CN105267211B - Aspochalasin classes compound prepare AntiHIV1 RT activity hide drug and treat AIDS-treating medicine in application - Google Patents
Aspochalasin classes compound prepare AntiHIV1 RT activity hide drug and treat AIDS-treating medicine in application Download PDFInfo
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- CN105267211B CN105267211B CN201510703674.2A CN201510703674A CN105267211B CN 105267211 B CN105267211 B CN 105267211B CN 201510703674 A CN201510703674 A CN 201510703674A CN 105267211 B CN105267211 B CN 105267211B
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Abstract
The invention discloses a kind of Aspochalasin classes compound prepare AntiHIV1 RT activity hide drug and treat AIDS-treating medicine in application, Aspochalasin classes compound be Formulas I structure, the R1、R2、R3、R4And R5For one or more of hydrogen, hydroxyl, carbonyl, double bond, epoxy, methyl, alkane amide, R1、R2、R3、R4And R5It is identical or differ.The Aspochalasin class compounds are had the function of that HIV is activated to hide, can be used in combination with antiretroviral drugs, can remove the cell for the latent infection being activated, be accelerated the removing in latent virus library with this, for the treatment of AIDS.
Description
Technical field
The present invention relates to the technical fields for the treatment of AIDS-treating medicine, and in particular to prepared by Aspochalasin classes compound
AntiHIV1 RT activity hide drug and treat AIDS-treating medicine in application.
Background technology
Acquired immunodeficiency syndrome (AIDS) is a kind of serious harm people as caused by infecting AIDS virus (HIV)
Highly active antiretroviral therapy (the Highly active of the communicable disease of life and health, at present clinical use
Antiretroviral therapy, HAART), although the life span and quality of aids patient can be greatlyd improve,
Meeting and host cell integral after HIV infection human body form the virus base that can not be removed by HAART.These latent virus are stopping
It can reactivate and quick rebound after HAART, therefore AIDS patient needs long-term administration, and long-term administration can cause virus variation,
Drug resistance increases, and adverse drug reaction increases and makes treatment failure (Ho, D.D.Toward HIV eradication or
remission:The tasks ahead.Science, 1998.280:1866–1867.).Studies have shown that HIV is difficult in vivo
A major reason being completely removed is that HIV can hide in the memory CD4+T cells of tranquillization, which is
It being generated by the activation CD4+T cell transformations of sub-fraction HIV infection, the provirus integrated lacks transcriptional activity, thus,
It will not be by immune system and the drug attack of anti-reverse transcription enzymophathy poison.Although infected individuals carry latent infected cells quantity compared with
It is few, but attenuation rate is so slow so that be intended within the individual survival phase only by HAART treatments by its thoroughly removing be impossible
's.Therefore, the tranquillization CD4+T cells of HIV latent infections are the main portions for forming body inner virus bunker (reservoir)
Point, while be also huge obstacle [Finzi, the D.et al.Latent that current clinical treatment cannot thoroughly remove HIV
infection of CD4+T cells provides a mechanism for lifelong persistence of
HIV-1,even in patients on effective combination therapy.Nature Med.1999,5,
512–517]。
Real successfully case prompting, " functionality " of AIDS cures what be can be achieved on, and removes HIV latent virus
Library be most promising method [realize the functional strategy cured of AIDS, China's AIDS venereal disease, 2015,21:253-
256], thus explore activation and remove HIV hide library method to obtain the clinical functioning healing of AIDS, be current AIDS
The hot spot of research.The HIV of clinical research at present activator of hiding has cell factor IL-2, cell factor IL-7, and histone goes second
Deacerylase inhibitors Vorinostat and methylase inhibitors.Grinding drug, all there are different deficiencies, such as activation effect above
Fruit is weak, and adverse reaction is apparent etc..Thus, it is found that more safely and effectively HIV hides activator and corresponding therapeutic scheme has been
The task of top priority.
Invention content
The present invention provides a kind of Aspochalasin classes compound prepare AntiHIV1 RT activity hide drug and prepare treatment Chinese mugwort
Grow the application in medicine.
Aspochalasin classes compound prepare AntiHIV1 RT activity hide drug and prepare treat AIDS-treating medicine in should
With Aspochalasin classes compound provided by the invention is shown in Formulas I for a kind of drug with activation HIV latent effects
Structure, the structure shown in Formula II is on the basis of Formulas I structure, is labelled with A, B, C, Aspochalasin classes of the invention
Object is closed, A, B, C ring form 5/6/11 tricyclic a pair of horses going side by side and closes structure, and the big rings of C there can be different substitutions.The i.e. described R1、R2、R3、R4With
R5For one or more of hydrogen, hydroxyl, carbonyl, double bond, epoxy, methyl, alkane amide etc. (including two kinds), R1、R2、
R3、R4And R5It is identical or differ.
