CN113509459A - Application of flavane compound in preparing anti-tumor medicine - Google Patents

Application of flavane compound in preparing anti-tumor medicine Download PDF

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CN113509459A
CN113509459A CN202010272671.9A CN202010272671A CN113509459A CN 113509459 A CN113509459 A CN 113509459A CN 202010272671 A CN202010272671 A CN 202010272671A CN 113509459 A CN113509459 A CN 113509459A
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cancer
methylflavan
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CN113509459B (en
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李军
胡仲冬
屠鹏飞
陈孝男
赵亚楠
杨爱琳
庞道然
苏小琴
霍会霞
田颖颖
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Beijing University of Chinese Medicine
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Abstract

The invention discloses an application of a flavane compound in preparing an anti-tumor medicament.

Description

Application of flavane compound in preparing anti-tumor medicine
Technical Field
The invention relates to an application of flavane compounds in preparing anti-tumor medicaments.
Background
Tumor, a disease seriously harming human health, has an increasing incidence and mortality rate year by year in recent years due to aging of social population, compact pace of life of young people, increased working pressure and development of bad lifestyle habits. The related statistical data of China shows that the number of deaths caused by tumors exceeds that of cardiovascular diseases, and the deaths become the first cause of death of urban and rural residents at present. The research on tumor resistance is a big problem faced by the medical field and a major problem to be solved urgently in society, and the promotion of research and development of tumor biology and tumor treatment drugs is urgent. Research in recent years shows that the search for novel antitumor drugs from natural products has wide prospects and great potential.
The sanguis Draxonis is prepared from resin exuded from fruit of Daemonorops draco Bl. of Palmae, is resin obtained by extracting lipid-containing wood of Dracaena cochinchinenis (Lour) S.C.Chen of Dracaena of Liliaceae with ethanol, and has pharmacological activities in promoting blood circulation, removing blood stasis, relieving inflammation and pain, promoting granulation, healing sore, and regulating immunity. Because the curative effects of the dragon's blood and the dragon's blood are obvious, the dragon's blood and the dragon's blood are gradually paid attention to by people, and the dragon's blood are more and more widely applied to clinical treatment. It is mainly used for cardiovascular diseases, digestive system diseases, diabetes and complications, dermatological diseases, gynecological diseases, and anorectal diseases.
Related researches find that the dracorhodin separated from the dragon's blood can induce the glioma cell U251 and the neuroblastoma cell SH-SY5Y to undergo apoptosis by activating MAPK signal channels. The 75% ethanol extraction part of the dragon's blood can inhibit the proliferation of human bile duct cancer cells, and can induce the human bile duct cancer cell lines HCCC9810 and QBC939 to be subjected to apoptosis by activating apoptosis-promoting proteins such as Caspase-8, PARP, Bax and the like. In addition, the 75% ethanol extraction part of the dragon blood can also inhibit the growth of tumors in a nude mouse bile duct cancer transplantation tumor model. The stilbene compounds are 4', 5-dihydroxy-3-methoxystilbene and other than pterostilbeneResveratrol can inhibit the proliferation of human melanoma cell HSC-1, and has the relationship of time effect and dose effect. 4', 5-dihydroxy-3-methoxystilbene and resveratrol in IC50The effect of 72 hours under the concentration can obviously promote the apoptosis of HSC-1 cells, block the cell cycle and effectively inhibit the proliferation of cancer cells in vitro, which is one of the anticancer action mechanisms.
Sanguis Draxonis contains lourerin A, lourerin B, flag leaf lourerin B, flavones, high isoflavanones, flavone oligomers, flavonoid compounds, flavan compounds, etc. CN105153100A discloses a preparation method and application of flavonoid compounds in dragon's blood; the flavonoid compound is separated from sanguis Draxonis and has basic skeleton of 4' -hydroxybenzyl chromane, wherein compound 1 is new compound, and compounds 2 and 3 are known compounds. The compound was named: the compound 1 is 5, 8-dimethoxy-7-hydroxy-4 ' -hydroxybenzyl chromane, the compound 2 is 4-methoxy-7-hydroxy-4 ' -hydroxybenzyl chromane, and the compound 3 is 7-hydroxy-4 ' -hydroxybenzyl chromane; the flavonoid compound has the capability of promoting differentiation of MSCs to osteoblasts, and has potential effect of treating osteoporosis. CN108017609A discloses a flavane monomer compound which is (2S) -6, 4' -dihydroxy-5-methoxy flavane, and the flavane monomer compound can be used for preparing medicines with antidiabetic effect, liver protection effect and antitumor effect.
At present, no significant cytotoxic activity of dragon blood or flavan compounds in dragon blood is found.
Disclosure of Invention
In view of the above, the present invention aims to provide an application of a flavane compound in the preparation of an anti-tumor medicament, wherein the flavane compound can effectively inhibit the proliferation of tumor cells, has a cytotoxic effect on at least eleven types of tumor cells, and has strong universality.
The invention adopts the following technical scheme to achieve the purpose.
The invention provides an application of a flavane compound in preparing an anti-tumor medicament, wherein the flavane compound has a structure shown in a formula I:
Figure BDA0002443665360000021
wherein:
R1is selected from-H or-CH3；
R2Is selected from-OH or-OCH3；
R3Is selected from-H or-CH3；
R4Selected from-H, -OH or-OCH3；
R5Is selected from-H or-OH;
R6is selected from-H or-OCH3or-OCH2CH3；
R7Is selected from-H or-OH;
R8selected from-H, -OH or-OCH3(ii) a And
R9is selected from-H or-OH;
at the same time, when R2is-OH and R4is-OCH3When R is1、R5、R6、R7、R8、R9At least one of which is not-H.
In the present invention, preferably, in the flavanoid compound, R1Is selected from-H or-CH3，R2is-OH, R3Is selected from-H or-CH3，R4is-OCH3，R5is-H, R6is-OCH3，R7is-H, R8is-H, and R9is-H.
