CN110169975A - Application of the 4- amino acid substitution pyrimidine nucleoside compound in hepatitis B virus resisting medicine - Google Patents
Application of the 4- amino acid substitution pyrimidine nucleoside compound in hepatitis B virus resisting medicine Download PDFInfo
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- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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Abstract
The invention discloses purposes of the 4- amino acid substitution pyrimidine nucleoside compound in hepatitis B virus resisting medicine, belong to field of medicinal chemistry.It has logical formula (I) structure:In formula, R1=H, CH3, CH2CH3,K,Na；R2=H, CH3, CH2CH3,K,Na；And R1、R2It is not simultaneously CH3Series 4- amino acid substitution Pyrmidine nucleoside derivatives low toxicity is found through experiments that, there is anti-hepatitis B virus activity, be applied to treatment hepatitis B virus medicaments, the development prospect having had.
Description
Technical field
The present invention relates to pyridimine nucleosides compound more particularly to 4- amino acid substitution pyrimidine nucleoside compounds, in anti-second
Purposes in Hepatitis virus drug belongs to field of medicinal chemistry.
Background technique
In global 6,000,000,000 populations, 1/2 people lives in the high stream of hepatitis type B virus (hepatitis B virus HBV)
Row area, about 2,000,000,000 people are proved to have HBV infection, and 3~400,000,000 people are HBV chronic infection, wherein 15%~25% will eventually die of
Cirrhosis and liver cancer.Before the whole world in 10 disease causes of the death, hepatitis B accounts for the 7th (the 5th, China), every year because of hepatitis B died
About 1,000,000.And China belongs to high Endemic Area, according to national hepatitis B (hepatitis B) seroepidemiological survey table in 2018
Bright, HBsAg prevalence rate is 5.1-10% in China's general population, accounts for whole world Chronic Patients with HBV Infection 1/3, and the whole nation is annual
Die of that account for total toll ratio with hepatitis B related liver disease death toll high, therefore hepatitis type B virus is to threaten China
Or even the major disease of the people of the world.
Ucleosides and the like plays an important role in terms of AntiHIV1 RT activity, HBV, HCV virus.Inventor early period
(CN201110245782.1) the 4- amino acid substitution pyrimidine nucleoside compound synthesized has preferable section Sa Qi B group virus living
Property, on the basis of early-stage study, we study the anti-hepatitis B virus activity of these compounds, find these
Compound has preferable anti-hepatitis B virus activity.
Summary of the invention
The main purpose of the present invention is to provide a kind of activity, and good, the low 4- amino acid substitution pyrimidine nucleoside compound of toxicity exists
Purposes in hepatitis B virus resisting medicine.
Purpose to realize the present invention, technical solution are as follows:
The 4- amino acid substitution pyrimidine nucleoside compound has logical formula (I) structure:
In formula, R1=H, CH3, CH2CH3,K,Na；
R2=H, CH3, CH2CH3,K,Na
And R1、R2It is not simultaneously CH3
It can be one of following compound and is not limited only to these compounds:
Its reaction route, method referring to patent (CN201811325280.8)。
The compound covered in general formula of the present invention causes disease medicament for treating or preventing or alleviating virus
Preparation, especially antiviral drugs, signified virus preferably anti-hepatitis B virus (HBV).
As hepatitis B virus resisting medicine active constituent, can be used alone, it can also be with other antiviral agent Internet of Things
It shares medicine, in the signified drug combination therapeutic process of the present invention, including spreads out at least one the compounds of this invention or its activity
Biology is used together with other one or more antiviral drugs to increase general curative effect.When dose when drug combination and administration
Between should be depending on most rational therapy effect acquired in the case where difference.
Innovative point of the present invention and advantage are: to 4- (Pidolidone dimethyl ester) -1- (2'- deoxidation -2'- β-fluoro -4'-
α-nitrine-β-D- furyl glycosyl) the Pidolidone dimethyl ester of cytimidine modified, it is found that the serial 4- amino acid of synthesis takes
There is the activity of anti-hepatitis B virus for Pyrmidine nucleoside derivatives, be applied to treatment hepatitis B virus medicaments, have
Good application prospect.
Detailed description of the invention
Fig. 1 is that GY001-GY004 acts on the HepG2.2.15 extracellular 6 days inhibiting effect histograms to HBV DNA；
Fig. 2 is that GY001-GY004 acts on the HepG2.2.15 intracellular 6 days inhibiting effect histograms to HBV DNA；With sky
White control group is compared, P < 0.01 * P < 0.05, * *, compared with positive controls,&P<0.05,□P<0.01；
Fig. 3 is that GY001-GY004 acts on the HepGRL1 extracellular 6 days inhibiting effect histograms to HBV DNA；With blank
Control group is compared, P < 0.01 * P < 0.05, * *, compared with positive controls,&P<0.05,□P<0.01；
Fig. 4 is that GY001-GY004 acts on the HepGRL1 intracellular 6 days inhibiting effect histograms to HBV DNA.
