CN101249087A - Applications of isobavachin for preparing antineoplastic, osteoporosis and senile dementia medicament - Google Patents
Applications of isobavachin for preparing antineoplastic, osteoporosis and senile dementia medicament Download PDFInfo
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- CN101249087A CN101249087A CNA2008101041501A CN200810104150A CN101249087A CN 101249087 A CN101249087 A CN 101249087A CN A2008101041501 A CNA2008101041501 A CN A2008101041501A CN 200810104150 A CN200810104150 A CN 200810104150A CN 101249087 A CN101249087 A CN 101249087A
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Abstract
The invention relates to the use of isobavachin in preparing drugs against tumors, osteoporosis and senile dementia, which belongs to the medical field. Isobavachin has the structural formula shown as the figure (I) and a chemical name thereof : 2,3-dihydro-7-hydroxy-2-(4-hydroxyphenyl)-8-(3-methyl-butyl-2-alkenyl)-4H-1-benzopyran-4-one. The compound, in low concentration, doesn't change the expressions of ERalpha66, ERalpha46 and ERalpha36, but in high concentration, inhibits the expressions thereof at the same time. Furthermore, the compound (I) can kill breast cancer cell line MCF7 that expresses ERalpha66, ERalpha46 and ERalpha36. The compound (I) can also be used as regulator of estrogen receptor ERalpha36 to treat diseases caused by abnormal expression of estrogen receptor ERalpha36, such as tumors, osteoporosis, asthma, heart diseases and senile dementia.
Description
Technical field
The invention belongs to field of medicaments, relate to native compound in preparation antineoplastic agent, osteoporosis, the application of medicine for senile dementia aspect.
Background technology
Estrogen is a kind of steroid hormone that is produced by hormonal system, its all play an important role in reproductive system, osseous tissue, cardiovascular, immune system and central nervous system [J Cell Sci, 2003; 116 (4): 585-586].The estrogen signal transduction system all plays very big effect in regulating cell growth, differentiation and apoptotic process.The estrogen-dependent type tumor, generation and development as breast carcinoma, ovarian cancer and carcinoma of endometrium etc. all have confidential relation [J SteroidBiochem.Mol.Biol. with estrogen, 2002,81 (1): 1-24, J Mammary Gland Biol.Neoplasia, 1998,3 (1): 49-61, Curr.Drug Targets Immune Endocr.Metabol.Disord; 2001,1 (1): 1-12, Cancer Res., 1998,58 (23): 5367-5373, J Psychiatry Neurosci, 2002; 27 (1): 1-27], therefore the development and application and significance [the Nat.Rev.Drug Discov. that instructs treatment of diseases such as estrogen-dependent type tumors that the research of estrogen receptor are had medicines such as instructing estrogen antagonist and estrogen receptor antagon, 2004,3 (11): 950-964].
Present known estrogen receptor is divided into two kinds of hypotypes of α, β.Estrogen receptor alpha in 1958 by people such as Toft and Gorski [Proc.Natl.Acad.Sci.USA, 1966,55 (6): 1574-1581] take the lead in from the mouse uterine cell, separating and obtain, Green[Nature in 1986,1986, the people clone human estrogen acceptor ER α that to obtain first molecular weight be 66kDa such as 320 (6058): 134-139] and Greene[Science, 1986,231 (4742): 1150-1154]; 1996, Kuiper etc. [Proc.Natl.Acad.Sci.USA, 1996,93 (12): 5925-5930] cloned from rat prostate and obtain another kind of estrogen receptor ER β.After this, people such as Mosselman [FEBS Lett.1996,392 (1): 49-53] clone from people's testis tissue and obtain incomplete people ER β; Ogawa[Biochem.Biophys.Res.Commun.1998,243 (1): 122-126] and people [Biochem.Biophys.Res.Commun., 1998,247 (1): 75-78] such as Moore clone in succession and obtain complete people ER β.Estrogen receptor ER α and ER β hypotype have similar sequence and form [FEBS Lett.2003,546:17-24, Biochem.Soc.Trans.2003,31:56-59]; They all by three independences but interactional functional areas form: be positioned at the A/B district of N end, intermediary C district, and the C D/E/F district of holding.The A/B district of N end is a transcription activating district (AF-1) that does not rely on part, is responsible for the combination and the relevant target gene (Fig. 1) of transcriptional activation of activation factor together.The C district is the DNA land, contains two zinc fingerses, for the dimerization of molecule and and specific dna sequence in conjunction with most important.The D/E/F district of C end is a ligand binding domain, and by the combination of its mediation part, the dimerization of receptor is appraised and decided the position, and the transcription activating function (AF-2) of ligand-dependent.
