CN102697768A - Application of luteolin flavonoid compounds in preparation of anti-tumor medicaments - Google Patents
Application of luteolin flavonoid compounds in preparation of anti-tumor medicaments Download PDFInfo
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- CN102697768A CN102697768A CN2012101864971A CN201210186497A CN102697768A CN 102697768 A CN102697768 A CN 102697768A CN 2012101864971 A CN2012101864971 A CN 2012101864971A CN 201210186497 A CN201210186497 A CN 201210186497A CN 102697768 A CN102697768 A CN 102697768A
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- VOCGSQHKPZSIKB-UHFFFAOYSA-N CC(C)=CCc(c(OC)c1)cc(C(C2)=O)c1OC2c(cc1)ccc1O Chemical compound CC(C)=CCc(c(OC)c1)cc(C(C2)=O)c1OC2c(cc1)ccc1O VOCGSQHKPZSIKB-UHFFFAOYSA-N 0.000 description 1
- VFMMPHCGEFXGIP-UHFFFAOYSA-N O=C1c(ccc2c3cccc2)c3OC(c2ccccc2)=C1 Chemical compound O=C1c(ccc2c3cccc2)c3OC(c2ccccc2)=C1 VFMMPHCGEFXGIP-UHFFFAOYSA-N 0.000 description 1
- SRNPMQHYWVKBAV-UHFFFAOYSA-N Oc(c(O)c1)ccc1C(Oc1c2cccc1)=CC2=O Chemical compound Oc(c(O)c1)ccc1C(Oc1c2cccc1)=CC2=O SRNPMQHYWVKBAV-UHFFFAOYSA-N 0.000 description 1
- IQPNAANSBPBGFQ-UHFFFAOYSA-N Oc(cc1O)cc(OC(c(cc2O)ccc2O)=C2)c1C2=O Chemical compound Oc(cc1O)cc(OC(c(cc2O)ccc2O)=C2)c1C2=O IQPNAANSBPBGFQ-UHFFFAOYSA-N 0.000 description 1
- FXNFHKRTJBSTCS-UHFFFAOYSA-N Oc1cc(OC(c2ccccc2)=CC2=O)c2c(O)c1O Chemical compound Oc1cc(OC(c2ccccc2)=CC2=O)c2c(O)c1O FXNFHKRTJBSTCS-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to application of luteolin flavonoid compounds in preparation of medicaments for treating diseases (such as tumors and autoimmune diseases) related with high expression of cell apoptosis resistant members in a Bc1-2 protein family based on computer-aided virtual medicament screening discovery. The invention also relates to application of the compounds in preparation of synergists. The synergists and other anti-tumor medicaments or radiotherapy are used together for treating the tumors.
Description
Technical field
The invention belongs to biotechnology and medical domain.Particularly, the present invention relates to a kind of purposes of one type of similar flavone compound of luteolin in the medicine of the preparation disease (like tumor, autoimmune disease etc.) relevant of finding based on area of computer aided medicine virtual screening with Bcl-2 protein family anti-apoptotic members high expressed.The invention still further relates to the purposes of this compounds in the preparation synergist, said synergist and other antitumor drug or radiotherapy share with the treatment tumor.
Background technology
Apoptosis is that cell receives the programmed cell death that carries out behind certain signal stimulus, is a kind of basic biological phenomena of cell.And the Bcl-2 protein family plays important regulatory role at the apoptosis path.It can be divided into anti-apoptosis member (like Bcl-2, Bcl-x
L, Mcl-1 etc.) and two types of short apoptosis members.Research shows that the overexpression of Bcl-2 protein family anti-apoptotic members can cause the normal cell apoptosis pathway to be obstructed, and is relevant with the generation of numerous disease (like tumor, autoimmune disease etc.), particularly tumor generation and one of drug-fast major reason takes place.(Nature?2000，407，796-801；Nat?Rev?Cancer?2004，4.592-603.)
