CN101627994B - Novel anti-tumor application of organic small-molecular compound JFD-03554 - Google Patents
Novel anti-tumor application of organic small-molecular compound JFD-03554 Download PDFInfo
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- CN101627994B CN101627994B CN2009100533664A CN200910053366A CN101627994B CN 101627994 B CN101627994 B CN 101627994B CN 2009100533664 A CN2009100533664 A CN 2009100533664A CN 200910053366 A CN200910053366 A CN 200910053366A CN 101627994 B CN101627994 B CN 101627994B
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- 0 *c(cc1)cc(C2=C3Sc4nc(cccc5)c5[n]4C3=O)c1NC2=O Chemical compound *c(cc1)cc(C2=C3Sc4nc(cccc5)c5[n]4C3=O)c1NC2=O 0.000 description 1
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Abstract
The invention relates to a novel application of organic small-molecular compounds represented by JFP-03554 which is detected by a virtual drug screening platform based on the combination of bioinformatics and computer technology in preparing anti-tumor drugs. Compared with the existing Top I inhibitor, the compounds have the advantages of novel structure, good water solubility and better selectivity in non-small cell lung cancer (NSCLC) A549 cells, indicating that the compounds have good prospect of development. The invention further relates to a drug combination containing the small-molecular compounds and an application thereof.
Description
Technical field
The invention belongs to biotechnology and medical domain.Particularly, the present invention relates to a kind ofly based on bioinformatics and computer technology, what find through virtual screening is the application of small molecule organic compound in the preparation antitumor drug of representative with JFD-03554.
Background technology
Topoisomerase I (Top1) is the one type of indispensable enzyme that extensively exists in the organism, participates in dna replication dna, transcribes, recombinates, all crucial nuclear internal procedures such as reparation.This fermentoid influences the DNA topological structure through regulating superhelix, chain/as to go chain and nucleic acid (unknotting) effect of unhitching.Along with Top1 specific inhibitor camptothecine and analog extensive use in clinical thereof, the inhibitor that acts on Top1 more and more receives people's attention.U.S. NCI drug action mechanism analysis computer network system has been classified the Top1 inhibitor as one of six big series antineoplastic medicaments of primary study at present.
Because the Top1 inhibitor has lot of superiority, this enzyme has become the important target enzyme of design new type anticancer medicine.This kind anti-cancer drugs curative effect is high, and antitumor spectra is wide.The more important thing is; Because kinds of tumor cells; Particularly the Top1 content of colon cancer, cervical cancer, ovarian cancer etc. is much higher than normal structure; Especially activity significantly improves in S phase tumor cell, and the medicine that therefore suppresses Top1 can suppress propagation phase tumor cell dna replication dna by selectivity, has selectivity preferably.
In recent years practice shows that very high to multiple solid tumor activity as the antitumor drug of target enzyme design with Top1, selectivity is better, has great importance for cancer chemotherapy.At present existing several Top1 inhibitor get into clinical trial, particularly camptothecine and indolocarbazole compounds in succession.Yet, so far about all kinds of inhibitor and Top1 or/and the mechanism of action of DNA is still indeterminate, and there are shortcomings such as complex structure, specificity are not high, toxicity is bigger in most Top1 inhibitor, at present clinical widely use still have only camptothecine.In addition, there are some researches show that mechanism of action is identical but antitumor drug that structure type is different has different antitumor spectrums.Therefore, search the topoisomerase I inhibitor of brand new type, significant to development of new topoisomerase I inhibitor series antineoplastic medicament.
Summary of the invention
We adopt molecular docking software DOCK4.0.1 to search the ACD-3D data base who contains more than 220,000 molecule three dimensional structure; In the hope of the lead compound of the topoisomerase I inhibitor of finding the brand new type, for the antitumor drug of developing one's own intellectual property lays the foundation.
This research early stage to the Top1-DNA complex on the medicine binding site analyse in depth on the basis, carried out the work of the Top1 inhibitor of large-scale molecular virtual screening brand new type.Some known Top1 inhibitor have successfully been found in this research, like camptothecine and indolocarbazole compounds, fully show the reliability of the search strategy that we adopt, and have also tentatively investigated the binding mode of these inhibitor simultaneously.
This patent relate to one type with JFD-03554 be the micromolecule organic compound of representative in the application that is used for preparing antitumor drug, its general formula is following
Wherein R represents hydrogen, C
1～C
6Straight chain or contain alkyl, the C of side chain
1～C
6Straight chain or contain alkoxyl, the halogen of side chain.
