CN107417580A - One kind has the gossypol L arginine Schiff bases compounds and its synthetic method of antitumor activity - Google Patents
One kind has the gossypol L arginine Schiff bases compounds and its synthetic method of antitumor activity Download PDFInfo
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- CN107417580A CN107417580A CN201710815411.XA CN201710815411A CN107417580A CN 107417580 A CN107417580 A CN 107417580A CN 201710815411 A CN201710815411 A CN 201710815411A CN 107417580 A CN107417580 A CN 107417580A
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- gossypol
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- 0 C*C(C(CCCCC(**)C(N=C)=O)=C)=C Chemical compound C*C(C(CCCCC(**)C(N=C)=O)=C)=C 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a kind of gossypol L arginine Schiff bases compounds and its synthetic method with antitumor activity.Such compound obtains gossypol L arginine Schiff bases compounds using gossypol and L arginine as raw material, in ethanol as reaction synthesis under solvent.This method processing safety is high, and reaction condition is gentle, suitable for industrialized production.Show that the type compound has preferable antitumor activity through preliminary biological activity test, there are important medical applications to be worth.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular to one kind has gossypol-L-arginine Schiff of antitumor activity
Alkaloid compound and its synthetic method.
Background technology
The yellow polyhydric phenols that gossypol system is present in the organs such as seed, leaf, stem and the root of Malvaceae cotton cotton
Class compound, it is the inhibitor of Bcl-2 families anti-apoptotic proteins, it is effective is not only Bcl-2, Bcl-xL and BH3 binding pocket
Small molecule blocking agent, while can also be combined with Mcl-1 (Bcl-2 homologous protein).
Arginine can effectively improve immunity, promotion immune system secretes NK, in phagocyte, white blood cell
The endogenous materials such as alkene element (interleukin-1), are advantageous to inhibiting tumor cell and pre- preventing virus infection.In addition, arginine is
The precursorses of ornithine (L-ornithine) and proline (L-proline), proline are the important members for forming collagen
Element, supplement arginine largely organize the health of maintenance to protect for needs such as severe trauma, burns, have obvious help, have simultaneously
Having reduces the effect of infection and inflammation.
Schiff base compounds are because its unique architectural feature, i.e. core group contain the N atoms with lone pair electrons, so as to have
There is good pairing ability, and the group both sides can obtain the derivative that property differs with various types of radical reactions
Thing, this causes its great characteristic in practical application, is especially widely used in terms of chemistry, biology.
Schiff bases and its metal complex containing O, S, N, with its good antibacterial, anticancer and antiviral bioactivity one
Directly it is valued by people.Gossypol combines to form twin medicine with L-arginine, produces synergy, strengthens antitumor pharmacological activity.
Therefore, the author is raw material using L-arginine and gossypol, and design has synthesized the novel gossypol-L-arginine schiff bases of a class formation
Class compound.
The content of the invention
The present invention provides a class formation novel gossypol-L-arginine Schiff bases compound and its synthetic method.
The structure of compound of the present invention is as shown in formula I：
The technical scheme is that L-arginine and gossypol are used as raw material, with ethanol as solvent, what is be heated to reflux
Under the conditions of synthesized.
The synthetic route of the compound provided by the invention is as follows：
In order to realize said synthesis route, synthesis step of the invention is as follows：
(1) L-arginine and gossypol in molar ratio 2:1~3:1, alcohol organic solvent is added, fully dissolving adds catalytic amount
Lewis acid catalyst, back flow reaction at 50 DEG C~100 DEG C；
(2) mixed liquor of reaction system is filtered, washed with organic solvent to complete by thin-layer chromatography method tracking reaction while hot
Wash, filtrate stands crystallization and obtains gossypol-L-arginine schiff bases crude product；
(3) gossypol-L-arginine schiff bases crude product is added in reactor, adds organic solvent and recrystallized, mistake
Filter, is dried to obtain target product.
The preferred methanol of organic solvent, ethanol or isopropanol in above-mentioned steps (1), (2), (3), more preferably second
Alcohol.
The mol ratio of L-arginine and gossypol in above-mentioned steps (1) is 2:1~3:1, more preferably 2.5:1.
Reaction time in above-mentioned steps (1) is preferably 2 hours.
Preferably 60 DEG C~80 DEG C of temperature in above-mentioned steps (1).