According to traditional theory, estrogen by with cytoplasm or nuclear in estrogen receptor (ER) combine and transcribe and bring into play biological function by regulator gene.Over past ten years the estrogen signal path has been had many new understanding again: the estrogen signal transduction pathway comprises nucleus approach (classical pathway) and cell membrane approach (non-classical approach).So estrogenic biological effect, the nucleus activated pathway of the ligand-receptor that do not place one's entire reliance upon also can play a role by other signal paths.Non-classical estrogen signal path is different in the effect that different cells produce, for example: 17 β estradiol (E2 β) can be regulated myocardial cell by film signal path and P38 kinases and PI3K kinases and transfer and die, thereby cardiovascular system had protective effect [Curr.Treat.OptionsCardiovasc.Med.2001,3 (1): 67-79]; In addition, several important signal transduction pathway such as G-protein signal path, phospholipase C in the cell, signal transduction pathway such as adenyl cyclase and MAPK all have interaction [Trends in Endocrinol.Metabol., 2002 with non-classical estrogen film signal path, 13,349-354].People think that extensively the high-level estrogen in the serum stimulates the epithelial lasting hypertrophy of glandular tube by classical and non-classical estrogen signal transduction path, thereby participate in the estrogen-dependent type tumor, as the generation and the development of breast tumor, carcinoma of endometrium and ovarian cancer.Yet the effect of non-classical estrogen film signal path it be not immediately clear.
Flouriot etc. [EMBO, 2001,19:4688-4700] discover that also having one except the ER-α 66 of total length has lacked coded 173 the amino acid whose ER-α homologies isomer of first exon.The ER-α homology isomer that this newfound molecular weight is 46kDa is called as ER-α 46, and the molecular weight of early finding is ER-α [Nature, 1986,320 (6058): 134-139 of 66kDa; Science, 1986,231 (4742): 1150-1154] just be called as ER-α 66.This isomer has lacked the AF1 functional areas, but has kept the integrity of other functional areas.Further discover the function of the AF1 of ER-α 46 energy competitive inhibition ER-α 66, and the effect of AF2 is not influenced.
The homology isomer that another molecular weight in 2005 is the brand-new ER-α of 36kDa is found and has cloned, and with its called after ER-α 36[Biochem.Biophy.Res.Commu.2005,336:1023-1027; Proc.Natl.Acad.Sci.USA, 2006,103 (24): 9063-9068].The promoter transcriptional start of this isomer from first intron that is present in ER-α 66 genes behind a bit of exon, utilizes the exon 2-6 of ER-α 66 to encode.Therefore, ER-α two functional transcription district AF1 of 36 disappearances and AF2, but kept DNA combined function district and dimerization functional areas.Importantly ER-α 36 hormone ligand binding domains (ligand binding domain) have lacked 8-12 helical region (helix), thereby have changed itself and bonded specificity of hormone part and affinity (Fig. 1) fully.Therefore, ER-α 36 has and ER-α 66 and the diverse hormone ligand binding capacity of ER-β, for the ligands specific that screens at ER-α 36 provides architecture basics.
Because of ER-α 36 disappearance AF1 and AF2 functional areas, ER-α 36 itself lacks any transcripting regulating function, but can suppress the estrogen nuclear signal path of the classics of ER-α 66 mediations effectively.ER-α 36 mainly is distributed in cell membrane and the cytoplasm, is distributed in the nucleus on a small quantity.Thereby ER-α 36 can be by non-classical estrogen film signal transduction pathway and through MAPK/ERK signal pipeline irritation cell division [Proc.Natl.Acad.Sci.USA, 2006,103 (24): 9063-9068].ER-α 36 is in different estrogen-dependent type tumors, as high expressed is all arranged in breast carcinoma, ovarian cancer and the carcinoma of endometrium.Therefore the signal pathway of ER-α 36 mediations may participate in the formation and development of multiple estrogen-dependent type tumor.
Summary of the invention
The objective of the invention is by research natural constituent, provide new can regulate ER-α and-chemical compound of the biological conducting system of β, can be used for antitumor, heart disease, the effect of osteoporosis and senile dementia.
The pharmaceutically acceptable salt or the solvate of formula (I) chemical compound or formula (I) chemical compound
Application in the medicine of the disease that preparation treatment causes because of estrogen receptor ER-alpha hypotype and ER-β hypotype, described ER-alpha hypotype comprises ER-α 36, ER-α 46 and ER-α 66.
The pharmaceutically acceptable salt of described formula (I) chemical compound or formula (I) chemical compound or solvate are the regulators as estrogen receptor ER-α and ER-β hypotype.