In the present invention, preferably, in the flavanoid compound, R1Is selected from-H or-CH3，R2Is selected from-OH or-OCH3， R3is-H, R4Is selected from-H or-OCH3，R5is-H, R6is-H, R7Selected from-H or-OH, R8Is selected from-OH or-OCH3And R is9is-H.
In the present invention, preferably, the flavanoid compound is selected from one or more of the following compounds:
5-hydroxy-7-methoxyflavan (compound 1);
(2R) -7-hydroxy-2, 5-dimethoxy-6-methylflavan (Compound 2);
(2S) -7-hydroxy-2, 5-dimethoxy-6-methylflavan (Compound 3);
(2R) -7-hydroxy-2, 5-dimethoxy-6, 8-dimethylflavan (Compound 4);
(2S) -7-hydroxy-2, 5-dimethoxy-6, 8-dimethylflavan (Compound 5);
7-hydroxy-2, 5-dimethoxy-8-methylflavan (compound 6);
7, 6' -dihydroxy-5-methoxy-6-methylflavan (compound 7);
3, 7-dihydroxy-2-ethoxy-5-methoxy-6-methylflavan (compound 8);
7-hydroxy-4' -methoxyflavan (compound 9);
(2R) -7, 4' -dihydroxy-8-methylflavan (compound 10);
4' -hydroxy-5, 7-dimethoxy-8 methylflavan (compound 11);
(2R) -4' -hydroxy-5, 7-dimethoxyflavan (Compound 12);
(2R) -7,3 '-dihydroxy-4' -methoxy-8-methylflavan (compound 13);
(2R) -5, 7-dihydroxy-4' -methoxy-8-methylflavan (compound 14); or
(2R) -7,3 '-dihydroxy-4' -methoxyflavan (Compound 15).
In the present invention, more preferably, said flavanoid compound is selected from one or more of the following compounds:
(2S) -7-hydroxy-2, 5-dimethoxy-6-methylflavan (Compound 3);
4' -hydroxy-5, 7-dimethoxy-8 methylflavan (compound 11);
(2R) -4' -hydroxy-5, 7-dimethoxyflavan (Compound 12);
(2R) -7,3 '-dihydroxy-4' -methoxy-8-methylflavan (compound 13);
(2R) -5, 7-dihydroxy-4' -methoxy-8-methylflavan (compound 14); or
(2R) -7,3 '-dihydroxy-4' -methoxyflavan (Compound 15).
In the present invention, it is further preferred that said flavanoid compound is selected from one or more of the following compounds:
(2R) -4' -hydroxy-5, 7-dimethoxyflavan (Compound 12);
(2R) -7,3 '-dihydroxy-4' -methoxy-8-methylflavan (compound 13);
(2R) -5, 7-dihydroxy-4' -methoxy-8-methylflavan (compound 14); or
(2R) -7,3 '-dihydroxy-4' -methoxyflavan (Compound 15).
In the present invention, most preferably, the flavanoid compound is (2R) -7,3 '-dihydroxy-4' -methoxy-8-methylflavan (compound 13).
In the present invention, preferably, the tumor is at least one selected from the group consisting of gastric cancer, lung cancer, liver cancer, colon cancer, cervical cancer, pancreatic cancer, melanoma, breast cancer, glioma, ovarian cancer and bladder cancer.
According to the use of the present invention, preferably, the medicament forms an anti-tumor pharmaceutical preparation; the pharmaceutical preparation comprises the flavane compound and pharmaceutically acceptable auxiliary materials.
According to the use of the present invention, preferably, said pharmaceutical formulation has said flavanoid compound as the sole active ingredient.
The flavane compound can be used for preparing anti-tumor medicaments, and different compounds have different inhibition effects on various tumors. The compounds 1-15 have the activity of inhibiting the growth of tumor cells on various tumor cells, have strong universality and have strong tumor cell toxicity. The (2R) -7,3 '-dihydroxy-4' -methoxy-8-methyl flavane has the strongest inhibition effect on various tumors, and is particularly suitable for preparing medicaments for treating gastric cancer, liver cancer, colon cancer, cervical cancer and glioma.
Drawings
FIG. 1 is an HPLC chromatogram of racemate of Compound 13.
Figure 2 is an HPLC chromatogram of compound 13 (i.e. R configuration).
FIG. 3 is an HPLC chromatogram of the corresponding S configuration of Compound 13.
FIG. 4 shows the single crystal diffraction results for Compound 13 (i.e., R configuration).
FIG. 5 shows single crystal diffraction results for the corresponding S configuration of Compound 13.
FIG. 6 is a drawing of Compound 71H NMR spectrum.
FIG. 7 is a drawing of Compound 713C NMR spectrum.
FIG. 8 is a drawing of Compound 81H NMR spectrum.
FIG. 9 is a drawing of Compound 813C NMR spectrum.
Detailed Description
The present invention will be further described with reference to the following specific examples, but the scope of the present invention is not limited thereto.
In the invention, the flavane compounds 1, 6, 9 and 11 are all known compounds in the field, and the preparation method can be obtained by adopting a known method, for example, the flavane compounds can be obtained by extracting and separating a dragon blood medicinal material or a dragon blood medicinal material, can also be obtained by a chemical synthesis method, and can also be obtained by commercial purchase. Therefore, the preparation method of the above compound is not described herein.