Aspochalasin classes compound provided by the invention can be mixture, or single compound,
Aspochalasin class compounds may include Aspochalasin E (R1、R2、R3、R4And R5Respectively OH, OH, OH, H and H),
Aspochalasin M(R1、R2、R3、R4And R5Respectively H ,=O, OH, H and H), Aspochalasin P (R1、R2、R3、R4With
R5Respectively H, OH ,=O, H and H), Aspochalasin C (R1、R2、R3Respectively H, OH, OH, R4And R5Form double bond) and
19,20-dihydro-Aspochalasin C(R1、R2、R3、R4And R5Respectively H, OH, OH, H and H) and combinations thereof.
The i.e. described Aspochalasin classes compound for Aspochalasin E, Aspochalasin M,
One or more of Aspochalasin P, Aspochalasin C, 19,20-dihydro-Aspochalasin C,
Wherein, R in Aspochalasin E1、R2、R3、R4And R5Respectively OH, OH, OH, H and H, R in Aspochalasin M1、R2、
R3、R4And R5Respectively H ,=O, OH, H and H, R in Aspochalasin P1、R2、R3、R4And R5Respectively H, OH ,=O, H and H,
R in Aspochalasin C1、R2、R3Respectively H, OH, OH, R4And R5Formation double bond, 19,20-dihydro-Aspochalasin
R in C1、R2、R3、R4And R5Respectively H, OH, OH, H and H.
Further preferably, the Aspochalasin classes compound is Aspochalasin C, Aspochalasin C
Middle R1、R2、R3Respectively H, OH, OH, R4And R5Form double bond.The HIV to hide in infection cell can significantly be made in low concentration
Expression, relative activation rate are high, are used in combination with antiretroviral drugs, can preferably remove the thin of the latent infection that is activated
Born of the same parents accelerate the removing in latent virus library with this, for the treatment of AIDS.
Aspochalasin classes compound can be commercially available, can also be by the mould Spicariaelegans of Qu Lisui
(Eur.J.Org.Chem.2009,3045-3051) or Trichodermagamsii (Fitoterapia, 2012,541-
544) or the fungus fermentation products such as aspergillus flavipes Aspergillus flavipes (J.Nat.Prod.2004,328-332) carry
It takes isolated.
The present invention carries out Activity Screening Test using HIV latent cells model, as a result shows Aspochalasin class chemical combination
Object can make the HIV to hide in infection cell expression, have the function of that intervening HIV hides, combining with antiretroviral drugs makes
With can remove the cell for the latent infection being activated, accelerate the removing in latent virus library with this, thorough cure for AIDS carries
For new approach.
Aspochalasin classes compound provided by the invention and antiretroviral drugs, which are combined, is preparing treatment AIDS
Application in medicine.
Aspochalasinl classes compound provided by the invention is particularly suitable for the drug combination with other AntiHIV1 RT activities.Especially
The active constituent of the present invention can be used in combination with antiretroviral drugs, the cell of latent infection be removed, for AIDS
The treatment of disease.The inverase includes：First, efabirenz：Zidovudine, didanosine, Zha Xita
Shore, stavudine, Lamivudine, Abacavir；2nd, non-nucleoside reverse transcriptase inhibitor：Nevirapine, Delavirdine, according to
Fei Weilun；Three and protease inhibitors：Inverase, indinavir, Ritonavir, Nai Feinawei, anpunave.It is i.e. described
Antiretroviral drugs for Zidovudine, didanosine, zalcitabine, stavudine, Lamivudine, Abacavir, how
One kind in Wei Laping, Delavirdine, efavirenz, inverase, indinavir, Ritonavir, Nai Feinawei, anpunave
Or two or more (including two kinds).
Compared with prior art, main advantages of the present invention include：
1. proposing the new application of Aspochalasin class compounds, can significantly make in infection cell in low concentration
Latent HIV expression.
2. Aspochalasin classes compound described in can be used as active constituent, prepare with activation HIV latent effects
Drug.
3. Aspochalasin classes compound described in can further can be used in combination with antiretroviral drugs, for Chinese mugwort
Thorough cure for growing disease provides new approach.
Specific embodiment
Embodiment 1
HIV hide induced activation experiment
By the cell of screening active ingredients by every hole 2 × 104A plantation adds in 100 microlitres per hole and contains 10%FBS in 96 orifice plates
1640 culture mediums (Gibco) of (fetal calf serum, Gibco).After 24 hours, certain density Aspochalasin classes chemical combination is added in
Object.After drug-treated cell 72 hours, in fluorescence microscopy Microscopic observation cell GFP expressions, and collect cell and carry out streaming
Cell art detects, analysis of fluorescence cell proportion.
