CN104208065B - Compound MEAN application in the medicine preparing Anti-HBV activity - Google Patents
Compound MEAN application in the medicine preparing Anti-HBV activity Download PDFInfo
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- CN104208065B CN104208065B CN201410437621.6A CN201410437621A CN104208065B CN 104208065 B CN104208065 B CN 104208065B CN 201410437621 A CN201410437621 A CN 201410437621A CN 104208065 B CN104208065 B CN 104208065B
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Abstract
The invention belongs to field of medicaments, relate to the new pharmaceutical usage of the compound MEAN (6-methoxyethylamino-numonafide) of targeted human PTB (polypyrimidine tract-binding protein) albumen, be specifically related to the noval chemical compound MEAN of the targeted human PTB albumen application in the medicine preparing Anti-HBV activity。It is shown that described MEAN compound has stronger antiviral activity especially reduces HBsAg expression activity, and there is the effect of targeting PTB albumen。The lead compound of the present invention has good application prospect；Described compound can be used for preparing the medicine of anti-hepatitis B virus, it is also possible to the medicine being target with PTB albumen in preparation。
Description
Technical field
The invention belongs to field of medicaments, relate to the new pharmaceutical usage of the compound MEAN (6-methoxyethylamino-numonafide) of targeted human PTB (polypyrimidinetract-bindingprotein) albumen, be specifically related to the noval chemical compound MEAN of the targeted human PTB albumen application in the medicine preparing Anti-HBV activity。
Background technology
Known hepatitis B is one of infectious disease of serious threat human health。Hepatitis B virus (HepatitisBVirus, HBV), belongs to and bites liver property Viraceae small DNA virus。This virus was found by red Na (Dane) in nineteen sixty-five, and by its called after pellet Na (Dane) granule (SeegerandMason2000)。HBV is global distribution, there are about 3.5 hundred million HBV chronic carriers at present in the world, there are about 1,000,000 people every year and dies from the HBV disease caused。China belongs to the high epidemic regions of HBV infection。2012 " China Health statistical yearbook " show, the sickness rate of viral hepatitis in 2011 is 102.34/10 ten thousand, mortality rate be 0.06/10 ten thousand and case fatality rate be 0.34%, viral hepatitis number of the infected in 2011 is 1372344 people and death toll 830 people；Wherein, 2007 " China Health statistical yearbook " shows that hepatitis B virus surface antigen carrying rate is up to 9.8%, and total number of persons is up to people more than 100,000,000。Nucleoside medicine (NAs) and interferon are the two class medicines that the approval of current U.S. FDA can be used for clinical treatment hepatitis B。Therapeutic goal should be remove to greatest extent or suppress HBV for a long time, alleviates the necrosis of hepatocyte inflammation and hepatic fibrosis, delays and reduce the generation of the deterioration of hepatopathy rationality and complication thereof, thus making the life better quality and prolongation time-to-live。The sustainable existence of HBV and constantly duplication are the key factors causing disease progression, and therefore, Anti-HBV activity treatment is the key means controlling hepatitis B PD。
Owing to chronic hepatitis-B infection needs prolonged application, the situation is tense for NAs drug resistance in addition, interferon therapy nonreply phenomenon, seriously limits the use of this two classes medicine。Due to drug resistance and immunne response failure, cccDNA cannot remove in addition, and this two classes medicine is difficult to radical cure hepatitis B。It addition, HBV is movable closely related with host cell, HBV had both directly or indirectly affected the function of host cell in intracellular parasitic processes and consequence, also affected the allomeric function of body。The replication cycle process suppressing HBV inevitably affects Normocellular function, has side effects。Therefore, the urgent demand of current the world of medicine a kind of for HBV infection and also specific medicament that side effect is less come out, to improve the therapeutic effect of the relevant malignant disease of HBV。
Exploitation new target drone and non-nucleoside are the key solving the problems referred to above like thing。Non-nucleoside Anti-HBV activity small-molecule drug is not yet had to be approved for the treatment of HBV infection at present。Along with people are to the pathogenetic further investigation of HBV, Anti-HBV drugs exploitation target, from viruses adsorption, DNA replication dna, assembling, release links associated protein, enzyme etc., extends to the corresponding target of mankind itself。People's vivo protein is the important cofactor of hbv replication such as (PTB), in vivo test finds that PTB is at flaviviridae inwardness ribosomal entry site (internalribosomeentrysites, IRES) translation initiation regulated plays an important role, the minimizing of PTB expression is probably destruction HBV posttranscriptional regulatory element (posttranscriptionalregulatoryelement, PRE) main cause of function, the function of interference PTB cofactor, the effective inhibition HBV replication of energy, therefore with PTB for drug target, it it is the ideal orientation of development of new Anti-HBV drugs。