In the invention, the compounds 7 and 8 are new compounds and are extracted and separated from the dragon's blood medicinal material. The preparation method can be adopted as follows: pulverizing sanguis Draxonis as raw material, sequentially extracting with 95%, 70% and 50% ethanol water solution for 2 times, recovering solvent, and mixing to obtain sanguis Draxonis total extract. Dispersing the sanguis Draxonis total extract with water, and extracting with petroleum ether and ethyl acetate respectively to obtain petroleum ether fraction, ethyl acetate fraction and water fraction. Eluting the ethyl acetate part with petroleum ether-ethyl acetate (10: 1-1: 3) and dichloromethane-methanol (20: 1-0: 1) sequentially to obtain 18 fractions (Fr.A-R), wherein Fr.G fraction is flavane aggregation part. G fraction is further separated by Sephadex LH-20 column chromatography with eluent CH at 50:50 volume ratio2Cl2MeOH, 5 fractions, Fr.G 1-G5, respectively. Wherein, Fr.G2 is purified by a semi-preparative liquid phase, and the volume ratio of a mobile phase is65:35 acetonitrile-water to give Compound 7 (t)R13.5 min). The fraction Fr.G3 is purified by semi-preparative liquid phase, the mobile phase is acetonitrile-water with the volume ratio of 70:30, and the compound 8 (t) is obtainedR 17.3min)。
In the present invention, racemates of compounds 2 to 5, 10 and 12 to 15 are all known compounds, and can be prepared according to a method described in the literature, for example, can be obtained by extraction and separation from a dragon blood drug or a dragon blood drug, can also be obtained by a chemical synthesis method, and can also be obtained by commercial purchase. And (3) carrying out chiral resolution on the corresponding racemate to respectively obtain pure compounds 2-5, 10 and 12-15 serving as optical isomers. The chiral resolution method may employ a resolution method that is conventional in the art.
The invention provides an application of a flavane compound in preparing an anti-tumor medicament, wherein the flavane compound has a structure shown in a formula I:
Figure BDA0002443665360000061
wherein: r1Is selected from-H or-CH3；R2Is selected from-OH or-OCH3；R3Is selected from-H or-CH3；R4Selected from-H, -OH or-OCH3；R5Is selected from-H or-OH; r6Is selected from-H or-OCH3or-OCH2CH3；R7Is selected from-H or-OH; r8Selected from-H, -OH or-OCH3(ii) a And R9Is selected from-H or-OH; at the same time, when R2is-OH and R4is-OCH3When R is1、R5、R6、R7、R8、R9At least one of which is not-H.
The flavanoid compound has better cytotoxic activity on human gastric cancer cell lines HGC-27, MGC-803, human lung cancer cell lines NCI-H1299, NCI-H358, human liver cancer cell lines HepG2, SK-HEP-1, human colon cancer cell lines HCT-116, HT29, human cervical cancer cell lines Hela, human pancreatic duct epithelial cancer cell lines PANC-1, human melanoma cell lines A875, human breast cancer cell lines MCF-7, human glioma cell lines H4, human ovarian cancer cell lines SK-OV-3, Caov-3 and human bladder cancer cell lines T24, and has good tumor cell proliferation inhibition effect. Therefore, the flavane compound has an anti-tumor effect, and the tumor is at least one selected from gastric cancer, lung cancer, liver cancer, colon cancer, cervical cancer, pancreatic cancer, melanoma, breast cancer, glioma, ovarian cancer and bladder cancer.
According to a preferred embodiment of the present invention, the structure of said flavanoid compound is represented by formula II, i.e. 5-hydroxy-7-methoxy flavan (Compound 1).
Figure BDA0002443665360000071
The 5-hydroxy-7-methoxy flavane (compound 1) has inhibition effect on gastric cancer, lung cancer, liver cancer, colon cancer, cervical cancer, pancreatic cancer, melanoma, breast cancer, glioma, ovarian cancer and bladder cancer, and especially has significant inhibition effect on gastric cancer, cervical cancer, glioma, ovarian cancer and bladder cancer. Therefore, according to a preferred embodiment of the present invention, the flavanoid compound is 5-hydroxy-7-methoxyflavan, and the tumor is selected from at least one of gastric cancer, cervical cancer, glioma, ovarian cancer and bladder cancer.
According to another preferred embodiment of the present invention, the structure of said flavanoid compound is represented by formula III, wherein R is represented by formula III1Is selected from-H or-CH3，R3Is selected from-H or-CH3；
Figure BDA0002443665360000072
According to a preferred embodiment of the present invention, the flavanoid compound represented by formula iii is selected from any one or more of (2R) -7-hydroxy-2, 5-dimethoxy-6-methylflavan (compound 2), (2S) -7-hydroxy-2, 5-dimethoxy-6-methylflavan (compound 3), (2R) -7-hydroxy-2, 5-dimethoxy-6, 8-dimethylflavan (compound 4), (2S) -7-hydroxy-2, 5-dimethoxy-6, 8-dimethylflavan (compound 5), and 7-hydroxy-2, 5-dimethoxy-8-methylflavan (compound 6).
In the invention, the compounds 2-6 have inhibition effects on gastric cancer, lung cancer, liver cancer, colon cancer, cervical cancer, pancreatic cancer, melanoma, breast cancer, glioma, ovarian cancer and bladder cancer, and the pertinence of each compound to each tumor is different. According to a preferred embodiment of the present invention, said flavanoid compound is compound 2 and said tumor is selected from at least one of gastric cancer, lung cancer, glioma, ovarian cancer and bladder cancer. According to a preferred embodiment of the present invention, said flavanoid compound is compound 3, and said tumor is selected from at least one of lung cancer, liver cancer, colon cancer, glioma. According to a preferred embodiment of the present invention, the flavanoid compound is compound 4, and the tumor is at least one selected from the group consisting of gastric cancer, lung cancer, liver cancer and glioma. According to a preferred embodiment of the present invention, the flavanoid compound is compound 5, and the tumor is at least one selected from the group consisting of gastric cancer, lung cancer, liver cancer and glioma. According to a preferred embodiment of the present invention, said flavanoid is compound 6 and said tumor is selected from at least one of lung cancer, liver cancer, glioma and bladder cancer.
In the present invention, compounds 2 and 3 are optical isomers, and in general, the tumor suppression rate of compound 3(S form) is slightly higher than that of compound 2(R form). In the present invention, the compounds 4 and 5 are optical isomers, and the compound 4(R form) has a tumor suppression rate equivalent to that of the compound 5(S form) as a whole.
