CN104000807A - Application of phenyl-amide compound in preparation of anti-HIV-1 virus medicines - Google Patents
Application of phenyl-amide compound in preparation of anti-HIV-1 virus medicines Download PDFInfo
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- CN104000807A CN104000807A CN201410231868.2A CN201410231868A CN104000807A CN 104000807 A CN104000807 A CN 104000807A CN 201410231868 A CN201410231868 A CN 201410231868A CN 104000807 A CN104000807 A CN 104000807A
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- 241000700605 Viruses Species 0.000 title claims abstract description 14
- -1 phenyl-amide compound Chemical class 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 title claims abstract description 9
- 229940079593 drug Drugs 0.000 title claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 abstract description 32
- 101710201961 Virion infectivity factor Proteins 0.000 abstract description 23
- 241000713772 Human immunodeficiency virus 1 Species 0.000 abstract description 22
- 230000000694 effects Effects 0.000 abstract description 13
- 238000002474 experimental method Methods 0.000 abstract description 9
- 239000005090 green fluorescent protein Substances 0.000 abstract description 9
- 210000001744 T-lymphocyte Anatomy 0.000 abstract description 6
- 208000015181 infectious disease Diseases 0.000 abstract description 6
- 238000012827 research and development Methods 0.000 abstract description 5
- 230000000840 anti-viral effect Effects 0.000 abstract description 4
- 238000012216 screening Methods 0.000 abstract description 4
- 108010043121 Green Fluorescent Proteins Proteins 0.000 abstract description 3
- 102000004144 Green Fluorescent Proteins Human genes 0.000 abstract description 3
- 230000002155 anti-virotic effect Effects 0.000 abstract description 3
- 230000034512 ubiquitination Effects 0.000 abstract description 3
- 238000010798 ubiquitination Methods 0.000 abstract description 3
- 108700020147 Human immunodeficiency virus 1 vif Proteins 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 102200021350 rs11203289 Human genes 0.000 abstract 2
- 230000015556 catabolic process Effects 0.000 abstract 1
- 238000006731 degradation reaction Methods 0.000 abstract 1
- 238000011161 development Methods 0.000 abstract 1
- 108010004483 APOBEC-3G Deaminase Proteins 0.000 description 15
- 102000002797 APOBEC-3G Deaminase Human genes 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 13
- 208000030507 AIDS Diseases 0.000 description 9
- 239000006228 supernatant Substances 0.000 description 6
- 208000011580 syndromic disease Diseases 0.000 description 6
- 241000725303 Human immunodeficiency virus Species 0.000 description 5
- 230000008485 antagonism Effects 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 102100038076 DNA dC->dU-editing enzyme APOBEC-3G Human genes 0.000 description 4
- 239000003443 antiviral agent Substances 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000009977 dual effect Effects 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920000209 Hexadimethrine bromide Polymers 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- 239000013504 Triton X-100 Substances 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- MURGITYSBWUQTI-UHFFFAOYSA-N fluorescin Chemical compound OC(=O)C1=CC=CC=C1C1C2=CC=C(O)C=C2OC2=CC(O)=CC=C21 MURGITYSBWUQTI-UHFFFAOYSA-N 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000010839 reverse transcription Methods 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108010044625 Proto-Oncogene Proteins c-mos Proteins 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- JYDCCPCHCSPGFA-UHFFFAOYSA-N n-(2-acetamidoethyl)-2-(4-iodophenoxy)acetamide Chemical compound CC(=O)NCCNC(=O)COC1=CC=C(I)C=C1 JYDCCPCHCSPGFA-UHFFFAOYSA-N 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 238000013326 plasmid cotransfection Methods 0.000 description 1
- 230000001566 pro-viral effect Effects 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- 101150059019 vif gene Proteins 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses an application of a phenyl-amide compound in the preparation of anti-HIV-1 virus medicines. The general formula of the used phenyl-amide compound is shown in the specification. The functional characteristic that HIV-1Vif protein can degrade A3G protein through ubiquitination is used by the inventor for proving that the phenyl-amide compound with the general formula can inhibit the degradation activity of the Vif protein on the A3G, so that the expression quantity of green fluorescent protein in a screening system rises again. The infection experiments of a wild type HIV-1 virus in a human primary CD4+T lymphocyte and CD4+T lymphocyte series such as H9 and SupT1 prove that the IC50 (half maximal inhibitory concentration) of N-(2- acetamido ethyl)-2-(4-iodophenyl) acetamide in H9 cells is 2 micrometers, and the N-(2- acetamido ethyl)-2-(4-iodophenyl) acetamide has a relatively good antivirus effect, provides powerful theoretical basis and practice basis for the further research and development of the antiviral medicines and has important research and development values and development significance.
