhibitor of apoptosis protein simultaneously by promoting that pro apoptotic protein is expressed and cause tumour cell generation apoptosis.
Claims (10)
1. an anti-tumor small molecular compound, is characterized in that, this compound is 3-(2-(([1,1'-biphenyl]-4-methylene radical) is amino) ethyl) phenol, and molecular formula is C
21h
21nO, molecular structural formula is:
2. the preparation method of anti-tumor small molecular compound according to claim 1, is characterized in that, comprises the following steps:
1) with a hydroxyl phenylacetic acid and 4-bromobenzylamine hydrochloride for raw material, obtain N-(4-bromobenzyl)-2-(3-hydroxyphenyl) ethanamide through acylation reaction;
2) N-(4-bromobenzyl)-2-(3-hydroxyphenyl) ethanamide and phenylo boric acid are substituted and are obtained by reacting N-([1,1'-biphenyl]-4-methylene radical)-2-(3-hydroxyphenyl) ethanamide;
3) N-([1,1'-biphenyl]-4-methylene radical)-2-(3-hydroxyphenyl) ethanamide obtains 3-(2-(([1,1'-biphenyl]-4-methylene radical) amino) ethyl through reduction reaction) phenol.
3. anti-tumor small molecular compound according to claim 1 is preparing the application in antitumor drug.
4. apply as claimed in claim 3, it is characterized in that, described antitumor drug is can breed and/or promote the medicine of apoptosis of tumor cells by inhibition tumor cell.
5. apply as claimed in claim 4, it is characterized in that, described antitumor drug is the medicine that can suppress lung carcinoma cell, breast cancer cell, pancreatic cancer cell and hepatoma cell proliferation and/or promote lung carcinoma cell and Apoptosis of Breast Cancer.
6. as the application in claim 3-5 as described in any one, it is characterized in that, described antitumor drug is the medicine that can promote that in tumour cell, pro apoptotic protein is expressed and/or in inhibition tumor cell, inhibitor of apoptosis protein is expressed.
7. apply as claimed in claim 6, it is characterized in that, described pro apoptotic protein is short apoptosis family protein Bak, and inhibitor of apoptosis protein is anti-apoptotic family protein Bcl-2 and Bcl-xl.
8. as the application in claim 3-5 as described in any one, it is characterized in that, described antitumor drug is the medicine that can promote that in tumour cell, DAN repair enzyme spliced body PARP expresses.
9. as the application in claim 3-5 as described in any one, it is characterized in that, described antitumor drug is 3-(2-(([1,1'-biphenyl]-4-methylene radical) amino) ethyl) phenol and the pharmaceutically medicine made of any one or a few auxiliary material and/or drug excipient.
10. apply as claimed in claim 9, it is characterized in that, the formulation of described antitumor drug comprises liquid preparation, tablet, electuary, soft capsule, soft capsule, sustained release dosage, dripping pill and injection, and its form of medication comprises oral administration and drug administration by injection.
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| CN110894182A (en) * | 2018-09-30 | 2020-03-20 | 中南大学湘雅医院 | Anti-tumor compound aiming at Fyn-CD147 signal channel target spot and preparation method and application thereof |
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| CN110894182B (en) * | 2018-09-30 | 2022-07-19 | 中南大学湘雅医院 | Anti-tumor compound aiming at Fyn-CD147 signal channel target spot and preparation method and application thereof |
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