According to still another preferred embodiment of the present invention, said flavanoid compound has the structure shown in formula IV, i.e. 7, 6' -dihydroxy-5-methoxy-6-methyl flavan (Compound 7),
Figure BDA0002443665360000081
the 7, 6' -dihydroxy-5-methoxy-6-methyl flavane (compound 7) has an inhibiting effect on gastric cancer, lung cancer, liver cancer, colon cancer, cervical cancer, pancreatic cancer, melanoma, breast cancer, glioma, ovarian cancer and bladder cancer, and particularly has an obvious inhibiting effect on gastric cancer, lung cancer, liver cancer, breast cancer and glioma. Therefore, according to a preferred embodiment of the present invention, said flavanoid compound is 7, 6' -dihydroxy-5-methoxy-6-methylflavan, and said tumor is selected from at least one of gastric cancer, lung cancer, liver cancer, breast cancer and glioma.
According to still another preferred embodiment of the present invention, said flavanoid compound has the structure shown in formula V, i.e. 3, 7-dihydroxy-2-ethoxy-5-methoxy-6-methylflavan (Compound 8),
Figure BDA0002443665360000082
the 3, 7-dihydroxy-2-ethoxy-5-methoxy-6-methyl flavane (compound 8) has an inhibiting effect on gastric cancer, lung cancer, liver cancer, colon cancer, cervical cancer, pancreatic cancer, melanoma, breast cancer, glioma, ovarian cancer and bladder cancer, and particularly has an obvious inhibiting effect on the liver cancer, the glioma and the ovarian cancer. Therefore, according to a preferred embodiment of the present invention, said flavanoid compound is 3, 7-dihydroxy-2-ethoxy-5-methoxy-6-methylflavan, and said tumor is selected from at least one of liver cancer, glioma and ovarian cancer.
According to still another preferred embodiment of the present invention, the flavanoid compound has a structure represented by formula VI, wherein R is1Is selected from-H or-CH3，R2Is selected from-OH or-OCH3，R4Is selected from-H or-OCH3，R7Selected from-H or-OH, R8Is selected from-OH or-OCH3。
Figure BDA0002443665360000091
According to a preferred embodiment of the invention, the flavanoid of formula VI is selected from the group consisting of 7-hydroxy-4 ' -methoxyflavan (Compound 9), (2R) -7,4 ' -dihydroxy-8-methylflavan (Compound 10), 4 ' -hydroxy-5, 7-dimethoxy-8-methylflavan (Compound 11), (2R) -4 ' -hydroxy-5, 7-dimethoxyflavan (Compound 12), (2R) -7,3 ' -dihydroxy-4 ' -methoxy-8-methylflavan (Compound 13), (2R) -5, 7-dihydroxy-4 ' -methoxy-8-methylflavan (Compound 14) and (2R) -7, any one or more of 3 '-dihydroxy-4' -methoxyflavan (compound 15).
In the invention, the compounds 9-15 have inhibition effects on gastric cancer, lung cancer, liver cancer, colon cancer, cervical cancer, pancreatic cancer, melanoma, breast cancer, glioma, ovarian cancer and bladder cancer, and the pertinence of the compounds to each tumor is different. According to a preferred embodiment of the present invention, said flavanoid compound is compound 9, and said tumor is selected from at least one of liver cancer, cervical cancer, pancreatic cancer, breast cancer and glioma. According to a preferred embodiment of the present invention, said flavanoid compound is compound 10 and said tumor is selected from at least one of gastric cancer, liver cancer and glioma. According to a preferred embodiment of the present invention, said flavanoid compound is compound 11, and said tumor is selected from at least one of gastric cancer, lung cancer, liver cancer, melanoma and glioma. According to a preferred embodiment of the present invention, said flavanoid compound is compound 12, and said tumor is selected from at least one of gastric cancer, lung cancer, cervical cancer, melanoma and glioma. According to a preferred embodiment of the present invention, said flavanoid compound is compound 14 and said tumor is selected from at least one of pancreatic cancer, melanoma, breast cancer, glioma and bladder cancer. According to a preferred embodiment of the present invention, said flavanoid compound is compound 15 and said tumor is at least one selected from the group consisting of gastric cancer, liver cancer, breast cancer, ovarian cancer and bladder cancer.
In the invention, the compounds 10 and 12-15 are R-type isomers, and the activity of inhibiting tumor cell proliferation is obviously higher than the respective corresponding S configuration. Particularly, the compound 13 has very obvious inhibition effect on the proliferation of various tumor cells, and is obviously higher than the S-type isomer.
In the invention, preferably, the flavane compound is selected from one or more of compounds 3 and 11-15, and the compound has better anti-tumor effect. More preferably, the flavane compound is selected from one or more compounds 12-15, and the compound has a remarkable anti-tumor effect.
According to a particularly preferred embodiment of the present invention, the flavanoid compound is compound 13, and the tumor is at least one selected from the group consisting of gastric cancer, liver cancer, colon cancer, cervical cancer and glioma, more preferably liver cancer. According to the invention, an antitumor activity screening experiment is carried out on a large number of flavane compounds, and the results show that the compounds 1-15 have the activity of inhibiting the growth of tumor cells, have strong universality and have strong tumor cell toxicity. And even if the structures of various other flavane compounds are similar, the antitumor activity is poor, and a part of the flavane compounds even do not show the tumor cytotoxicity effect; some tumor cell lines only show tumor cell toxicity, and most tumor cell lines do not show tumor cell toxicity, so that the universality is poor. For example, the S-type optical isomer of compound 10, the S-type optical isomer of compound 13, compound 16 (represented by formula VII), and the like are poor in activity and universality.
Figure RE-GDA0002490639480000101
In the invention, the anti-tumor medicine can be a raw material medicine or a medicinal preparation.
In the invention, the medicament can form an anti-tumor medicinal preparation; the pharmaceutical preparation comprises the flavane compound and pharmaceutically acceptable auxiliary materials.