Description
Technical field
The present invention relates to a kind of new application of compound, the particularly application of phenyl-amides compound in preparing anti-HIV-1 virus drugs.
Background technology
HIV-1 virus is found at first the 1981 Nian U.S. and finds, by a series of unknown causes, after the syndrome that the cellular immunity deficiency of take is feature occurs, research worker has started the searching to its etiology.Nineteen eighty-three France research group, from a lymph enlargement syndrome patient lymph node, is isolated HIV-1 virus.It is a kind of slow virus that infects human immunity system cells, this virus is destroyed the immunity of human body, cause immune system to lose resistance, and cause various diseases and cancer to be able to survive in human body, thereby 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 infects still in rising trend, especially in China, has entered especially the rapid growth phase.Stop as early as possible acquired immune deficiency syndrome (AIDS) to become an instant major issue at China popular.Therefore; continue to expand our understanding to HIV-1 mechanism of causing a disease; develop more effective; more economical; still less the antiviral drugs of side effect copies to remove remaining HIV-1 completely; and the vaccine of developing strong and long-acting anti-HIV-1 is with protection Susceptible population, will be the key that can we finally defeat acquired immune deficiency syndrome (AIDS).
Phenyl-the amides compound with following general formula:
in formula, X is halogen, is arranged on phenyl ring 1～No. 3 position on any, the chain alkylene that R is C1～C4, and n1, n2 are independently 1～3 integer, as
(N-(2-acetylamino ethyl)-2-(4-iodophenyl) acetamide, N-(2-acetamidoethyl)-2-(4-iodophenoxy) acetamide) can be purchased from Enamine company or carry out on its basis synthetic, do not report that this compounds is for antiviral experiment or other possible effects at present.
Summary of the invention
The object of the present invention is to provide phenyl-amides compound to apply in preparing anti-HIV-1 virus drugs.
Phenyl-amides compound used in the present invention has following general formula:
In formula, X is halogen, is arranged on phenyl ring 1～No. 3 position on any, the chain alkylene that R is C1～C4, and n1, n2 are independently 1～3 integer.
As a further improvement on the present invention, the alkenyl group that the R in above-claimed cpd is C1～C3.
As a further improvement on the present invention, the X in above-claimed cpd is I, Cl.
As a further improvement on the present invention, the X in above-claimed cpd is positioned on No. 2 positions of phenyl ring.
As a further improvement on the present invention, the X in above-claimed cpd is I, is positioned on No. 2 positions of phenyl ring; N1, n2 are that 1, R is methyl.
Inventor uses the HIV-1 Vif albumen can be by the degrade functional characteristic of A3G albumen of ubiquitination, confirm the phenyl-amides compound of above-mentioned general formula, N-(2-acetylamino ethyl particularly)-2-(4-iodophenyl) acetamide can suppress the activity of Vif protein degradation A3G, causes the expression of screening system Green fluorescin to go up.By carrying out the infection experiment of wild type HIV-1 virus in the CD4+ T lymphocyte series such as the primary CD4+ T lymphocyte people and H9, SupT 1, confirm, N-(2-acetylamino ethyl)-2-(4-iodophenyl) acetamide has good antivirus action, for strong theoretical basis and the practical basis that further antiviral drugs research and development provide, there are important research and development and be worth and develop meaning.