The preferred glacial acetic acid of lewis acid catalyst, ZnCl in above-mentioned steps (3)2, p-methyl benzenesulfonic acid, more preferably ice
Acetic acid, preferably optimum amount are 2%~3%.
The advantages of this synthetic route, is：Raw material environmental protection, production cost is low, and processing safety is high, and reaction condition is gentle, instead
Raw material is answered to utilize abundant, suitable for industrialized production.
Embodiment：
With reference to specific embodiment, the present invention is further elaborated.Mesh of these embodiments merely for explanation
, and do not limit the scope of the invention and essence.
Embodiment 1
1.74g (10mmol) L-arginines and 2.07g (4mmol) gossypol are added into 100mL three-necked flasks, is dissolved in
In 50mL absolute ethyl alcohols, 3 drop glacial acetic acid are added, magnetic agitation makes it dissolve in 60 DEG C of water-baths, is reacted.TLC monitorings are anti-
Should, after the completion of raw material reaction, stand, separate out solid, filter residue is washed 3 times with ethanol, obtains crude product, recrystallized with absolute ethyl alcohol, is done
It is dry to obtain yellow solid 1.88g, yield 56.61%.
Yellow crystalline powder, M.P.182.3 DEG C1H-NMR(300MHz,DMSO-d6)δ(ppm):13.76(2H,s),12.32
(2H, s), 10.31 (2H, s), 9.94 (2H, s), 9.58 (2H, s), 9.46 (2H, s), 8.75 (4H, d, J=7.8Hz), 8.74
(2H, d, J=7.8Hz), 8.25 (2H, s), 7.81 (2H, s), 3.42 (2H, q, J=8.0Hz), 3.30 (2H, q, J=
8.0Hz), 2.87 (2H, m, J=7.8Hz), 2.78 (6H, s), 1.75 (4H, q, J=7.8Hz), 1.50 (4H, m, J=
7.8Hz), 1.33 (12H, d, J=7.8Hz)；13C-NMR(75MHz,DMSO-d6)δ(ppm):175.7,163.7,153.4,
146.1,153.4,146.1,144.1,132.5,130.7,128.7,119.0,117.4,112.2,109.7,101.4,55.5,
37.9,28.5,27.1,24.6,24.0；MS(ESI)for(M+H)+:831.4.
Embodiment 2
1.74g (10mmol) L-arginines and 2.07g (4mmol) gossypol are added into 100mL three-necked flasks, is dissolved in
In 50mL absolute methanols, 0.05g (0.2mmol) p-methyl benzenesulfonic acid is added, magnetic agitation makes it dissolve in 60 DEG C of water-baths,
Reacted.TLC monitoring reactions, after the completion of raw material reaction, are stood, separate out solid, and filter cake is washed 3 times with methanol, obtains crude product, is used
Absolute methanol recrystallizes, dry yellow solid 1.43g, yield 43.06%.
Embodiment 3
1.74g (10mmol) L-arginines and 2.07g (4mmol) gossypol are added into 100mL three-necked flasks, is dissolved in
In 50mL anhydrous propyl alcohols, 0.04g (0.2mmol) ZnCl is added2, magnetic agitation makes its dissolving in 80 DEG C of water-baths, is reacted
1h.TLC monitoring reactions, after the completion of raw material reaction, stand, separate out solid, filter residue is washed 3 times with ethanol, crude product is obtained, with anhydrous second
Alcohol recrystallizes, dry yellow solid 0.97g, yield 28.90%.
Embodiment 4
1.74g (8mmol) L-arginines and 2.07g (4mmol) gossypol are added into 100mL three-necked flasks, is dissolved in
In 50mL absolute ethyl alcohols, 0.04g (0.2mmol) ZnCl is added2, magnetic agitation makes it dissolve in 70 DEG C of water-baths, carries out anti-
Should.TLC monitoring reactions, after the completion of raw material reaction, stand, separate out solid, filter residue is washed 3 times with ethanol, crude product is obtained, with anhydrous second
Alcohol recrystallizes, dry yellow solid 0.65g, yield 19.40%.
Embodiment 5
The antitumor activity test of the compounds of this invention
Cytostatic to tumor cell experiment is carried out to the compound of the present invention, test method is using conventional mtt assay.
Cell line is selected：Human liver cancer cell (HepG2), human lung carcinoma cell (A-549), gastric carcinoma cells (SGC-7901).