In the present invention, the pharmaceutical formulation may have the flavanoid compound as the sole active ingredient; other active ingredients with antitumor effect can also be contained. Preferably, said pharmaceutical formulation has said flavanoid compound as the sole active ingredient.
In the invention, the dosage form of the pharmaceutical preparation is not limited, and can be tablets, granules, capsules, pills, oral liquid, injection and the like. The pharmaceutical formulation may further comprise pharmaceutically acceptable excipients. The kind of the pharmaceutically acceptable auxiliary material is not limited. The adjuvants can be filler, correctant, lubricant, etc. Fillers are also known as diluents, such as wheat starch, tapioca starch, corn starch, potato starch, dextrin, lactose, and the like. Examples of flavoring agents include, but are not limited to, sucralose, isomaltulose, aspartame, acesulfame k and the like. Examples of lubricants include, but are not limited to, magnesium stearate, talc, aerosil, magnesium lauryl sulfate, and the like.
The technical effects of the present invention will be described below by way of specific preparation examples and examples.
Preparation example 1 preparation of Compounds 2, 3
Chiral resolution is carried out on 7-hydroxy-2, 5-dimethoxy-6-methyl flavane racemate to respectively obtain R type compounds and S type compounds of corresponding compounds, namely compounds 2 and 3. The preparation is carried out by semi-preparative liquid chromatography. The model is as follows: shimadzu LC-20AT (Shimadzu corporation, japan), chiral column: CHIRALPAK IA 5 μm, 4.6mm × 150mm, optical rotation detector: rudolph Autopol IV full automatic optical rotator (Lu Dov, USA). The preparation conditions were as follows:
mobile phase: ethanol-n-hexane 10: 90;
flow rate: 0.5 ml/min.
Preparation example 2 preparation of Compounds 4, 5
Chiral resolution is carried out on 7-hydroxy-2, 5-dimethoxy-6, 8-dimethyl flavane racemate to respectively obtain R type compounds and S type compounds of corresponding compounds, namely compounds 4 and 5. The preparation is carried out by adopting a semi-preparative liquid phase. The model is as follows: shimadzu LC-20AT (Shimadzu, Japan), chiral column: CHIRALPAK IA 5 μm, 4.6mm × 150mm, optical rotation detector: rudolph Autopol IV full automatic optical rotator (Lu Dov, USA).
The preparation conditions were as follows:
mobile phase: ethanol-n-hexane 15: 85;
flow rate: 0.5 ml/min.
PREPARATION EXAMPLE 3 preparation of Compounds 10, 12, 13, 14 and 15
Chiral resolution is carried out on corresponding racemates of the compounds 10, 12, 13, 14 and 15 respectively to obtain R type compounds and S type compounds of the corresponding compounds, wherein the R type compounds are the compounds 10, 12, 13, 14 and 15.
The instrument comprises the following steps: shimadzu LC-20A (Shimadzu corporation, japan), column: superchiral S-AD (Shanghai Lianli Biotechnology Co., Ltd.), 0.46 cm. times.15 cm,5um, column temperature: 35 ℃, mobile phase: MeOH/fomic acid 100/0.05(v/v), uv detection wavelength: 220nm, optical rotation detector: advanced Laser polar imeter@670nm (PDR-partitions LLC), flow rate: 0.5 ml/min.
Taking the resolution result of compound 13 as an example, the chiral resolution result is shown in fig. 1-3. The peak in figure 2 is an R configuration compound and the peak in figure 3 is an S configuration compound, both configurations being > 98% pure. After the splitting is finished, the structure and the configuration are accurate through nuclear magnetic resonance and single crystal diffraction verification. The single crystal diffraction results are shown in fig. 4 and 5. FIG. 4 shows the R configuration and FIG. 5 shows the S configuration. Chiral resolution is carried out on racemates of the compounds 10, 12, 14 and 15 to obtain corresponding R-configuration and S-configuration compounds, and the structures and the configurations are accurate after nuclear magnetic resonance and single crystal diffraction verification, and are not described one by one.
Preparation example 4 preparation of Compounds 7, 8
Pulverizing sanguis Draxonis fruit (4.1kg), sequentially extracting with 95%, 70% and 50% ethanol water solution for 2 times, recovering solvent, and mixing to obtain sanguis Draxonis total extract. Dispersing the sanguis Draxonis total extract with water, and extracting with petroleum ether and ethyl acetate respectively to obtain petroleum ether fraction (24.6g), ethyl acetate fraction (682.6g) and water fraction (368.9 g). Eluting the ethyl acetate part with petroleum ether-ethyl acetate (10: 1-1: 3) and dichloromethane-methanol (20: 1-0: 1) in sequence to obtain 18 fractions (Fr.A-R), wherein Fr.G fraction is flavane aggregation part. Fr.G was separated by Sephadex LH-20 column chromatography, elution conditions CH2Cl2-MeOH (volume ratio 50:50) to give 5 fractions, each of which wasG1-G5. Wherein fr.g2 is purified by a semi-preparative liquid phase with a mobile phase of acetonitrile-water (volume ratio 65:35) to give compound 7(3.5mg, t)R13.5 min). G3 was purified by a semi-preparative liquid phase with acetonitrile-water (volume ratio 70:30) to give compound 8(4.2mg, t)R17.3 min). The NMR spectra of compounds 7 and 8 are shown in FIGS. 6-9.
Example 1
1. Test materials and measurement indices
DMEM basal medium, 1640 basal medium, McCoy's 5A basal medium, fetal bovine serum, penicillin streptomycin mixture, 0.25% trypsin-EDTA from Corning, USA.
Dimethyl sulfoxide DMSO, MTT reagent from Sigma, USA.