Described medicine comprises tablet, chewing agent, capsule, suspension liquor, solution.
Described disease comprises tumor, osteoporosis, asthma, heart disease and senile dementia.
Described tumor is breast carcinoma, ovarian cancer, carcinoma of endometrium, gastric cancer, colon cancer, carcinoma of prostate, leukemia or pulmonary carcinoma.
Described tumor is a breast carcinoma, carcinoma of prostate.
Described tumor is a breast carcinoma.
Formula (I) chemical compound can obtain (Li Anjuan, the content assaying method Review Study of psoralen and isopsoralen in Fructus Psoraleae medical material and the preparation thereof, Chinese drug standard, 2002, (2): 6-10 by extraction separation from the legumes psoraleae fruit; Lin Ruimin, Wang Dawei, Xiong Zhili etc., the high-performance liquid chromatogram determination of two flavones ingredients in the Fructus Psoraleae, CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2002, (9): 669-671; Yu Lili, Huang Rong, Chen Yegao, the separation of Fructus Psoraleae anticancer component and evaluation, Yunnan chemical, 2003, (5): 25-27; Yang Min, Liu Juan, Zhu Zhaorong etc., different extraction processes are to the influence of bavachin stripping, traditional Chinese veterinary medicine magazine, 2004, (5): 5-8; Yang Tongtong, Qin Minjian, YANG Tong-tong etc., the separation of new isoflavones components and structure are identified in the Fructus Psoraleae, Acta Pharmaceutica Sinica, 2006, (1): 76-79; Chen Yegao, Yu Lili, Huang Rong, the separation of the chemical constituent of Fructus Psoraleae and evaluation, Yunnan chemical, 2005,32 (2), 3-5; Lv Juan, speckle Rui Shan, the chemical constituent of Fructus Psoraleae and Advance on Pharmacological Activities, Shenyang Pharmaceutical University's journal, 1996,13,220).Fructus Psoraleae fruit acrid in the mouth, hardship is returned the kidney spleen channel, has kidney warming and yang invigorating, improving inspiration by invigorating kidney-QI, the effect of antidiarrheal (Chinese Pharmacopoeia Commission. Pharmacopoeia of People's Republic of China, Beijing: Chemical Industry Press, 2005,129-130).But single chemical compound, suc as formula the structural formula shown in (I), it is to the biological activity of ER receptor, and especially to the ER hypotype: the biological activity of the receptor of ER-α 36 and consequent drug effect are not reported.
Experiment shows: the normal breast epithelial cell is expressed a small amount of ER-α 36, and in the inspection of 700 routine breast carcinoma, find about 39.9% breast carcinoma sample high expressed ER-α 36, though and the breast carcinoma sample of 40% estrogen receptor negative do not express ER-α 66, can express ER-α 36.ER-α 36 also is expressed in 100%ER-, PR-and HER-2+ breast carcinoma sample. and The above results shows: ER-α 36 not only participates in the formation and development of the male breast carcinoma of ER, and may participate in the formation and development of the breast carcinoma that is considered to the ER feminine gender over.Further studies show that, express the breast tumor prognosis extreme difference of ER-α 36, and the antagonism estrogenic, not strong as the therapeutic response of tamoxifen.
The breast cancer cell line MDA-MB-231 of estrogen receptor negative does not express ER-α 66, but high expressed ER-α 36, and estrogen can promote MDA-MB-231 cell fast breeding.Therefore the promoting growth of cell signal transduction of ER-α 36 startups can cause cell proliferation.Express the positive MCF7 cell of ER-of ER-α 66 and ER-α 36 simultaneously, estrogen is stimulated to produce stronger breeder reaction, and antagonism estrogenic such as tamoxifen phenol there are resistant function.
In addition, studies show that, heart disease, diseases such as osteoporosis and senile dementia have direct relation with the biological function of ER-α 36. and be that the target spot screening of medicaments will provide a kind of new screening antitumor therefore with ER-α 36, heart disease, the approach of osteoporosis and medicine for senile dementia.
Prove that by experiment formula (I) chemical compound under low consistency conditions, does not change ER α 66, the expression of ER α 46 and ER α 36.Yet the chemical compound of high concentration (I) can suppress three's expression simultaneously; Chemical compound (I) can kill and express ER α 66, the breast cancer cell MCF7 cell of ER α 46 and ER α 36 simultaneously.And formula (I) chemical compound also can be used as the regulator of estrogen receptor ER α 36, is used for the treatment of the disease that the unconventionality expression because of estrogen receptor ER α 36 causes, as tumor, and osteoporosis, asthma, diseases such as heart disease or senile dementia.