Compound MEAN (6-methoxyethylamino-numonafide) is a newly synthesized class numonafide compound, the synthesis path document of this compound has been reported (JohnT.Norton, Anti-CancerDrugs2008,19 (11)), but its antiviral activity has no report, the present invention provides the new application of compound MEAN (6-methoxyethylamino-numonafide) Anti-HBV effect。
The structural formula of compound MEAN (6-methoxyethylamino-numonafide) is as follows:
Molecular weight: 342.18。
Summary of the invention
The invention aims to provide the application of the compound MEAN of the Anti-HBV activity function with targeted human PTB。
The compound MEAN (6-methoxyethylamino-numonafide) application in preparing Anti-HBV activity preparation or medicine shown in formula (1)。
Compound MEAN suppresses the application in the medicine of emiocytosis HBsAg in preparation。
Compound MEAN suppresses the application in the medicine of emiocytosis HBeAg in preparation。
Compound MEAN application in the preparation or medicine of preparation treatment hepatitis B。
A kind of Anti-HBV activity preparation, is 8 μMs including concentration, the compound MEAN of 4 μMs or 2 μMs。Preferably, in described preparation, compound MEAN concentration is 8 μMs。This preferred concentration, for suppressing the most obvious concentration of virus effectiveness under safe dose。
Compound MEAN is being prepared with PTB albumen for the application in the medicine of target。
Compound MEAN is being prepared with people's PTB albumen for the application in the medicine of target。
MEAN compound is carried out Anti-HBV activity inhibition of DNA replication experiment at cellular level by the present invention, whether detection MEAN suppresses virus, find that MEAN can suppress HBsAg (HBsAg) and E antigen (HBeAg) to be secreted into supernatant, then detect MEAN with westernblotting and can lower PTB expression。It is shown that described MEAN compound has stronger antiviral activity especially reduces HBsAg expression activity, and there is the effect of targeting PTB albumen。The lead compound of the present invention has good application prospect；Described compound can be used for preparing the medicine of anti-hepatitis B virus, it is also possible to the medicine being target with PTB albumen in preparation。
The compound MEAN of the present invention as the further structure optimization of lead compound, can prepare preparation or the medicine of Anti-HBV effect。This patent report external impact of MEAN is as the PTB expressing quantity of the HBV infection cell model of DNA viruses, and existing bibliographical information MEAN can the PTB of vitro inhibition picornavirus infection cell model from nucleus to Cytoplasm transposition, thus suppressing the duplication of RNA viruses。
Having the advantages of of the MEAN compound of the targeted human PTB albumen of the present invention:
1, there is stronger Anti-HBV effect and the effect of targeting PTB albumen；
2, described MEAN compound can be used for preparing preparation or the medicine of Anti-HBV effect or treatment hepatitis B；
3 and for preparing the medicine being target with PTB albumen。
Accompanying drawing explanation
Fig. 1 shows the MEAN compound of the present invention toxic effect to HepG2.2.15 cell。
Fig. 2 shows that the MEAN compound of the present invention is to the inhibitory action of HBVDNA in HepG2.2.15 cell, found that HBV inhibition is not as notable。
Fig. 3 shows that MEAN compound of the present invention is to the inhibitory action of HBeAg in HepG2.2.15 cell, and wherein, 8 μMs of concentration are better to HBeAg inhibition。
Fig. 4 shows the impact on HepG2.2.15 emiocytosis HBsAg of the MEAN compound of the present invention, wherein, 8 μMs, 4 μMs and 2 μMs of concentration HBsAg inhibition is all better, and in dose-dependent effect。
Fig. 5 shows that compound of the present invention is to the inhibitory action of PTB albumen in HepG2.2.15 cell, and result display MEAN substantially lowers PTB expressing quantity in cell。
Specific embodiment
By concrete drawings and Examples, the MEAN compound of the targeted human PTB albumen of the present invention will be described in detail in order to make it easy to understand, following。It needs to be noted, instantiation and accompanying drawing are merely to explanation, the present invention according to illustrating herein, can be made various correction and change by obvious those of ordinary skill in the art within the scope of the invention, and these are revised and change and also include in the scope of the present invention。
In the following example, method therefor is if no special instructions, is conventional method。Material required in following example or reagent, be market if no special instructions and buy。
The synthesis path document of compound MEAN (6-methoxyethylamino-numonafide) has been reported (JohnT.Norton, Anti-CancerDrugs2008,19 (11))。Data analysis in embodiment adopts SPSS16.0 statistical analysis software to carry out one factor analysis of variance and One-WayANOVA multiple-group analysis。
Embodiment 1
Target compound is on the HBVDNA impact replicated
As it is shown in figure 1,40 μMs and 20 μMs of compounds HepG2.2.15 cell is toxic, 10 μMs to HepG2.2.15 cytotoxic, IC50 is 14.89 μMs。Therefore adopt 10 μMs or and following concentration as intervene concentration measure Anti-HBV activity drug effect。