Human gastric cancer cell lines HGC-27, MGC-803, SGC-7901, human lung cancer cell lines NCI-H1299, NCI-H358, human liver cancer cell lines HepG2, SK-HEP-1, human colon cancer cell lines HCT-116, HT29, human cervical cancer cell lines Hela, human pancreatic ductal epithelial cancer cell lines PANC-1, human melanoma cell line A875, human breast cancer cell lines MCF-7, human glioma cell line H4, human ovarian cancer cell lines SK-OV-3, Caov-3, and human bladder cancer cell line T24 were purchased from the cell center of the institute of basic medicine of Chinese medical sciences. Wherein MGC-803, HepG2, SK-HEP-1, HT29, PANC-1, A875, MCF-7, H4, Caov-3, T24 cells were cultured in DMEM complete medium (containing 10% FBS, 100U/ml penicillin, 100g/ml streptomycin), HGC-27, SGC-7901, NCI-H1299, NCI-H358, Hela cells were cultured in 1640 complete medium (containing 10% FBS, 100U/ml penicillin, 100g/ml streptomycin), HCT-116, SK-OV-3 cells were cultured in McCoy's 5A complete medium (containing 10% FBS, 100U/ml penicillin, 100g/ml streptomycin), and the cell culture conditions were 37 ℃ and 5% CO2And culturing at saturated humidity.
Male BALB/c nude mice: 18-22g, age 4-5 weeks, purchased from Weitongli Hua, Beijing.
2. Experimental methods
2.1 MTT method cell proliferation assay
Taking the upper part of logarithmic growth phasePreparing cell suspension from the tumor cells, respectively, and adjusting the cell number to 2 × 104Per/mL, add to 96-well plates, 100. mu.l per well. And culturing the cells for 24 hours to ensure that the cells are completely attached to the wall, and diluting mother liquor of flavane compounds 1-15, S-configuration isomer of compound 13, S-configuration isomer of compound 10 and compound 16 into working solutions with different concentrations by using a complete culture medium, wherein 6 multiple holes are arranged at each concentration. After adding drugs for 48 hours, the original culture medium in the pore plate is separated out, 5mg/ml MTT reagent is prepared into a concentration of 10% by using a basic culture medium and added into a 96 pore plate, and the pore plate is placed in a cell culture box at 37 ℃ for incubation for 4 hours. Then, the wells were taken out, 150. mu.l DMSO was added to each well, the wells were dissolved and shaken for 10min, and the OD (optical Density) thereof was measured at a wavelength of 570nm by a microplate reader, and the inhibition ratio of each group was calculated by the formula.
Cell growth inhibition (%) × (1-mean OD value in experimental group/mean OD value in blank control group) × 100%.
2.2 nude mice transplantation tumor model drug administration experiment
Culturing human liver cancer HepG2 cell to logarithmic growth phase, digesting with 0.25% pancreatin without EDTA, washing cell twice with PBS, centrifuging at 1000rpm for 5min, adjusting cell suspension concentration to 2 × 10 with PBS7And/ml, 0.2ml is injected into the shoulder of each nude mouse subcutaneously. When the tumor volume reaches 100-200mm3The nude mice were randomly and equally divided into two groups of 8 mice each, which were set as a blank control group and a compound 13-treated group, respectively. The blank control group was intraperitoneally administered with the same volume of blank solvent per day, and the compound 13 treatment group was intraperitoneally administered with 20mg/kg per day. Observing general conditions such as spirit, diet, activity, defecation and the like every day, weighing the weight of the nude mice every two days, measuring the maximum length (a) and the width (b) of a tumor body by using a vernier caliper, and obtaining the maximum length (a) and the width (b) of the tumor body according to the formula V (ab)2And/2, calculating the change multiple of the tumor volume and calculating the tumor inhibition rate.
Tumor inhibition rate (1-fold change in tumor volume in treatment group/fold change in tumor volume in blank group) × 100%.
3. Results of the experiment
3.1 proliferation inhibition of tumor cells by Compound 13
The compound 13 (namely, the optical isomer with the R configuration) can inhibit the proliferation of various human tumor cells, but the optical isomer with the S configuration has no obvious or ineffective effect on inhibiting the proliferation of various human tumor cells.
The effects of compound 13 on the proliferation activities of human gastric cancer cell lines HGC-27, MGC-803, human lung cancer cell lines NCI-H1299, NCI-H358, human liver cancer cell lines HepG2, SK-HEP-1, human colon cancer cell lines HCT-116, HT29, human cervical cancer cell line Hela, human pancreatic ductal epithelial cancer cell line PANC-1, human melanoma cell line A875, human breast cancer cell line MCF-7, human glioma cell line H4, human ovarian cancer cell lines SK-OV-3, Caov-3, and human bladder cancer cell line T24 at a concentration of 0.2. mu.M-1.0. mu.M were determined by the MTT method, and the results are shown in Table 1. The proliferation inhibition rate increases significantly with increasing drug concentration. Therefore, the compound 13 has obvious proliferation inhibition effect on various tumor cells.
The optical isomer of the S configuration of the compound 13 showed inhibitory effects on the proliferation activities of human gastric cancer cell lines HGC-27, MGC-803 and human liver cancer cell line HepG2, but even at higher concentrations, the activity was still much lower than that of the compound 13, and the proliferation inhibitory effects on various human tumor cells were weak or substantially ineffective, with the results shown in Table 2.
TABLE 1 inhibition of proliferation of Compound 13 on various tumor cells
Figure BDA0002443665360000151
TABLE 2 inhibition of tumor cell proliferation by S-isomer of Compound 13
Figure BDA0002443665360000152
3.2 antitumor Effect of Compounds 1 to 12 and 14 to 15, S-isomer corresponding to Compound 10, and Compound 16
The influence of 1-12, 14-15 flavane compounds and corresponding S-configuration isomers of compound 10 on human gastric cancer cell lines HGC-27, MGC-803, human lung cancer cell lines NCI-H1299, NCI-H358, human liver cancer cell lines HepG2, SK-HEP-1, human colon cancer cell lines HCT-116, HT29, human cervical cancer cell lines Hela, human pancreatic ductal epithelial cancer cell lines PANC-1, human melanoma cell lines A875, human breast cancer cell lines MCF-7, human glioma cell lines H4, human ovarian cancer cell lines SK-OV-3, Caov-3 and human bladder T24 proliferation activity was determined by MTT method at the concentration of 5-20 muM, and the results are shown in Table 3. The proliferation inhibition rate of the medicine is obviously increased along with the increase of the concentration of the medicine. Therefore, the flavane compounds 1-12 and 14-15 have obvious proliferation inhibition effect on all the tumor cells. The S-isomer of compound 10 and compound 16 showed inhibitory effects only on several tumor cells, and the inhibitory rate was low, and showed no inhibitory effect on the remaining tumor cells, and the specific results are shown in tables 17 and 18.