Description of drawings
The structural division of Fig. 1 estrogen receptor
Fig. 2 ER α 66, ER α 46 and the expression of ER α 36 in 6 different patients' breast cancer tissue.
1, normal galactophore tissue 2, IDC tissue, 3, the IDC tissue, 4, the IDC tissue, 5, ILC, 6, ILC, 7, the non-infiltration duct carcinoma
Fig. 3 in breast cancer cell MDA-MB-231, anti-ER α 36 specific antibodies colour developing situation
α ER-α 36, positive findings is shown in green, DAPI, positive findings is shown as blueness, unites colour developing person and is labeled as " Merge ".
Fig. 4 MCF7 cell is after chemical compound (I) is handled, and Western blot detects ER α 66, the situation that ER α 46 and ER α 36 express.
Fig. 5 MCF7 cell after chemical compound (I) is handled, survivaling cell number change situation.
Specific implementation method
Embodiment 1The external biological test of formula (I) chemical compound
Formula (I) chemical compound: 2,3-dihydro-7-hydroxyl-2-(4-hydroxyphenyl)-8-(3-methyl-butyl-2-thiazolinyl)-4H-1-.alpha.-5:6-benzopyran-4-ketone is thought Bioisystech Co., Ltd from the Shanghai friend and is bought.
Test 1:
Test method: contain different patient breast cancer tissues proteic pre-blot filter membrane sheet purchase to ProSci company (Poway, CA).[ER-α 36 specific antibodies (at 20 aminoacid of ER-α 36C-end) are by Alpha Diagnostic International (San Antonio to use ER α 36 specific anti-ER α 36 antibody, TX) preparation, can consult Proc.Natl.Acad.Sci.USA, 2006,103 (24): 9063-9068], two anti-and enhanced chemiluminescence reagent (ECL, AmerShamPharmacia Biotech) detection filter membrane sheet and colour developings of HRP labelling.Behind this membrane elution, use can detect anti-ER Alpha antibodies H222 (Novocastra Laboratories Ltd, UK) the detection diaphragm of three kinds of hypotypes of ER (ER α 66, ER α 46 and ER α 36) simultaneously.(see figure 2)
Result of the test: ER α 66, ER α 46 and ER α 36 express in IDC (swimming lane 2), ILC (swimming lane 5) and non-infiltration duct carcinoma (swimming lane 7).In addition, ER α 36 expresses in IDC (swimming lane 4) and ILC (swimming lane 6).Swimming lane 2 is the IDCs that derive from two different patients with swimming lane 3.Swimming lane 5 is the ILCs that derive from two different patients with swimming lane 6.This result shows that ER α 36 can express, and does not express (swimming lane 1) and have in normal galactophore tissue in the breast carcinoma of ER α 66 and ER α 46 expression feminine genders.
Test 2:
Test method: MDA-MB-231 cell line is breast cancer cell line [the Relevance of breast cancer cell lines as models for breast tumors:an update.BreastCancer Research and Treatment 2004 that the shortage ER α 66 that generally acknowledges and ER α 46 express, 83:249-289] MDA-MB-231 cell (purchasing the cell bank to ATCC) goes down to posterity and places 8 hole BIOCOAT slides (BD Science Discovery Labware), be incubated at the DMEM culture medium that contains 10% hyclone, and, cultivated 12 hours under the condition of 5%CO2 at 37 ℃.(the PBS preparation PH7.4) is fixed 30 minutes in room temperature to use aseptic PBS flushing twice, 4% paraformaldehyde; Wash with PBS then and 0.5% (v/v) TritonX-100 rupture of membranes 10 minutes; PBS washes, and 3% serum was room temperature sealing 1 hour; Anti-ER α 36 specific antibodies are incubated at room 1 hour, and the PBS (PBST) that contains 0.5%Triton X-100 gives a baby a bath on the third day after its birth time; Fluorescence two anti-the hatching 1 hour of Fluorescein isothiocyanate (FITC) labelling; PBST gives a baby a bath on the third day after its birth inferior, and PBS washes once; Anti-cancellation mountant (Molecular Probes, Eugene, OR) mounting.Observe in Niken E600 microscopically, use MRC-1024 laser confocal microscope (Bio-Rad) photographic images.(see figure 3)
Result of the test: express among the negative breast cancer cell MDA-MB-231 at ER α 66 and ER α 46, anti-ER α 36 specific antibodies colour developing positive (be labeled as α ER-α 36, positive findings is shown in green), and the polypeptide that can be used as immunity is blocked.Nucleus uses 4,6-connection miaow-2-phenyl-1H-indole dyeing (be labeled as DAPI, positive findings is shown as blueness).Associating colour developing person is labeled as " Merge ".(among the figure+Peptide show and in experiment, add immunogenic polypeptide and come blocking antibody)
Test 3:
After the MCF7 cell was chemical compound (I) processing of 0 μ m to 25 μ m through concentration, immunoblotting (Western blot) detected ER α 66, the situation that ER α 46 and ER α 36 express.(see figure 4).