Accompanying drawing explanation
Fig. 1: the structure schematic diagram of cell screening model;
Fig. 2: N-(2-acetylamino ethyl)-2-(4-iodophenyl) acetamide has the effect that suppresses Vif activity;
Fig. 3: N-(2-acetylamino ethyl)-2-(4-iodophenyl) acetamide suppresses the print effect of wild type HIV-1 in expressing the H9 cell of A3G albumen and not expressing the SupT1 cell of A3G albumen;
Fig. 4: N-(2-acetylamino ethyl)-2-(4-iodophenyl) acetamide suppresses the titration of the IC50 copying of wild type HIV-1 in H9 cell.
The specific embodiment
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 H IV-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 the virion into HIV-1, brings into play its extremely strong antivirus action in HIV-1 reverse transcription process.For this reason, HIV-1 self the Vif albumen of having encoded carrys out the antiviral activity of specificity antagonism APOBEC3G, and it can import APOBEC3G ubiquitin system and degraded (Figure 1A).Therefore, how deactivation Vif, is a very important target of research and development anti-HIV-1 virus drugs.
According to the molecule mechanism of Vif antagonism APOBEC3G, the Vif that filters out some HIV of the allowing small-molecule drug of APOBEC3G of cannot degrading.We are setting up a kind of easy living cells screening system for this reason, as shown in Fig. 1 B, by the plasmid co-transfection of expressing APOBEC3G-GFP fusion rotein and expressing Vif in cell.With APOBEC3G-GFP fusion rotein, whether be degraded to index.As long as certain compound can also make APOBEC3G-GFP fusion rotein not be degraded (being that GFP fluorescence also exists) in the situation that Vif exists, this compound is exactly the inhibitor of Vif.By the further evaluation to Vif target, confirm that compound acts on host cell or acts on the Vif of virus protein.
In order to understand better essence of the present invention, below in conjunction with experiment and result, N-(2-acetylamino ethyl is described)-2-(4-iodophenyl) acetamide applies in preparing anti-HIV-1 virus drugs.
?
experiment one
1) get cell strain 239t cell on well-grown people's kidney, be inoculated in the 96 transparent flat undersides in hole every hole 5 * 10
4cell.The culture medium of using is complete medium: DMEM in high glucose, and 10% hyclone and 1% dual anti-, condition of culture is 5% carbon dioxide, 37 ℃;
2) 24h adherent after, two kinds of plasmids of cotransfection PEGFP-A3G and pcDNA3.1-Vif.Transfection adopts liposome transfection, and reagent is used lipo2000, transfection liquid 20 μ l;
3) after transfection 4h, add compound to be screened, every hole 2 μ l, final concentration is 50 μ M;
4) cultivate after 48h, detect the expression of green fluorescent protein GFP.If there is green fluorescent protein GFP, express the situation rising, this compound may become antiviral drug candidate.
Experimental result as shown in Figure 2, can be found out from experimental result, N-(2-acetylamino ethyl)-2-(4-iodophenyl) acetamide all has the effect that suppresses Vif activity.
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, can not be in above-mentioned " non-permission " time multiplexed cell system; And the wild strain virus that contains vif gene can be in above-mentioned time multiplexed cell system.After some target cell of Vif gene-deleted strain cell entry, reverse transcription can be carried out, but proviral DNA can not be synthesized.Studies show that HIV copies appearance or the disappearance of putting to death in a kind of cytostatic factor, this endogenic inhibitive factor is APOBEC3G, it belongs to intracellular rna editing enzymes, can make the cytosine deaminizating in mRNA form uracil, cause the accumulation of G and A mutant, and then be viral DNA degraded, vif forms the inhibition activity of complex blocking-up APOBEC3G by being combined with APOBEC3G.The cell line existing at APOBEC3G as H9 cell in, APOBEC3G and vif protein binding are degraded by ubiquitination system, if compound can suppress APOBEC3G by vif protein degradation, host cell can not be infected by HIV-1; And the non-existent feelings cell line of APOBEC3G as SupT1 cell in, HIV-1 albumen can normally infect this host cell; This compound will likely become the compound of anti-HIV-1 Vif albumen so.