Embodiment 2
With the Aspochalasin E (R of final concentration of 20 mcg/ml1、R2、R3、R4And R5Respectively OH, OH, OH, H and
H HIV latent infected cells models) are handled, after it is acted on 3 days, pass through the fluorescence microscopy to reporter gene green fluorescent protein
Sem observation and Flow cytometry analyze the activation efficiency of HIV latent infected cells, the results show that HIV latent infected cells
Relative activation rate is 62% after Aspochalasin E processing.
Embodiment 3
With the Aspochalasin C (R of final concentration of 20 mcg/ml1、R2、R3Respectively H, OH, OH, R4And R5It is formed
Double bond) processing HIV latent infected cells models, after it is acted on 3 days, shown by the fluorescence to reporter gene green fluorescent protein
Micro mirror is observed and Flow cytometry, the activation efficiency of HIV latent infected cells is analyzed, the results show that HIV latent infections are thin
Relative activation rate is 80% to born of the same parents after processing.
Embodiment 4
With the 19,20-dihydro-Aspochalasin C (R of final concentration of 20 mcg/ml1、R2、R3、R4And R5Respectively
For H, OH, OH, H and H) processing HIV latent infected cells models, after it is acted on 3 days, by reporter gene green fluorescence egg
White fluorescence microscope and Flow cytometry analyze the activation efficiency of HIV latent infected cells, the results show that HIV
Latent infected cells relative activation rate after 19,20-dihydro-Aspochalasin C processing is 56%.
Embodiment 5
With the composition of the Aspochalasin class compounds of final concentration of 20 mcg/ml, including Aspochalasin
E(R1、R2、R3、R4And R5Respectively OH, OH, OH, H and H), Aspochalasin M (R1、R2、R3、R4And R5Respectively H ,=O,
OH, H and H) and Aspochalasin P (R1、R2、R3、R4And R5Respectively H, OH ,=O, H and H), three's mass ratio 1：1：1, place
HIV latent infected cells models are managed, after it is acted on 3 days, are seen by the fluorescence microscope to reporter gene green fluorescent protein
It examines and Flow cytometry, analyzes the activation efficiency of HIV latent infected cells, the results show that HIV latent infected cells are handled
Activity ratio is 51% afterwards.
Embodiment 6
Take Aspochalasin C (R1、R2、R3Respectively H, OH, OH, R4And R5Form double bond) 4g and medical starch 10g,
Capsule, every net weight 200mg are recorded into, which has the function of that HIV is activated to hide, and infection can be significantly made in low concentration
Latent HIV expression into the cell.
Embodiment 7
Take Aspochalasin C (R1、R2、R3Respectively H, OH, OH, R4And R5Formed double bond) 4g, Zidovudine 4g, medicine
With starch 10g, capsule, every net weight 200mg are recorded into, which has the function of that HIV is activated to hide, with antiretroviral
Drug azidothymidine is used in combination, and can remove the cell for the latent infection being activated, and accelerates the removing in latent virus library with this, from
And it is used for the treatment of AIDS.
Claims (2)
1.Aspochalasin classes compound is in the application for preparing AntiHIV1 RT activity and hiding in drug, which is characterized in that described
Aspochalasin classes compound is the structure shown in Formulas I,
The Aspochalasin classes compound for Aspochalasin E, Aspochalasin P, Aspochalasin C,
One or more of 19,20-dihydro-Aspochalasin C, wherein, R in Aspochalasin E1、R2、R3、
R4And R5Respectively OH, OH, OH, H and H, R in Aspochalasin P1、R2、R3、R4And R5Respectively H, OH ,=O, H and H,
R in Aspochalasin C1、R2、R3Respectively H, OH, OH, R4And R5Formation double bond, 19,20-dihydro-Aspochalasin
R in C1、R2、R3、R4And R5Respectively H, OH, OH, H and H.
2. application according to claim 1, which is characterized in that the Aspochalasin class compounds are
R in Aspochalasin C, Aspochalasin C1、R2、R3Respectively H, OH, OH, R4And R5Form double bond.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103787953A (en) * | 2014-01-17 | 2014-05-14 | 杭州维康科技有限公司 | Compound Aspochalasin V and preparation method and application thereof |
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| US20050069999A1 (en) * | 2001-07-09 | 2005-03-31 | Sharma Sreenath V | Sh3 domain binding inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103787953A (en) * | 2014-01-17 | 2014-05-14 | 杭州维康科技有限公司 | Compound Aspochalasin V and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| A Novel Aspochalasin with HIV-1 Integrase Inhibitory Activity from Aspergillus flavipes;Simone Rochfort 等;《THE JOURNAL OF ANTIBIOTICS》;20051231;第58卷(第4期);279–283 * |
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