TABLE 3 inhibition of tumor cell proliferation by Compound 1
Figure BDA0002443665360000161
TABLE 4 inhibition of tumor cell proliferation by Compound 2
Figure BDA0002443665360000162
Figure BDA0002443665360000171
TABLE 5 inhibition of tumor cell proliferation by Compound 3
Figure BDA0002443665360000172
TABLE 6 inhibition of tumor cell proliferation by Compound 4
Figure BDA0002443665360000173
Figure BDA0002443665360000181
TABLE 7 inhibition of tumor cell proliferation by Compound 5
Figure BDA0002443665360000182
TABLE 8 inhibition of tumor cell proliferation by Compound 6
Figure BDA0002443665360000191
TABLE 9 inhibition of tumor cell proliferation by Compound 7
Figure BDA0002443665360000192
Figure BDA0002443665360000201
TABLE 10 inhibition of tumor cell proliferation by Compound 8
Figure BDA0002443665360000202
TABLE 11 inhibition of tumor cell proliferation by Compound 9
Figure BDA0002443665360000203
Figure BDA0002443665360000211
TABLE 12 inhibition of tumor cell proliferation by Compound 10
Figure BDA0002443665360000212
TABLE 13 inhibition of tumor cell proliferation by Compound 11
Figure BDA0002443665360000213
Figure BDA0002443665360000221
TABLE 14 inhibition of tumor cell proliferation by Compound 12
Figure BDA0002443665360000222
TABLE 15 inhibition of tumor cell proliferation by Compound 14
Figure BDA0002443665360000223
Figure BDA0002443665360000231
TABLE 16 inhibition of tumor cell proliferation by Compound 15
Figure BDA0002443665360000232
TABLE 17 inhibition of tumor cell proliferation by S-isomer of Compound 10
Figure BDA0002443665360000233
Figure BDA0002443665360000241
TABLE 18 inhibition of tumor cell proliferation by Compound 16
Figure BDA0002443665360000242
3.3 in vivo antitumor Activity of Compound 13
Will be about 2X 106The HepG2 cells of the individual liver cancer are inoculated under the skin (0.2ml) of a nude mouse until the tumor volume grows to 100-3At about the time, compound 13 was administered by intraperitoneal injection at a dose of 20mg/kg once a day, and the growth of tumors was measured by regular observation. The results are shown in table 19, and the compound 13 can effectively inhibit the in vivo tumor formation ability of liver cancer HepG2 cells, and the tumor inhibition rate is 35.46%. Body weight data as shown in table 20, compound 13 did not significantly change the body weight of nude mice.
TABLE 19 antitumor Effect of Compound 13 on human hepatoma HepG2 cells
Figure BDA0002443665360000243
TABLE 20 Effect of Compound 13 on body weight of nude mice
Figure BDA0002443665360000251
The present invention is not limited to the above-described embodiments, and any variations, modifications, and substitutions which may occur to those skilled in the art may be made without departing from the spirit of the invention.

Claims (10)

1. The application of flavane compounds in preparing anti-tumor medicaments is disclosed, wherein the flavane compounds have a structure shown as a formula I:
Figure FDA0002443665350000011
wherein R is1Is selected from-H or-CH3；R2Is selected from-OH or-OCH3；R3Is selected from-H or-CH3；R4Selected from-H, -OH or-OCH3；R5Is selected from-H or-OH; r6Is selected from-H or-OCH3or-OCH2CH3；R7Is selected from-H or-OH; r8Selected from-H, -OH or-OCH3(ii) a And R9Is selected from-H or-OH; at the same time, when R2is-OH and R4is-OCH3When R is1、R5、R6、R7、R8、R9At least one of which is not-H.
2. Use according to claim 1, characterized in that R1Is selected from-H or-CH3，R2is-OH, R3Is selected from-H or-CH3，R4is-OCH3，R5is-H, R6is-OCH3，R7is-H, R8is-H, and R9is-H.
3. Use according to claim 1, characterized in that R1Is selected from-H or-CH3，R2Is selected from-OH or-OCH3，R3is-H, R4Is selected from-H or-OCH3，R5is-H, R6is-H, R7Selected from-H or-OH, R8Is selected from-OH or-OCH3And R is9is-H.
4. The use of claim 1, wherein said flavanoid compound is selected from one or more of the following compounds:
5-hydroxy-7-methoxyflavan;
(2R) -7-hydroxy-2, 5-dimethoxy-6-methylflavan;
(2S) -7-hydroxy-2, 5-dimethoxy-6-methylflavan;
(2R) -7-hydroxy-2, 5-dimethoxy-6, 8-dimethylflavan;
(2S) -7-hydroxy-2, 5-dimethoxy-6, 8-dimethylflavan;
7-hydroxy-2, 5-dimethoxy-8-methylflavan;
7, 6' -dihydroxy-5-methoxy-6-methylflavan;
3, 7-dihydroxy-2-ethoxy-5-methoxy-6-methylflavan;
7-hydroxy-4' -methoxyflavan;
(2R) -7, 4' -dihydroxy-8-methylflavan;
4' -hydroxy-5, 7-dimethoxy-8 methylflavan;
(2R) -4' -hydroxy-5, 7-dimethoxyflavan;
(2R) -7,3 '-dihydroxy-4' -methoxy-8-methylflavan;
(2R) -5, 7-dihydroxy-4' -methoxy-8-methylflavan; or
(2R) -7,3 '-dihydroxy-4' -methoxy flavan.
