CN104013628B - Benzo hexa-member heterocycle compounds is preparing the application in anti-HIV-1 virus drugs - Google Patents
Benzo hexa-member heterocycle compounds is preparing the application in anti-HIV-1 virus drugs Download PDFInfo
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- 229940079593 drug Drugs 0.000 title claims abstract description 8
- 101710201961 Virion infectivity factor Proteins 0.000 abstract description 23
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- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
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- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 2
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- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 2
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- 102000004169 proteins and genes Human genes 0.000 description 2
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Abstract
The invention discloses benzo hexa-member heterocycle compounds and preparing the application in anti-HIV-1 virus drugs, does is the general formula of this compound
Description
Technical field
The present invention relates to a kind of new opplication of compound, particularly benzo hexa-member heterocycle compounds is preparing the application in anti-HIV-1 virus drugs.
Background technology
HIV-1 virus is found in 1981 at first in the U.S. and finds, by a series of unknown cause, is that after the syndrome of feature occurs, research worker starts the searching to its etiology with cellular immunity deficiency.Nineteen eighty-three, France's research group was from the lymph node of a lymph enlargement syndrome patient, isolated HIV-1 virus.It is a kind of slow virus infecting human immune system's cell, the immunity of this viral subversive human body, cause immune system to lose resistance, and cause various disease and cancer to be able to survive in human body, thus cause acquired immune deficiency syndrome (AIDS)---acquired immune deficiency syndrome (AIDS).At present, universal insufficient due to AIDS education, the HIV in the whole world is still in rising trend, especially enters the quick rise period especially in China.Acquired immune deficiency syndrome (AIDS) is stoped to become an instant major issue at the popular of China as early as possible.Therefore; continue to expand us to the understanding of HIV-1 mechanism of causing a disease; develop more effective; more economical; the antiviral drugs of less side effect copies to remove remaining HIV-1 completely; and the vaccine developing strong and long-acting anti-HIV-1 is to protect Susceptible population, will be that can we finally defeat the key of acquired immune deficiency syndrome (AIDS).
There is the benzo hexa-member heterocycle compounds of following general formula:
In formula:
R is with phosphoamide group and amounts to the group being no more than 15 carbon atoms, is connected in 1 ~ No. 4 position of phenyl ring;
R ' is the chain alkylene of H, C1 ~ C3;
X is C, O, N or S, as
(2-{ [(3,5-dimethyl-1,2-oxazole-4-base) methyl] sulfenyl }-N-(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-base) acetamide, 2-(((3,5-dimethylisoxazol-4-yl) methyl) thio)-N-(2-methyl-3-oxo-3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] oxazin-6-yl) acetamide),
(2-methyl-N-(3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-base) propionic acid amide., N-(3-oxo-3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] oxazin-6-yl) isobutyramide) or
(N-[(4-chlorphenyl) (1-methyl isophthalic acid hydrogen-imidazoles-2-base) methyl]-2-[(2-oxo-1,2,3,4-tetrahydroquinoline-6-base) oxygen base] acetamide, N-((4-chlorophenyl) (1-methyl-1H-imidazol-2-yl) methyl)-2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy) acetamide) synthetic can be carried out purchased from Enamine company or on its basis, do not report that this compounds is for Antiviral breeding or other similar effects at present.
Summary of the invention
Benzo hexa-member heterocycle compounds is the object of the present invention is to provide to apply preparing in anti-HIV-1 virus drugs.
Benzo hexa-member heterocycle compounds used in the present invention has following general formula:
In formula:
R is with phosphoamide group and amounts to the group being no more than 15 carbon atoms, is connected in 1 ~ No. 4 position of phenyl ring;
R ' is the chain alkylene of H, C1 ~ C3;
X is C, O, N or S.
Preferably, the R group in above-mentioned benzo hexa-member heterocycle compounds is:
,
or
;
In formula, Y
1for the bridge joint group of C1 ~ C3, Y
2~ Y
5independent is C1 ~ C5 chain alkylene, Y
4be positioned on the carbon atom of five-ring heterocycles, or Y
4for H;
X
1for H or halogen, be positioned on phenyl ring;
N is the integer between 1 ~ 3.
Preferably, the R group in above-mentioned benzo hexa-member heterocycle compounds is positioned at 2 or No. 3 positions of phenyl ring.
Preferably, the X in above-mentioned benzo hexa-member heterocycle compounds is C or O.
Preferably, the X in above-mentioned benzo hexa-member heterocycle compounds
1for Cl, be arranged in No. 1 position of formula (1) phenyl ring.
Preferably, the Y in above-mentioned benzo hexa-member heterocycle compounds
1for-CH
2-; N=1, Y
4for methyl or ethyl, be positioned on No. 1 carbon atom of five-ring heterocycles; Y
5for isopropyl.
R ' is the alkane of H or C1 ~ C3.
Preferably, above-mentioned benzo hexa-member heterocycle compounds is selected from
,
or
.