Research shows that Bcl-2 protein family anti-apoptotic members is found in overexpression in many tumors, and the expression in different tumors and different tumors subtypes is different, and (Oncogene 2003,22,8590-607; Oncogene 2008,27,6398-406).Through suppressing the anti-apoptotic effect of the anti-apoptotic members of overexpression in the tumor cell, can recover its normal apoptosis pathway, increase its sensitivity to chemotherapy radiotherapy, be the New Policy of treatment tumor.The anti-apoptosis member of Bcl-2 protein family anti-cell combines to interact with short apoptosis member's Bcl-2 protein family conservative region (BH) 3 through its surperficial hydrophobic groove, regulates the normal physiology apoptosis of cell.Micromolecular inhibitor can disturb short apoptosis member BH3 zone to combine with it to play and promote apoptotic effect through being incorporated into anti-apoptosis member surface hydrophobicity groove.(Nat Rev Cancer 2005,5,876-85; Kelly, P.N.; Cell Death Differ2011; 18; 1414-24.) in recent years this type small molecular inhibitor caused the extensive interest of researcher, found a series of micromolecular inhibitors through different approaches, three (ABT-263 are wherein arranged; AT-101 GX15-07) gets into clinical research as oral antitumor drug.Result of study shows that Bcl-2 protein family anti-apoptotic members micromolecular inhibitor shows the good antitumor effect and to other antitumor drug or radiocurable potentiation synergism, has good development prospect.(Nat Rev Drug Discov 2008,7,989-100; Chinese Journal of New Drugs 2008,17,2008-2013.; Pharmacy progress 2004,28,97-103; Clin Cancer Res 2012,18,1-7; J Thorac Oncol 2011,6,1757-1760; Lung Cancer 2011,74,481-485)
Summary of the invention
This research is (Bioorg Med Chem Lett, 2012,22,39-44 on the basis of in earlier stage analysing in depth Bcl-2 protein family anti-apoptotic members inhibitor binding cavity and the three-dimensional Pharmacophore Model of structure micromolecular inhibitor; Bioorgan Med Chem, 2007,15,6407-6417; SCI, 2008,29,591-595; The chemistry journal, 2006,64,2327-2332; The chemistry journal; 2006,64,2215-2220); Carried out area of computer aided medicine virtual screening, in the hope of the lead compound of the Bcl-2 protein family anti-apoptotic members micromolecular inhibitor of finding the brand new type to this breadboard natural product active substance structural database.The higher chemical compound of marking carries out the evaluation of target protein affinity to it in the virtual screening through buying, the discovery that we are successful luteolin have preferably that Bcl-2 protein family anti-apoptotic members suppresses activity.Then on this basis, we have further bought the similar flavone compound of a collection of luteolin and have carried out the evaluation of target protein affinity, in the hope of finding better Bcl-2 protein family anti-apoptotic members micromolecular inhibitor.
The present invention relates to suc as formula the purposes of the flavone compound shown in the I in the medicine of the preparation disease (like tumor, autoimmune disease etc.) relevant with Bcl-2 protein family anti-apoptotic members high expressed.
Available from the brilliant pure Industrial Co., Ltd. (Aladdin reagent) in Shanghai, A Faaisha chemistry company limited (Alfa Aesar) and Sa grace chemical technology (Shanghai) Co., Ltd. (An Naiji chemistry), the purposes that its Bcl-2 protein family anti-apoptotic members suppresses in the activity treatment of diseases medicine relevant with Bcl-2 protein family anti-apoptotic members high expressed with preparation is not seen bibliographical information to above chemical compound respectively.
Through fluorescence polarization (FP) method test b cl-2 protein family anti-apoptotic members affinity; The similar flavone compound of luteolin shown in the discoverable type I can disturb short apoptosis member BH3 zone to combine with it through being incorporated into the anti-apoptosis member of Bcl-2 protein family surface hydrophobicity groove as a result.Therefore this compounds can play and promote apoptotic effect, can be used as with the relevant treatment of diseases medicine of Bcl-2 protein family anti-apoptotic members high expressed to be used for animal, is preferred for mammal, particularly the people.
Through mtt assay test anti tumor activity in vitro, the result shows the propagation of the tumor cell of the ability of chemical compound shown in formula I better inhibited Bcl-2 protein family anti-apoptotic members high expressed.Tumor comprises the esophageal carcinoma, laryngeal carcinoma, thyroid carcinoma, pulmonary carcinoma, breast carcinoma, leukemia, melanoma, carcinoma of prostate, hepatocarcinoma, breast carcinoma, cervical cancer and colon cancer.
The invention still further relates to suc as formula the purposes of the flavone compound shown in the I in the medicine of the preparation disease (like tumor, autoimmune disease etc.) relevant with Bcl-2 protein family anti-apoptotic members high expressed, described medicine contains pharmaceutically acceptable carrier.