5. The use of claim 4, wherein said flavanoid compound is selected from one or more of the following compounds:
(2S) -7-hydroxy-2, 5-dimethoxy-6-methylflavan;
4' -hydroxy-5, 7-dimethoxy-8 methylflavan;
(2R) -4' -hydroxy-5, 7-dimethoxyflavan;
(2R) -7,3 '-dihydroxy-4' -methoxy-8-methylflavan;
(2R) -5, 7-dihydroxy-4' -methoxy-8-methylflavan; or
(2R) -7,3 '-dihydroxy-4' -methoxy flavan.
6. The use of claim 5, wherein said flavanoid compound is selected from one or more of the following compounds:
(2R) -4' -hydroxy-5, 7-dimethoxyflavan;
(2R) -7,3 '-dihydroxy-4' -methoxy-8-methylflavan;
(2R) -5, 7-dihydroxy-4' -methoxy-8-methylflavan; or
(2R) -7,3 '-dihydroxy-4' -methoxy flavan.
7. The use of claim 6, wherein said flavanoid compound is (2R) -7,3 '-dihydroxy-4' -methoxy-8-methylflavan.
8. The use according to any one of claims 1 to 6, wherein the tumor is at least one selected from the group consisting of gastric cancer, lung cancer, liver cancer, colon cancer, cervical cancer, pancreatic cancer, melanoma, breast cancer, glioma, ovarian cancer and bladder cancer.
9. Use according to claim 8, characterized in that the medicament forms an anti-tumour pharmaceutical preparation; the pharmaceutical preparation comprises the flavane compound and pharmaceutically acceptable auxiliary materials.
10. The use according to claim 9, wherein said pharmaceutical formulation has said flavanoid compound as the sole active ingredient.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116637102A (en) * 2020-04-09 2023-08-25 北京中医药大学 Application of flavane compound in preparation of antitumor drugs
CN117050047A (en) * 2023-08-14 2023-11-14 河南中医药大学 Preparation method of 5,7-dimethoxy-8-methyl-4 ʹ -hydroxyflavan

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103675113A (en) * 2012-09-17 2014-03-26 天津马克生物技术有限公司 Fingerprint detection method for daemonorps dracoblume
CN104744418A (en) * 2013-12-30 2015-07-01 桂林三金药业股份有限公司 Method for simultaneous preparation of 7-hydroxy-4 '-methoxy flavan and pterostilbene
CN108017609A (en) * 2017-12-11 2018-05-11 武汉华益通生物科技有限公司 A kind of flavanoid monomeric compound and its preparation method and application
CN108283680A (en) * 2018-01-22 2018-07-17 江苏苏轩堂药业有限公司 The direct oral traditional Chinese medicine medicine materical crude slice of dragon blood powder
CN110559382A (en) * 2019-10-25 2019-12-13 北京中医药大学 preparation method and application of dragon's blood extract

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2081565A2 (en) * 2006-10-13 2009-07-29 Reliance Life Sciences Pvt., Ltd. Cinnamic acid, vanillic acid and benzofuran derivatives for use in the treatment of inflammation and cancer
JP5655416B2 (en) * 2010-07-30 2015-01-21 ユーハ味覚糖株式会社 New flavan compounds
CN102526022A (en) * 2010-12-14 2012-07-04 复旦大学 Application of epigallocatechin-3-gallate in preparation of antitumor drug
EP2633885A1 (en) * 2012-03-02 2013-09-04 Symrise AG Compounds and mixtures for affecting inflammatory conditions
CN104013636B (en) * 2014-06-16 2016-06-08 王学勇 Watt careless Pentacyclic triterpene saponins compounds anti-tumor drug purposes
KR20180121117A (en) * 2017-04-28 2018-11-07 연세대학교 산학협력단 Pharmarceutical composition for preventing or treating cancer
CN109106710B (en) * 2018-10-23 2020-12-08 北京中医药大学 Use of compounds
CN110357847B (en) * 2019-07-22 2022-05-13 四川大学 Isoflavane compound and preparation method and application thereof
CN113509459B (en) * 2020-04-09 2023-07-28 北京中医药大学 Application of flavane compound in preparation of antitumor drugs

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103675113A (en) * 2012-09-17 2014-03-26 天津马克生物技术有限公司 Fingerprint detection method for daemonorps dracoblume
CN104744418A (en) * 2013-12-30 2015-07-01 桂林三金药业股份有限公司 Method for simultaneous preparation of 7-hydroxy-4 '-methoxy flavan and pterostilbene
CN108017609A (en) * 2017-12-11 2018-05-11 武汉华益通生物科技有限公司 A kind of flavanoid monomeric compound and its preparation method and application
CN108283680A (en) * 2018-01-22 2018-07-17 江苏苏轩堂药业有限公司 The direct oral traditional Chinese medicine medicine materical crude slice of dragon blood powder
CN110559382A (en) * 2019-10-25 2019-12-13 北京中医药大学 preparation method and application of dragon's blood extract

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JIAN LIU等: ""A new cytotoxic homoisoflavonoid from Dracaena cambodiana"", 《JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH》 *
JIAN LIU等: "A new cytotoxic homoisoflavonoid from Dracaena cambodiana", 《JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH》 *
QIAN HAO: "Three new flavans in dragon’s blood from Daemonorops draco", 《NATURAL PRODUCT RESEARCH》 *
张丽等: "血竭及龙血竭化学成分、药理作用研究进展", 《中国现代应用药学》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116637102A (en) * 2020-04-09 2023-08-25 北京中医药大学 Application of flavane compound in preparation of antitumor drugs
CN116637102B (en) * 2020-04-09 2024-04-09 北京中医药大学 Application of flavane compound in preparation of antitumor drugs
CN117050047A (en) * 2023-08-14 2023-11-14 河南中医药大学 Preparation method of 5,7-dimethoxy-8-methyl-4 ʹ -hydroxyflavan

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