Compound is with 8 μMs, and 4 μMs and 2 μMs of concentration intervention HepG2.2.15 cell 2d, employing fluorescence quantitative PCR method detects HBVDNA level in cell conditioned medium liquid。Instrument used is ABI7500 type real-time fluorescence quantitative PCR system。Concrete steps operate according to the description of hbv nucleic acid immue quantitative detection reagent box, it is briefly described below: with the viral DNA of the nucleic acid extraction liquid extracting cells and supernatant of test kit, then with viral DNA for template, the reaction system of preparation includes the components such as fluorescence quantitative PCR reaction solution, primer and probe。PCR reaction condition is 95 DEG C of 3min of denaturation；95 DEG C of 10s of degeneration, annealing extends and 60 DEG C of 35s of fluorescent collecting, 40 circulations totally。
As in figure 2 it is shown, compared with blank group, MEAN suppresses virus effectiveness there was no significant difference。
Embodiment 2
The target compound impact on HBeAg secreting, expressing
By compound with 8 μMs, 4 μMs and 2 μMs of concentration intervention HepG2.2.15 cell 2d, adopt HBeAg level in Electrochemiluminescence technology detection cell conditioned medium liquid, instrument used is AbbottArchitectI2000sr (Abbott), reagent used is hepatitis B HBeAg detection by quantitative description (Abbott) supporting with AbbottArchitectI2000sr instrument, and concrete steps operate to specifications。
As it is shown on figure 3, compared with blank group, HBeAg inhibition is had significant difference by 8 μMs of compound MEAN, and other concentration there was no significant difference。
The target compound impact on HBsAg secreting, expressing
By compound with 8 μMs, 4 μMs and 2 μMs of concentration intervention HepG2.2.15 cell 2d, adopt HBsAg level in Electrochemiluminescence technology detection cell conditioned medium liquid, instrument used is AbbottArchitectI2000sr (Abbott), reagent used is hepatitis B HBsAg detection by quantitative description (Abbott) supporting with AbbottArchitectI2000sr instrument, and concrete steps operate to specifications。
As shown in Figure 4, compared with blank group, 8 μMs, 4 μMs and 2 μMs of concentration all that HBsAg inhibition is better, have significant difference compared with blank group, and in dose-dependent effect, in safe-dosaging limits, 8 μMs is preferred concentration, it is suppressed that virus HBsAg effect is the most obvious。
Embodiment 3
The target compound impact on PTB protein expression
WesternBlot detects PTB protein expression level。Extract total protein of cell and carry out quantitative analysis according to the operating instruction of BCA protein quantification test kit。Taking above-mentioned total protein of cell 40 μ g uses SDS-PAGE to separate and transfer on nitrocellulose filter。After 1% bovine serum albumin is closed, by film and antibody PTB (self-control) and 4 DEG C of overnight incubation of β-actin (Cellsignalingtechnology), two anti-hatch 1 hour after detect with chemical illuminating reagent ECL (Pierce)。
As it is shown in figure 5, compared with blank group, MEAN can significantly lower PTB expressing quantity in cell, has significant difference。With bibliographical information the difference is that, for RNA viruses, MEAN can the PTB karyon-kytoplasm transposition of vitro inhibition RNA infection cell model, but the expression of PTB total protein can not be suppressed。
Claims (6)
1. compound MEAN application in preparing Anti-HBV activity preparation or medicine shown in formula (1)。
2. application according to claim 1, it is characterised in that: described Anti-HBV activity preparation or medicine are the medicine suppressing emiocytosis HBsAg。
3. application according to claim 1, it is characterised in that: described Anti-HBV activity preparation or medicine are the medicine suppressing emiocytosis HBeAg。
4. compound MEAN application in the preparation or medicine of preparation treatment hepatitis B。
5. the application according to claim 1 or 2 or 3, it is characterised in that: it is 8 μMs that described medicine or preparation include concentration, the compound MEAN of 4 μMs or 2 μMs。
6. application according to claim 5, it is characterised in that: in described preparation, compound MEAN concentration is 8 μMs。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410437621.6A CN104208065B (en) | 2014-08-31 | 2014-08-31 | Compound MEAN application in the medicine preparing Anti-HBV activity |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410437621.6A CN104208065B (en) | 2014-08-31 | 2014-08-31 | Compound MEAN application in the medicine preparing Anti-HBV activity |
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| CN104208065A CN104208065A (en) | 2014-12-17 |
| CN104208065B true CN104208065B (en) | 2016-06-22 |
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| CN201410437621.6A Expired - Fee Related CN104208065B (en) | 2014-08-31 | 2014-08-31 | Compound MEAN application in the medicine preparing Anti-HBV activity |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009089537A2 (en) * | 2008-01-11 | 2009-07-16 | Northwestern University | Anti-cancer compounds |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009089537A2 (en) * | 2008-01-11 | 2009-07-16 | Northwestern University | Anti-cancer compounds |
Non-Patent Citations (2)
| Title |
|---|
| Methoxyethylamino-numonafide Is an Efficacious and Minimally Toxic Amonafide Derivative in Murine Models of Human Cancer;Yanning Liu 等;《Neoplasia》;20111231;第13卷(第5期);第453-460页 * |
| Microfluidic fabrication of 6-methoxyethylamino numonafide-eluting magnetic microspheres;D.-H. Kim 等;《Acta Biomaterialia》;20140228;第10卷(第2期);第742-750页 * |
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| CN104208065A (en) | 2014-12-17 |
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