The invention still further relates to suc as formula the purposes of the flavone compound shown in the I in the medicine of the preparation disease (like tumor, autoimmune disease etc.) relevant with Bcl-2 protein family anti-apoptotic members high expressed, described pharmaceutical dosage form is tablet, capsule, powder agent, granule, suspensoid or injection.
Research shows that Bcl-2 protein family anti-apoptotic members micromolecular inhibitor and other antitumor drug or radiotherapy share and have potentiation synergism preferably; Other antitumor drug comprise etoposide, amycin, cisplatin, paclitaxel, methylprednisolone, melphalan, dexamethasone etc., and (Nature 2005; 435,677-81; J.Med.Chem.2006,49,1165-1181, Cancer res.2006,66,8731-8739; Clin.Cancer Res.2007,13,621-629).Therefore the invention still further relates to suc as formula the purposes of the flavone compound shown in the I in the preparation synergist, said synergist and other antitumor drug or radiotherapy share with the treatment tumor.
Description of drawings
Bcl-2, the Bcl-x of the different tumor cell lines of Fig. 1
LWith the Mcl-1 expressing quantity
The practical implementation method
The present invention can be able to explanation through following embodiment, but these embodiment do not mean that the present invention is had any restriction.
Embodiment 1: similar flavone compound of luteolin and Bcl-2, Bcl-x
LWith three kinds of albumen affinity tests of Mcl-1
Experimental technique: with reference to previous work and pertinent literature (Bioorg Med Chem Lett 2012,22,39-44; ChemMedChem 2011,6,904-21),, adopt fluorescence polarization (FP) method to investigate the target compound competition and suppress Bcl-2, Bcl-x as the contrast medicine with ABT-263
LEstimate the affinity of itself and target protein with the bonded ability of BH3 peptide section (fluorescein-labelled) of Mcl-1 albumen and pro apoptotic protein Bim or Bid.The fluorescence polarization signal is to detect under the condition of 535nm at excitation wavelength 485nm and wavelength of transmitted light by spectrofluorophotometer.With the BH3 peptide section of series concentration target compound and fluorescein-labeled Bim or Bid and Bcl-2, Bcl-x
LOr after Mcl-1 albumen at room temperature cultivates 20 minutes together, detect its fluorescence polarization signal, calculate the IC of this chemical compound
50Value.And according to employed albumen total concentration, the total concentration of fluorescent polypeptide, the dissociation constant of albumen-polypeptide complex and the IC of detection compound in measuring
50Value, the competitive inhibition constant K of calculating detection compound
i
Experimental result: 1-6 of chemical compound shown in the formula I and ABT-263 and Bcl-2, Bcl-x
LAs shown in the table with Mcl-1 protein affinity test result.
The result shows, similar flavone compound of these luteolins and Bcl-2, Bcl-x
LHas wide spectrum binding ability in various degree with Mcl-1 albumen; Wherein the affinity of chemical compound 1-3 is superior to chemical compound 4-6 generally; The affinity of part of compounds and target protein is suitable with positive control medicine AT-101, and part of compounds obviously is better than positive control medicine ABT-263 for the proteic affinity of Mcl-1.Therefore the similar flavone compound of these luteolins has preparation and the relevant treatment of diseases medicine of Bcl-2 protein family anti-apoptotic members high expressed, and prepares synergist and other antitumor drug or radiotherapy and share to treat the potential use of tumor.
Embodiment 2: human tumour cell line's Bcl-2, Bcl-x
LDetect with three kinds of albumen expressions of Mcl-1
Experimental technique: with reference to pertinent literature (J.Med.Chem.; 2007; 50 (8), 1723-1726), be that HUVEC is as contrast with normal person's huve cell;, adopt DC test kit (BIO-RAD company) that different tumor cell lines are carried out Western-blot and detect its protein B cl-2, Bcl-x as interior mark with GAPDH
LWith the Mcl-1 expressing quantity.
Experimental result: with normal person's huve cell is that HUVEC compares, Bcl-2, the Bcl-x of human esophagus cancer KYSE-150, people's laryngeal carcinoma Hep2, human thyroid cancer CNE, people's pulmonary carcinoma A549, human breast carcinoma MDA-MB-435, human leukemia THP-1, HL-60, K562, Humanmachine tumour A375, human prostata cancer PC3, people's hepatocarcinoma HepG2, human breast carcinoma MCF-7, human cervical carcinoma HELA and human colon carcinoma HCT116 cell line
LWith three kinds of albumen of Mcl-1 to a certain degree high expressed is arranged.The protein expression situation of different tumor kinds is variant, and wherein proteic expression is starkly lower than other cell line in HELA and the HCT116 cell line.The dissimilar protein expression situation of tumor of the same race are also variant, and wherein proteic expression is starkly lower than MDA-MB-435 in the MCF-7 cell line.Part Western-blot testing result is as shown in Figure 1.