Nutrient solution is that DMEM+15%NBS+ is dual anti-.
The preparation of sample liquid：After being dissolved with DMSO (Merck), add 100 μm of ol/L solution that PBS (-) is made into or
Uniform suspension, then with DMSO PBS (-) dilution, ultimate density is respectively 0.1,1,10,20,40,60,80,100 μ
mol/L。
The anti-fibroid medicine gossypol (acetate) of listing is made into reference substance solution with same condition.
Cell culture：Adherent growth tumor cell is incubated at containing 10% inactivation NBCS and penicillin, strepto-
In the 1640 culture medium of plain (each 1,000,000 U/L), 37 DEG C are placed in, 5%CO2, cultivate in the CO2gas incubator of saturated humidity.
Cell attachment is grown, and passes on 1 time within every 2~3 days, pours out nutrient solution first during passage, and PBS is washed 2 times, after pancreatin digestion, is added new
Fresh nutrient solution piping and druming is uniform, and adjustment cell to debita spissitudo is moved into new blake bottle, and addition nutrient solution is to appropriate.Take the logarithm
Growth period cell is used to test.
Mtt assay detects cytoactive and IC50Measure：
Experimental principle：The MTT of yellow can be reduced into bluish violet product not soluble in water by dehydrogenase in living cells mitochondria
Formazan (MTT formazan), and be deposited in cell, the amount of generation is directly proportional to number of viable cells, and dead cell is not this
Function.DMSO can dissolve bluish violet crystal, and shade is directly proportional to contained amount, therefore the light absorbs determined with ELIASA
Value can reflect cell survival rate.
Experimental method：Take the logarithm growth period cell, digestion, count, 96 well culture plates are inoculated in 2 × 104/mL density
In, per the μ l of hole 100.Culture 24 hours after, by testing compound with 0.1,1,10,20,40,60,80,100 μm of ol/L concentration at
Manage cell.The each concentration of experimental group sets 5 multiple holes, is compared with the nutrient solution containing 0.4%DMSO.After medicine acts on 48 hours,
Supernatant is removed, 100 μ l MTT (2- (4,5- dimethyl -2- thiazolyls) -3,5- diphenyl -2H- tetrazoliums hydrobromate) are added per hole
(1mg/mL), continue culture 4 hours, abandon supernatant, 100 μ l DMSO are added per hole, vibration is mixed, surveyed with ELIASA at 570nm
Absorbance is determined, using IC50Software for calculation obtains half-inhibition concentration (IC50)。
Result of the test refers to table 1, wherein, sample refers to the gossypol-L-arginine Schiff bases prepared in corresponding embodiment
Compound, sample number into spectrum correspondingly prepare the specific numbering of compound resulting in embodiment.
Half-inhibition concentration IC of the compound of table 1 to different tumour cells50(unit：μmol/L)
Good antitumor activity is shown in 3 kinds of cell lines of gossypol-L-arginine Schiff bases compound,
A549 in SCG-7901 cell lines with showing the antitumor activity better than gossypol.Above test result indicates that, it is of the invention
Compound has good antitumor activity, and its antitumor activity in specific cells strain is better than or be equal to gossypol, can be used for
The research and application of antineoplastic.
Claims (9)
1. the compound shown in structure formula (I),
2. compound according to claim 1, it is characterised in that：It is raw material by L-arginine and gossypol, it is organic in alcohols
Solvent under conditions of reaction dissolvent as being synthesized.
3. synthetic method according to claim 2, it is characterised in that synthetic route is as follows：
Specific preparation process is as follows：
(1) L-arginine and gossypol in molar ratio 2:1~3:1, alcohol organic solvent is added, fully dissolving adds the road of catalytic amount
Lewis acid catalyst, back flow reaction at 50 DEG C~100 DEG C；
(2) thin-layer chromatography method tracking reaction filters the mixed liquor of reaction system to complete while hot, with organic solvent washing,
Filtrate stands crystallization and obtains gossypol-L-arginine schiff bases crude product；
(3) gossypol-L-arginine schiff bases crude product is added in reactor, adds organic solvent and recrystallized, filtered, done
It is dry to obtain target product.
4. the synthetic method of gossypol according to claim 3-L-arginine Schiff bases compound, it is characterised in that：Institute
State the preferred methanol of organic solvent, ethanol or the isopropanol in step (1), (2), (3), more preferably ethanol.