Inventor utilizes the interaction of Vif-APOBEC3G, confirm the benzo hexa-member heterocycle compounds of above-mentioned general formula, particularly proved invention benzo hexa-member heterocycle compounds can suppress the activity of Vif protein degradation A3G, causes the expression of screening system Green fluorescin to go up.Confirmed by the infection experiment carrying out wild type HIV-1 virus in the CD4+T lymphocyte series such as the primary CD4+T lymphocyte of people and H9, SupT1, benzo hexa-member heterocycle compounds of the present invention has good antivirus action, for further antiviral drugs researches and develops the strong theoretical basis and practical basis provided, there is important research and development value and development significance.
Accompanying drawing explanation
Fig. 1: the structure principle of cell screening model;
Fig. 2: benzo hexa-member heterocycle compounds of the present invention has the effect suppressing Vif activity;
Fig. 3: benzo hexa-member heterocycle compounds of the present invention suppresses the print effect of wild type HIV-1 in the H9 cell of expressing A3G albumen and the SupT1 cell of not expressing A3G albumen.
Detailed description of the invention
Vif is one of indispensable protein of HIV, and its major function is antiviral agent APOBEC3G natural in antagonism host.APOBEC3G is that one of HIV-1 virus threatens greatly, and it is present in the natural host cell of HIV-1 (as CD4+T cell and macrophage), can be wrapped into HIV-1 virion, play the antivirus action that it is extremely strong in HIV-1 process of reverse-transcription.For this reason, HIV-1 self encodes the antiviral activity that Vif albumen carrys out specificity antagonism APOBEC3G, and APOBEC3G can be imported ubiquitin system and degraded (Figure 1A) by it.Therefore, how deactivation Vif is the very important target of of research and development anti-HIV-1 virus drugs.
According to the molecule mechanism of Vif antagonism APOBEC3G, the Vif filtering out some HIV of allowing cannot degrade the small-molecule drug of APOBEC3G.We will set up a kind of easy living cells screening system for this reason, as shown in Figure 1B, will express the plasmid co-transfection of APOBEC3G-GFP fusion rotein and expression Vif in cell.Whether index is degraded to APOBEC3G-GFP fusion rotein.APOBEC3G-GFP fusion rotein can also be made in case not to be degraded (namely GFP fluorescence also exists) as long as certain compound is deposited at Vif, this compound is exactly the inhibitor of Vif.By the further qualification to Vif target, confirm that compound acts on host cell or acts on the Vif of virus protein.
In order to understand essence of the present invention better, illustrate that benzo hexa-member heterocycle compounds of the present invention is applied preparing in anti-HIV-1 virus drugs below in conjunction with experiment and result.
Below in experiment, conveniently, compound 1 ~ 3 refers to respectively:
2-{ [(3,5-dimethyl-1,2-oxazole-4-base) methyl] sulfenyl }-N-(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-base) acetamide (compound 1),
2-methyl-N-(3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-base) propionic acid amide. (compound 2),
N-[(4-chlorphenyl) (1-methyl isophthalic acid hydrogen-imidazoles-2-base) methyl]-2-[(2-oxo-1,2,3,4-tetrahydroquinoline-6-base) oxygen base] acetamide (compound 3).
experiment one
1) get cell strain 239t cell on well-grown people's kidney, be inoculated in 96 hole clear flat bottom plates, every hole 5 × 10
4cell.The culture medium used is complete medium: DMEM in high glucose, 10% hyclone and 1% dual anti-, condition of culture be 5% carbon dioxide, 37 DEG C;
2) 24h adherent after, cotransfection PEGFP-A3G and pcDNA3.1-Vif two kinds of plasmids.Transfection adopts liposome transfection, and reagent uses lipo2000, transfection liquid 20 μ l;
3) after transfection 4h, add compound to be screened, every hole 2 μ l, final concentration is 50 μMs;
4), after cultivating 48h, the expression of green fluorescent protein GFP is detected.Express the situation risen if there is green fluorescent protein GFP, this compound may become antiviral drug candidate.
As shown in Figure 2, as can be seen from experimental result, benzo hexa-member heterocycle compounds of the present invention all has the effect suppressing Vif activity to experimental result.
experiment two
Vif albumen has important function in HIV-1 virus replication, and the HIV virus of vif defect can not copy in CD4+T cell, macrophage, namely can not in above-mentioned " non-permitted " time multiplexed cell system; And the wild strain virus containing vif gene can in above-mentioned time multiplexed cell system.Can reverse transcription be carried out after some target cell of Vif gene-deleted strain cell entry, but can not proviral DNA be synthesized.Research display HIV copies the appearance or disappearance of putting to death in a kind of cytostatic factor, this endogenic inhibitive factor is APOBEC3G, it belongs to intracellular rna editing enzymes, the cytosine deamination in mRNA can be made to form uracil, cause the accumulation of G and A mutant, and then be viral DNA degraded, vif is by being combined the inhibit activities forming complex blocks APOBEC3G with APOBEC3G.APOBEC3G exist cell line as in H9 cell, APOBEC3G and vif protein binding is degraded by ubiquitination system, if compound can suppress APOBEC3G by vif protein degradation, host cell can not be infected by HIV-1; And in the non-existent feelings cell line of APOBEC3G as in SupT1 cell, HIV-1 albumen can this host cell of normal infection; So this compound will likely become the compound of anti-HIV-1 Vif albumen.