Result of the test: as shown in the figure, along with the rising of chemical compound (I) concentration, the expression of ER α 66 and ER α 46 descends.Yet the chemical compound of high concentration (I) can suppress three's expression.
Test 4:
Test method: MCF7 cell line is high expressed ER α 66, the breast cancer cell line of ER α 46 and ER α 36 (Relevance ofbreast cancer cell lines as models for breast tumors:an update.Marc Lacroix, GuyLeclercq, Breast Cancer Research and Treatment 2004,83; 249-289.) MCF7 cell (purchasing the cell bank to ATCC) is incubated at the DMEM/F12 culture medium (Invitrogen) that contains 10% hyclone, in the condition of 37 ℃ and 5%CO2, cultivated 12 hours.Chemical compound (I) (purchase have to Shanghai think of biotech company) is by the DMSO dissolved dilution.The MCF7 cell is by 1 * 10
5Density be inoculated in the culture dish of 100mm diameter, be after the chemical compound (I) of 0 μ m to 25 μ m handled for two weeks, to use blood cell calculator the cell of survival to be counted by concentration at microscopically.Divide into groups according to concentration, 5 culture dishs are one group.The illustrated MCF7 of the being cell of (see figure 5) is respectively 0 μ m through concentration, 5 μ m, and 10 μ m, 15 μ m, after the chemical compound (I) of 20 μ m. and 25 μ m handled for two weeks, the performance that cell number changes.Cytometric unit is 1 * 10
4Individual.
Result of the test: as shown in the figure, the MCF7 cell is that living cells quantity obviously descended after the chemical compound (I) of 5 μ m was handled through concentration.
Claims (7)
1, formula (I) chemical compound or formula (I) chemical compound pharmaceutically acceptable salt or solvate
Application in the medicine of the disease that preparation treatment causes because of estrogen receptor ER-alpha hypotype and ER-β hypotype, described ER-alpha hypotype comprises ER-α 36, ER-α 46 and ER-α 66.
2, the described application of claim 1, the pharmaceutically acceptable salt of described formula (I) chemical compound or formula (I) chemical compound or solvate are the regulators as estrogen receptor ER-α and ER-β hypotype.
3, the described application of claim 1, described medicine comprises tablet, chewing agent, capsule, suspension liquor, solution.
4, the described application of claim 1, described disease comprises tumor, osteoporosis, asthma, heart disease and senile dementia.
5, the described application of claim 4, described tumor are breast carcinoma, ovarian cancer, carcinoma of endometrium, gastric cancer, colon cancer, carcinoma of prostate, leukemia or pulmonary carcinoma.
6, the described application of claim 5, described tumor are breast carcinoma, carcinoma of prostate.
7, the described application of claim 5, described tumor are breast carcinoma.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101406513B (en) * | 2008-12-03 | 2011-04-27 | 天津中医药大学 | Malaytea scurfpea fruit extract, pharmaceutical composition containing the same, and preparation method and application thereof |
| CN105963291A (en) * | 2016-06-02 | 2016-09-28 | 上海中医药大学 | Isobavachin and medical application of isobavachin analogue |
| CN106420904A (en) * | 2016-11-21 | 2017-02-22 | 北京大学 | Preparation method of total flavonoids in psoralea corylifolia and new medical application of total flavonoids in psoralea corylifolia |
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2008
- 2008-04-16 CN CNA2008101041501A patent/CN101249087A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101406513B (en) * | 2008-12-03 | 2011-04-27 | 天津中医药大学 | Malaytea scurfpea fruit extract, pharmaceutical composition containing the same, and preparation method and application thereof |
| CN105963291A (en) * | 2016-06-02 | 2016-09-28 | 上海中医药大学 | Isobavachin and medical application of isobavachin analogue |
| CN105963291B (en) * | 2016-06-02 | 2019-05-24 | 上海中医药大学 | The medical usage of different Corylifolin and the like |
| CN106420904A (en) * | 2016-11-21 | 2017-02-22 | 北京大学 | Preparation method of total flavonoids in psoralea corylifolia and new medical application of total flavonoids in psoralea corylifolia |
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Open date: 20080827 |