Embodiment 3: the similar flavone compound of luteolin is for the in-vitro multiplication inhibitory action of human body tumour cell
Experimental technique: detect and pertinent literature (Bioorg Med Chem Lett 2012,22,39-44 according to experiment; Nature.2005,437,677-681), select protein B cl-2, Bcl-x
LThe tumor cell line of different expression with Mcl-1 albumen.As the contrast medicine, detect the activity that all target compounds suppress tumor cell proliferation with ABT-263 with mtt assay.Tumor cell is divided in 96 orifice plates, add the target compound of variable concentrations, with the culture medium culturing that contains serum 4 days.Add MTT afterwards, detect the trap of solution with ELIASA at 37 ℃ after down cultivating 4 hours, through relatively estimating its cell inhibitory effect situation with blank.
Experimental result: 1-6 of chemical compound shown in the formula I and ABT-263 are as shown in the table to the inhibition activity of different people tumor cell line.
ND: not test
Experimental result shows that the similar flavone compound of these luteolins has extensive inhibition activity for multiple human body tumour cell, and wherein part of compounds is suitable with AT-101 to the inhibitory action and the positive control medicine ABT-263 of kinds of tumors.The higher chemical compound 1-3 of target protein affinity is for Bcl-2, Bcl-x
LObviously be superior to the lower cell line of expression (HCT116, HELA and MCF-7) with the inhibitory action of Mcl-1 expression tumors of higher cell line.These results all show the similar flavone compound of these luteolins and Bcl-2 protein family anti-apoptotic members to combine possibly be major reason of its performance antitumor action, therefore have the potential use in the tumor treatment medicine of preparation Bcl-2 protein family anti-apoptotic members high expressed.
Claims (6)
1. suc as formula the purposes of the arbitrary flavone compound shown in the I in the preparation treatment of diseases medicine relevant with Bcl-2 protein family anti-apoptotic members high expressed.
2. purposes as claimed in claim 1 is characterized in that, described disease is a tumor.
3. tumor as claimed in claim 2 is selected from human esophagus cancer, people's laryngeal carcinoma, human thyroid cancer, people's pulmonary carcinoma, human breast carcinoma, human leukemia, Humanmachine tumour, human prostata cancer, people's hepatocarcinoma, human breast carcinoma, human cervical carcinoma and human colon carcinoma.
4. purposes as claimed in claim 1 is characterized in that described medicine contains pharmaceutically acceptable carrier.
5. purposes as claimed in claim 1 is characterized in that, described pharmaceutical dosage form is tablet, capsule, powder agent, granule, suspensoid or injection.
6. the arbitrary flavone compound shown in claim 1 Chinese style I is in the purposes of preparation in the synergist, and said synergist and other antitumor drug or radiotherapy share to treat tumor.
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| CN104955831A (en) * | 2012-10-11 | 2015-09-30 | 阿玛纶生物有限公司 | Novel flavonoid compounds and uses thereof |
| US20160368886A1 (en) * | 2013-06-25 | 2016-12-22 | Universita' Degli Studi Di Siena | Multitarget hedgehog pathway inhibitors and uses thereof |
| CN107320470A (en) * | 2017-07-06 | 2017-11-07 | 中国科学院上海有机化学研究所 | A kind of application of flavone compound |
| CN113713026A (en) * | 2021-08-20 | 2021-11-30 | 上海市第七人民医院(上海中医药大学附属第七人民医院) | Anti-tumor extract of daphne genkwa as well as preparation method and application thereof |
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| CN104230869A (en) * | 2014-08-01 | 2014-12-24 | 中国人民解放军第二军医大学 | Substitutive flavonoid compound as well as preparation method and application thereof |
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| CN113713026A (en) * | 2021-08-20 | 2021-11-30 | 上海市第七人民医院(上海中医药大学附属第七人民医院) | Anti-tumor extract of daphne genkwa as well as preparation method and application thereof |
| CN113713026B (en) * | 2021-08-20 | 2022-08-16 | 上海市第七人民医院(上海中医药大学附属第七人民医院) | Anti-tumor extract of daphne genkwa as well as preparation method and application thereof |
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Application publication date: 20121003 |