Specific embodiment
For the present invention is better described, anti-hepatitis B virus activity experiment is as follows:
1 anti-hepatitis B virus of embodiment (HBV) activity test in vitro:
Experimental method
1.1MTT method measures GY001-GY004 to the toxicity of HepG2 cell
(1) recovery HepG2 cell, passage guarantee that cell state is good, digest after adherent and single cell suspension is made, count
Adjusting its density later is 5 × 104A/ml.
(2) 96 orifice plates are spread, the cell suspension that every hole adds 100 μ l uniformly mixed is placed in incubator.
(3) after 1d, culture medium in hole is discarded, the pastille culture medium of 100 μ l various concentrations, each concentration setting is added in every hole
Three multiple holes, while positive and blank control is set, continue to cultivate 72h.
(4) every hole discards liquid in hole after adding 20 μ l MTT, 4h, and every hole adds the DMSO of 150 μ l.
(5) 37 DEG C of shaking tables shake 10min, preheat microplate reader, measure the OD value in each hole, and measurement wavelength is 490nm, control
Wavelength is 630nm.
(6) Compound cellular inhibiting rate is calculated, formula is as follows:
According to each drug to the growth inhibition ratio of cell, drug is calculated to cell half toxic concentration CC50.
1.2 ELISA methods measure influence of the GY001-GY004 to HBeAg and HBsAg
By HepG2.2.15 cell and HepGRL1 respectively with 2 × 104A/ml and 1 × 104The density of a/ml is inoculated in 96
In well culture plate, every 100 μ l of hole is placed in CO2It is incubated in incubator.After 24 hours, according to requirement of experiment, various concentration is added
GY001-GY004, and Normal group and positive controls are set, 3 multiple holes are set.Third day press dosing in first day the step of into
Row dressing collects 6 days supernatants, -20 DEG C is stored in after label.With HBeAg and HBsAg in ELISA kit detection supernatant
Content, concrete operations are as follows:
(1) preparation before testing: from 4 DEG C of taking-up kits and institute's test sample sheet, room temperature is placed.
(2) it prepares cleaning solution: the cleaning solution in kit being diluted 25 times with purified water, is mixed well, for use.
(3) sample is added: taking out micro reaction plate from kit, cell supernatant to be measured is added, according to testing before
Accumulation, e antigen detection be added 50 μ l supernatant (with PBS dilute 5 times), S antigen detection be added 75 μ l supernatant (use
PBS dilutes 20 times).
(4) enzyme conjugate: every enzyme 50 μ l enzyme conjugates of conjugate in hole, and carefully put to 10s on shaking table and shake up, set 37
It is incubated in DEG C constant incubator, the detection of e antigen is incubated for 30min, and the detection of s antigen is incubated for 60min.
(5) board-washing: discarding liquid in hole, adds the washing lotion of 250 μ l, shakes uniformly, abandons cleaning solution and dries, claps on newspaper
It is dry, it washs 6 times.
(6) develop the color: every hole adds the color developing agent A and B of 50 μ l, is sealed up plate with patch, carefully rocks to mixing well, e is anti-
The detection of former and s antigen sets 37 DEG C and is incubated for 15min, 30min respectively.
(7) terminate reaction: every hole adds 50 μ l terminate liquids, and putting makes to mix completely on oscillator.
(8) measurement result: taking wavelength 450nm, with the microplate reader colorimetric of reference wavelength 630nm dual wavelength, is read with microplate reader
Number, reads the OD value in every hole.
The inhibiting rate of compound on intracellular is calculated according to formula, formula is as follows:
1.3 FQ-PCR methods detect influence of the GY001-GY004 to HBV DNA copy number in cell supernatant
1.3.1 the Cell culture invitro of GY001-GY004
HepG2.2.15 cell and HepGRL1 cell are inoculated in 24 holes respectively with 1 × 104/ml and 8 × 103/ml
In culture plate, every hole 1ml is placed in CO2After being incubated for 24 hours in incubator, takes out, the GY001-GY004 of various concentration is added,
And set blank control group and positive controls.Supernatant was collected in the 6th day, and plate inner cell is closed at into sterilized EP and is managed, and set -20
DEG C save.
1.3.2 the extraction of supernatant DNA
HBV in above-mentioned collection cell conditioned medium is detected with hbv nucleic acid (DNA) detection kit (fluorescent PCR method)
The content of DNA, operating procedure are as follows:
(1) prepare enough 1.5ml sterile centrifugation tubes, negative control, positive control and qualitative reference product A~D, every hole
Add 250 μ l samples to be tested, before mixes well in addition.