Preferred especially, R is a methyl, and this chemical compound code name is JFD-03554, and available from Maybridge company, through mtt assay test anti tumor activity in vitro, the result finds the IC of this micromolecule organic compound to nonsmall-cell lung cancer A549 cell line
50Value is 15.16ug/mL, and the inhibition to Colo205 when 100ug/mL of this chemical compound is merely 44.66%.This this chemical compound of explanation has certain selectivity to nonsmall-cell lung cancer.The more existing Top1 inhibitor of this chemical compound, novel structure, good water solubility, and nonsmall-cell lung cancer A549 cell line had selectivity preferably, this shows that all this chemical compound has good DEVELOPMENT PROSPECT.
The invention still further relates to a kind of with JFD-03554 be the micromolecule organic compound of representative in the application that is used for preparing antitumor drug, described medicine contains pharmaceutically acceptable carrier and this micromolecular compound or its pharmaceutically acceptable salt.
The invention still further relates to a kind of is that the micromolecule organic compound of representative is in the application that is used for preparing antitumor drug with JFD-03554; Described medicine contains pharmaceutically acceptable carrier and this micromolecular compound or its pharmaceutically acceptable salt, and described pharmaceutical dosage form is tablet, capsule, powder agent, granule, suspensoid or injection.
The specific embodiment
Below in conjunction with embodiment the present invention is done specific descriptions, but the following example should not regarded limitation of the scope of the invention as.
The anti-tumor activity experiment of embodiment 1.JFD-03554
The compounds of this invention JFD-03554 has been carried out tumor cell proliferation suppressed experiment, experimental technique adopts conventional mtt assay.
1. sample preparation: after DMSO (Merck) dissolving, add solution or uniform suspension that PBS (-) is made into 1000 μ g/ml, then with PBS (-) dilution that contains DMSO.Positive control drug is amycin (DOX).
2. cell strain: A549 (human lung carcinoma cell) and Colo205 (human colon cancer cell), above cell strain by this laboratory frozen with go down to posterity.
3. culture fluid: RPMI1640+15%NBS+ is two anti-
4. other materials: full-automatic ELIASA, model: WellscanMK-2, production firm: Labsystems.Import 96 well culture plates etc.
5. test method: mtt assay.It is 4～5 * 10 that the every hole of 96 orifice plates adds concentration
4The cell suspension 100 μ l of individual/ml put 37 ℃, 5%CO
2In the incubator.Behind the 24h, add sample liquid, two multiple holes are established in 10 μ l/ holes, and 37 ℃, 5%CO
2Effect 72h.Every hole adds the MTT solution 20 μ l of 5mg/ml, adds lysate behind the effect 4h, and put in the incubator in 100 μ l/ holes, and 570nm OD value is surveyed with the full-automatic ELIASA of MK-2 in the dissolving back.
6. result of the test
Table .JFD03554 is to the in-vitro multiplication inhibitory action of human body tumour cell
Claims (3)
1. an organic micromolecule compound is in the application that is used for preparing anti-nonsmall-cell lung cancer or colon cancer medicine, and its structure is following:
Wherein, R is a methyl.
2. purposes as claimed in claim 1 is characterized in that, described medicine contains pharmaceutically acceptable carrier and this micromolecular compound or its pharmaceutically acceptable salt.
3. purposes as claimed in claim 2 is characterized in that, described pharmaceutical dosage form is tablet, capsule, powder agent, granule, suspensoid or injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2009100533664A CN101627994B (en) | 2009-06-18 | 2009-06-18 | Novel anti-tumor application of organic small-molecular compound JFD-03554 |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2009100533664A CN101627994B (en) | 2009-06-18 | 2009-06-18 | Novel anti-tumor application of organic small-molecular compound JFD-03554 |
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| CN101627994A CN101627994A (en) | 2010-01-20 |
| CN101627994B true CN101627994B (en) | 2012-05-30 |
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| CN2009100533664A Expired - Fee Related CN101627994B (en) | 2009-06-18 | 2009-06-18 | Novel anti-tumor application of organic small-molecular compound JFD-03554 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3799946A (en) * | 1972-03-13 | 1974-03-26 | Smithkline Corp | Dibenzo(b,d)pyran compounds |
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2009
- 2009-06-18 CN CN2009100533664A patent/CN101627994B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3799946A (en) * | 1972-03-13 | 1974-03-26 | Smithkline Corp | Dibenzo(b,d)pyran compounds |
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