APOBEC3G is the self-protective mechanism of cell, but vif is the albumen of HIV-1 virus antagonism APOBEC3G function, causes HIV-1 virus to escape self-reset procedure in cell.Utilize the permission cell of HIV-1 and do not allow the effect comparison of antiviral in cell experiment, thereby can further in wild type Viral experiment, determine the Vif albumen that target compound can antagonism HIV-1, suppress copying of HIV-1 virus.
1) get well-grown lymphocyte series H9 and Supt 1, cell consumption is 2 * 10
5/ hole, infects respectively packaged HIV-1 virus supernatant, and viral consumption is 10ng/1 * 10
6cell; (during infection, using the short reagent polybrene that infects);
2) after infection 3h, change liquid, use PBS to clean three times, abandon supernatant, use 1640 culture medium (10% hyclone, 1% is dual anti-) to cultivate, the every hole 200 μ l of culture medium, the every hole 2 μ l(final concentration 50 μ M of compound);
3) use 2%Triton X-100 to process the supernatant of receiving sample, receive the cell conditioned medium of having cultivated 4day, survey P24 Elisa.
Experimental result as shown in Figure 3.From experimental result, can find out N-(2-acetylamino ethyl)-2-(4-iodophenyl) acetamide has good anti-HIV-1 virus function, and there is no effect in SupT1 cell in H9 cell.
experiment three
1) get well-grown lymphocyte series H9, cell consumption is 2 * 10
5/ hole, infects packaged HIV-1 virus supernatant, and viral consumption is 10ng/1 * 10
6cell; (during infection, using the short reagent polybrene that infects);
2) after infection 3h, change liquid, use PBS to clean three times, abandon supernatant, use 1640 culture medium (10% hyclone, 1% is dual anti-) to cultivate, the every hole 200 μ l of culture medium, add the every hole 2 μ l of compound, final concentration is respectively 50 μ M, 5 μ M, 0.5 μ M, 0.05 μ M, 0.005 μ M, 0.0005 μ M, 0 μ M;
3) use 2%Triton X-100 to process the supernatant of receiving sample, receive sample 4day, survey P24 Elisa.
Experimental result as shown in Figure 4.From experimental result, can find out N-(2-acetylamino ethyl)-2-(4-iodophenyl) IC of acetamide in H9 cell
50be 2 μ M, there is the viral effect of good inhibition.
Claims (5)
1. the application of phenyl-amides compound in preparing anti-HIV-1 virus drugs, described phenyl-amides compound has following general formula:
In formula, X is halogen, is arranged on phenyl ring 1～No. 3 position on any, the chain alkylene that R is C1～C4, and n1, n2 are independently 1～3 integer.
2. application according to claim 1, is characterized in that: the alkenyl group that R is C1～C3.
3. application according to claim 1 and 2, is characterized in that: X is I, Cl.
4. application according to claim 1 and 2, is characterized in that: X is positioned on No. 2 positions of phenyl ring.
5. application according to claim 1, is characterized in that: X is I, is positioned on No. 2 positions of phenyl ring; N1, n2 are that 1, R is methyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410231868.2A CN104000807B (en) | 2014-05-28 | 2014-05-28 | Phenyl-amides compound is in the application of preparing in anti-HIV-1 virus drugs |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410231868.2A CN104000807B (en) | 2014-05-28 | 2014-05-28 | Phenyl-amides compound is in the application of preparing in anti-HIV-1 virus drugs |
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| Publication Number | Publication Date |
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| CN104000807A true CN104000807A (en) | 2014-08-27 |
| CN104000807B CN104000807B (en) | 2016-05-18 |
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| CN201410231868.2A Expired - Fee Related CN104000807B (en) | 2014-05-28 | 2014-05-28 | Phenyl-amides compound is in the application of preparing in anti-HIV-1 virus drugs |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1107835A (en) * | 1990-07-10 | 1995-09-06 | 詹森药业有限公司 | A process for preparing pharmaceutical composition showing properties in against human immunodeficiency virus |
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2014
- 2014-05-28 CN CN201410231868.2A patent/CN104000807B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1107835A (en) * | 1990-07-10 | 1995-09-06 | 詹森药业有限公司 | A process for preparing pharmaceutical composition showing properties in against human immunodeficiency virus |
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