CN104013626B - Pyridine-piperazine compounds is preparing the application in anti-HIV-1 virus drugs - Google Patents
Pyridine-piperazine compounds is preparing the application in anti-HIV-1 virus drugs Download PDFInfo
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- CN104013626B CN104013626B CN201410231992.9A CN201410231992A CN104013626B CN 104013626 B CN104013626 B CN 104013626B CN 201410231992 A CN201410231992 A CN 201410231992A CN 104013626 B CN104013626 B CN 104013626B
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- 241000700605 Viruses Species 0.000 title claims abstract description 13
- DMGRIHSPRIYFEI-UHFFFAOYSA-N piperazine;pyridine Chemical class C1CNCCN1.C1=CC=NC=C1 DMGRIHSPRIYFEI-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 239000003814 drug Substances 0.000 title claims abstract description 8
- 229940079593 drug Drugs 0.000 title claims abstract description 8
- 241000713772 Human immunodeficiency virus 1 Species 0.000 abstract description 23
- 101710201961 Virion infectivity factor Proteins 0.000 abstract description 23
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract description 22
- 150000001875 compounds Chemical class 0.000 abstract description 15
- 230000000694 effects Effects 0.000 abstract description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 11
- 238000002474 experimental method Methods 0.000 abstract description 7
- 208000015181 infectious disease Diseases 0.000 abstract description 7
- 210000001744 T-lymphocyte Anatomy 0.000 abstract description 6
- 239000003443 antiviral agent Substances 0.000 abstract description 5
- 238000011160 research Methods 0.000 abstract description 5
- 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 abstract description 4
- 238000012216 screening Methods 0.000 abstract description 4
- 230000009471 action Effects 0.000 abstract description 3
- 125000002947 alkylene group Chemical group 0.000 abstract description 3
- 230000002155 anti-virotic effect Effects 0.000 abstract description 3
- 230000017854 proteolysis Effects 0.000 abstract description 3
- 238000012827 research and development Methods 0.000 abstract description 3
- 238000011161 development Methods 0.000 abstract description 2
- 230000003993 interaction Effects 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 31
- 108010004483 APOBEC-3G Deaminase Proteins 0.000 description 15
- 102000002797 APOBEC-3G Deaminase Human genes 0.000 description 15
- 208000030507 AIDS Diseases 0.000 description 9
- 239000005090 green fluorescent protein Substances 0.000 description 8
- 230000003612 virological effect Effects 0.000 description 7
- 239000006228 supernatant Substances 0.000 description 6
- 208000011580 syndromic disease Diseases 0.000 description 6
- 241000725303 Human immunodeficiency virus Species 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 230000008485 antagonism Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 102100038076 DNA dC->dU-editing enzyme APOBEC-3G Human genes 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- 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
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 2
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 2
- 229920000209 Hexadimethrine bromide Polymers 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 238000009395 breeding Methods 0.000 description 2
- 230000001488 breeding effect 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
- 210000000987 immune system Anatomy 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
- 238000010839 reverse transcription Methods 0.000 description 2
- SNBABKBRSVDMHT-UHFFFAOYSA-N (4-cyclopentylpiperazin-1-yl)-pyridin-2-ylmethanone Chemical compound C=1C=CC=NC=1C(=O)N(CC1)CCN1C1CCCC1 SNBABKBRSVDMHT-UHFFFAOYSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 0 C[C@]1(C=NC=CC=C1)C(N1CCN(*)CC1)=C Chemical compound C[C@]1(C=NC=CC=C1)C(N1CCN(*)CC1)=C 0.000 description 1
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- 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
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- 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
- 125000003342 alkenyl group Chemical group 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
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
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- 230000007812 deficiency Effects 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
- 238000001914 filtration Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 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
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- 239000002609 medium Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 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
- 238000012797 qualification Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination 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)
Abstract
The invention discloses pyridine-piperazine compounds and preparing the application in anti-HIV-1 virus drugs, does is the general formula of this compound
in formula:
Description
Technical field
The present invention relates to a kind of new opplication of compound, particularly pyridine-piperazine 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 pyridine-piperazine compounds of following general formula:
In formula:
base is positioned at 1 or No. 2 position;
R is the chain alkylene of C1 ~ C5 or the cyclic hydrocarbon radical of C4 ~ C6, as
(1-cyclopenta-4-[(pyridine-2-base) carbonyl] piperazine, (4-cyclopentylpiperazin-1-yl) (pyridin-2-yl) methanone) 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
Pyridine-piperazine compounds is the object of the present invention is to provide to apply preparing in anti-HIV-1 virus drugs.
Pyridine-piperazine compounds used in the present invention has following general formula:
In formula:
base is positioned at 1 or No. 2 position;
R is the chain alkylene of C1 ~ C5 or the cyclic hydrocarbon radical of C4 ~ C6.
Preferably, the R in above-mentioned pyridine-piperazine compounds is the alkenyl group of C3 ~ C5 or the cycloalkyl group of C5 or C6.Especially, R is Pentamethylene. base.
Preferably, in above-mentioned pyridine-piperazine compounds
base is positioned at No. 2 positions.
Preferably, above-mentioned pyridine-piperazine compounds is
.
Inventor utilizes the interaction of Vif-APOBEC3G, confirm the pyridine-piperazine compounds of above-mentioned general formula, particularly confirm that 1-cyclopenta-4-[(pyridine-2-base) carbonyl] piperazine can suppress the activity of Vif protein degradation A3G, cause 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, SupT1,1-cyclopenta-4-[(pyridine-2-base) carbonyl] piperazine 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: 1-cyclopenta-4-[(pyridine-2-base) carbonyl] piperazine has the effect suppressing Vif activity;
Fig. 3: 1-cyclopenta-4-[(pyridine-2-base) carbonyl] piperazine 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;
Fig. 4: 1-cyclopenta-4-[(pyridine-2-base) carbonyl] piperazine suppresses the titration of the IC50 copied of wild type HIV-1 in H9 cell.
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 1-cyclopenta-4-[(pyridine-2-base) carbonyl] piperazine is applied preparing in anti-HIV-1 virus drugs below in conjunction with experiment and result.
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, 1-cyclopenta-4-[(pyridine-2-base) carbonyl] piperazine 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, 1-cyclopenta-4-[(pyridine-2-base) carbonyl] piperazine 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 as shown in Figure 4.As can be seen from experimental result, 1-cyclopenta-4-[(pyridine-2-base) carbonyl] IC of piperazine in H9 cell
50for 2.75nM, there is the effect suppressing virus preferably.
Claims (1)
1. pyridine-piperazine compounds is preparing the application in anti-HIV-1 virus drugs, and described pyridine-piperazine compounds is
.
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| CN101432278A (en) * | 2006-04-25 | 2009-05-13 | 布里斯托尔-迈尔斯斯奎布公司 | Diketo-piperazine and piperidine derivatives as antiviral agents |
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| CN101432278A (en) * | 2006-04-25 | 2009-05-13 | 布里斯托尔-迈尔斯斯奎布公司 | Diketo-piperazine and piperidine derivatives as antiviral agents |
Non-Patent Citations (1)
| Title |
|---|
| 非核苷类HIV-1逆转录酶抑制剂研究进展;孟歌;《中国医药导报》;20100331;第7卷(第8期);第9-12页 * |
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