5. the synthetic method of gossypol according to claim 3-L-arginine Schiff bases compound, it is characterised in that：On
The mol ratio for stating the L-arginine in step (1) and gossypol is 2:1~3:1, more preferably 2.5:1.
6. the synthetic method of gossypol according to claim 3-L-arginine Schiff bases compound, it is characterised in that：On
It is preferably 2 hours to state the reaction time in step (1).
7. the synthetic method of gossypol according to claim 3-L-arginine Schiff bases compound, it is characterised in that：On
State preferably 60 DEG C~80 DEG C of temperature in step (1).
8. the synthetic method of gossypol according to claim 3-L-arginine Schiff bases compound, it is characterised in that：On
State the preferred glacial acetic acid of lewis acid catalyst, ZnCl in step (3)2, p-methyl benzenesulfonic acid, more preferably glacial acetic acid, preferably
Optimum amount is 2%~3%.
9. application of the compound described in claim 1 in treatment liver cancer, lung cancer, gastric cancer medicament is prepared.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710815411.XA CN107417580A (en) | 2017-09-12 | 2017-09-12 | One kind has the gossypol L arginine Schiff bases compounds and its synthetic method of antitumor activity |
| US15/798,877 US9975849B1 (en) | 2017-03-27 | 2017-10-31 | Gossypol l-arginine schiff base compound with antitumor activities and a method of preparing the same |
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| CN201710815411.XA CN107417580A (en) | 2017-09-12 | 2017-09-12 | One kind has the gossypol L arginine Schiff bases compounds and its synthetic method of antitumor activity |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109180621A (en) * | 2018-08-01 | 2019-01-11 | 河南省锐达医药科技有限公司 | The preparation and the application in terms for the treatment of of cancer of a kind of New Schiff Base class compound |
| CN109942455A (en) * | 2019-03-10 | 2019-06-28 | 陕西科技大学 | Gossypol with anti-tumor activity-Eflornithine schiff base compounds and its synthetic method |
| CN112624942A (en) * | 2020-07-08 | 2021-04-09 | 陕西盘龙医药股份有限公司 | Gossypol isocyanate derivative with anti-leukemia activity and synthesis method thereof |
| CN114315673A (en) * | 2022-01-12 | 2022-04-12 | 陕西科技大学 | Gossypol-selenocysteine Schiff base compound and synthetic method and application thereof |
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| CN105503627A (en) * | 2015-12-10 | 2016-04-20 | 武汉大学 | Novel gossypol Schiff-base derivative and preparation and application thereof |
| CN105884634A (en) * | 2015-01-05 | 2016-08-24 | 南开大学 | Gossypol derivatives and preparation thereof, application of gossypol derivatives in pesticide and anti-cancer activity |
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Patent Citations (4)
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| CN102311449A (en) * | 2010-07-02 | 2012-01-11 | 中国科学院上海生命科学研究院 | Application of gossypol derivative to preparing anti-tumor medicament |
| CN103265560A (en) * | 2013-05-17 | 2013-08-28 | 上海中科高等研究院 | Gossypol/ cotton ketone derivative and preparation method thereof and application of derivative in anti-tumor medicament |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109180621A (en) * | 2018-08-01 | 2019-01-11 | 河南省锐达医药科技有限公司 | The preparation and the application in terms for the treatment of of cancer of a kind of New Schiff Base class compound |
| CN109942455A (en) * | 2019-03-10 | 2019-06-28 | 陕西科技大学 | Gossypol with anti-tumor activity-Eflornithine schiff base compounds and its synthetic method |
| CN112624942A (en) * | 2020-07-08 | 2021-04-09 | 陕西盘龙医药股份有限公司 | Gossypol isocyanate derivative with anti-leukemia activity and synthesis method thereof |
| CN112624942B (en) * | 2020-07-08 | 2024-04-02 | 陕西盘龙医药股份有限公司 | Gossypol isocyanate derivative with anti-leukemia activity and synthesis method thereof |
| CN114315673A (en) * | 2022-01-12 | 2022-04-12 | 陕西科技大学 | Gossypol-selenocysteine Schiff base compound and synthetic method and application thereof |
| CN114315673B (en) * | 2022-01-12 | 2024-05-28 | 陕西科技大学 | Gossypol-selenocysteine Schiff base compound and synthetic method and application thereof |
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Application publication date: 20171201 |