APOBEC3G is the self-protective mechanism of cell, but vif is the albumen of HIV-1 virus countermeasure APOBEC3G function, causes self-reset procedure in HIV-1 viral escape cell.Utilize the permission cell of HIV-1 and do not allow the effectiveness comparison of the Antiviral breeding in cell, thus can determine that target compound can the Vif albumen of antagonism HIV-1 further in wild type Viral experiment, suppressing copying of HIV-1 virus.
1) get well-grown lymphocyte series H9 and Supt1, cell consumption is 2 × 10
5/hole, infects packaged HIV-1 viral supernatants respectively, and viral dose is 10ng/1 × 10
6cell; (during infection, using short infection reagent polybrene);
2) change liquid after infecting 3h, use PBS to clean three times, abandon supernatant, use 1640 culture medium (10% hyclone, 1% is dual anti-) to cultivate, culture medium every hole 200 μ l, compound every hole 2 μ l(final concentration 50 μMs);
3) use 2%TritonX-100 process to receive the supernatant of sample, receive and cultivated the cell conditioned medium of 4day, survey P24Elisa.
Experimental result as shown in Figure 3.As can be seen from experimental result, benzo hexa-member heterocycle compounds of the present invention has good anti-HIV-1 virus function in H9 cell, and does not have effect in SupT1 cell.
experiment three
1) get well-grown lymphocyte series H9, cell consumption is 2 × 10
5/ hole, infects packaged HIV-1 viral supernatants, and viral dose is 10ng/1 × 10
6cell; (during infection, using short infection reagent polybrene);
2) change liquid after infecting 3h, use PBS to clean three times, abandon supernatant, 1640 culture medium (10% hyclone, 1% is dual anti-) are used to cultivate, culture medium every hole 200 μ l, add compound every hole 2 μ l, final concentration is respectively 50 μMs, 5 μMs, 0.5 μM, 0.05 μM, 0.005 μM, 0.0005 μM, 0 μM;
3) use 2%TritonX-100 process to receive the supernatant of sample, receive sample 4day, survey P24Elisa.
Experimental result is as shown in the table, the IC of benzo hexa-member heterocycle compounds of the present invention
50be worth as shown in the table:
。
As can be known from the table data, benzo hexa-member heterocycle compounds of the present invention has the effect suppressing virus preferably.
experiment four
MTS (3-(4,5-dimethylthiazol-2-yl)-5 (3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium, innersalt) be a kind of tetrazole compound of new synthesis, it is identical with the application principle of MTT, namely be reduced into first a ceremonial jade-ladle, used in libation product coloured separately by the multiple dehydrogenase in living cells mitochondrion, the viable count of its shade and some sensitive cells strain is within the specific limits in height correlation.According to the absorbance (OD value) of the 490n recorded, judge living cells quantity, OD value is larger, and cytoactive is stronger, then represent that drug toxicity is less.
1) inoculating cell, is made into individual cells suspension with the DMEM culture fluid containing 10% tire calf serum by 293t, is inoculated into 96 orifice plates, every pore volume 200 μ l with 1000, every hole cell;
2) 24h adherent after add compound, every hole 2 μ l, final concentration is respectively 50 μMs, 5 μMs, 0.5 μM, 0.05 μM, 0.005 μM, 0.0005 μM, 0 μM;
3), after cultivating 48h, every hole adds MTS solution 20 μ l, continues to hatch 2 ~ 4h in incubator;
4) select 490nm wavelength, enzyme linked immunological monitor measures each hole absorbance value, observe compound to the cytotoxicity of 293t cell.
Experimental result is as shown in the table, the CC of benzo hexa-member heterocycle compounds of the present invention
50be worth as shown in the table:
。
As can be seen from experimental result, benzo hexa-member heterocycle compounds toxicity of the present invention is lower, all in ready-made acellular malicious phenomenon in 293t cell.
Claims (1)
1. benzo hexa-member heterocycle compounds is preparing the application in anti-HIV-1 virus drugs, described benzo hexa-member heterocycle class
Be selected from
,
or
.
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| Title |
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| A Small Molecule, Lys-Ala-7-amido-4-methylcoumarin, Facilitates RNA Dimer Maturation of a Stem-Loop 1 Transcript in Vitro: Structure-Activity Relationship of the Activator;Janet Chung et al;《Biochemistry》;20081231;第47卷;8148–8156 * |
| Binding Characteristics of Small Molecules That Mimic Nucleocapsid Protein-Induced Maturation of Stem-Loop 1 of HIV-1 RNA;Janet Chung et al;《Biochemistry》;20101231;第49卷;6341–6351 * |
| Structure-Based Identification and Neutralization Mechanism of Tyrosine Sulfate Mimetics That Inhibit HIV-1 Entry;Priyamvada Acharya et al;《ACS Chem. Biol》;20110630;第6卷;1069–1077 * |
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