(2) every hole adds I 270 μ l of DNA extracting solution, 30 μ l, DNA extracting solution of isopropanol, II 100 μ l, 1 μ l internal standard, 20 μ l albumen
Enzyme K, 10 μ l magnetic beads (magnetic bead is easy to mix before sedimentation pays attention in addition).Vortex 10s is shaken, room temperature turns upside down 10min, room temperature
1000rpm is centrifuged 5s, collects the liquid on side wall and lid.
(4) EP pipe is placed on magnetic frame, magnetic bead is adsorbed in inside after 2min, and pipette tips paste pipe lateral wall, careful to draw
Liquid avoids cross contamination from replacing pipette tips in time.
(5) every hole adds extracting solution 3 (550 μ l), vortex 10s, and 1000rpm is collected by centrifugation after liquid and operates magnetic according to step 4
Liquid is discarded after power absorption.
(6) every hole adds 400 μ l extracting solutions 4, on vortex 10s postposition magnetic frame, inhales and stands 2min after abandoning liquid, rear 5 μ l
Liquid-transfering gun draws residual liquid.
(7) every hole is blown and beaten after adding 50 μ l extracting solutions 5,55 DEG C of water-bath 10min, is during which blown and beaten four times or so, and magnetic is placed
On power frame, -20 DEG C of liquid preservations are collected.
1.3.3 sample-adding and PCR amplification
(1) add 30 μ l PCR reaction solutions into 8 townhouse pipes respectively by the sample handled well, each 20 μ l of plasmid standards for quantitation A~D
It is added to the PCR pipe equipped with reaction system and is relayed to amplification region.
(2) PCR reaction plate is placed in detection slot, blank control, plasmid standards for quantitation A is respectively set by its corresponding sequence
~D and sample to be tested, and sample ID and qualitative reference product concentration are set.
(3) select fluorescence detection channel: selection FAM sense channel, HBV internal standard select VIC Air conduct measurement, and reference fluorescent is set
It is set to None.
(4) loop parameter is set:
Table 1
1.3.4 result judgement
Sample copy value is 4 × 102~4 × 109Between copies/ml, then illustrate that institute's measured data is available, if sample is copied
Shellfish value ﹥ 4 × 109Copies/ml then illustrates that not in detection range, reply sample is diluted, but detected value cannot be below 4
×102copies/ml。
1.3.5 inhibiting rate calculates
GY001-GY004 is calculated to the inhibiting rate of HBV DNA in cell supernatant by following formula:
1.4 FQ-PCR methods detect influence of the tested material to intracellular HBV DNA copy number
After drug effect cell 6 days, 1 × 106 cell extraction genomic DNA is collected in every hole.Genes within cells group DNA's
It extracts and uses Tissue DNA Kit kit, steps are as follows:
(1) cell that freezes is taken out, 1 after room-temperature dissolution, 000 × g is centrifuged 5min, inhales and abandons supernatant, and PBS washed once, and uses
Cell precipitation is resuspended in the PBS of 200 4 DEG C of μ l pre-cooling.
(2) 25 μ l OB protease are added in above-mentioned cell suspension, vortex oscillation.
(3) add 220 μ l BL Buffer, oscillation, 65 DEG C of water-bath 10min.
(4) add the 220 anhydrous Ethanol of μ l, oscillation.It is transferred in HiBind DNA adsorption column, is stored at room temperature 2min, 8,000
× g is centrifuged 1min, abandons waste liquid in collecting pipe.
(5) 500 μ l HB Buffer are added in DNA adsorption column, are stored at room temperature 3min, the next same step 4 of operation.
(6) the DNA Wash Buffer after the anhydrous Ethanol dilution of 700 μ l is added into DNA adsorption column, is stored at room temperature
After 2min, the next same step 4 of operation.
(7) it is primary to repeat step (6) operation.
(8) DNA adsorption column is placed back in collecting pipe, 12,000 × g is centrifuged 2min, puts it into new 1.5ml mark
The sterile centrifugation tube recorded a demerit.
(9) be vertically added into DNA adsorption column 60 μ l shift to an earlier date preheated Elution Buffer (place 65 DEG C of water-baths it is pre-
Heat), after being stored at room temperature 5min, 10,000 × g is centrifuged 2min.
It (11) is the genes within cells group DNA extracted in centrifuge tube, -20 DEG C save backup.
Statistical analysis
-
Experimental result is handled through 17.0 statistical software of SPSS, is as a result indicated with X ± S, and one-way analysis of variance is carried out, and is shown
It writes inspection result and uses LSD tournament method, α=0.05 is significance test standard.P < 0.05 is that statistical difference is significant, P <
0.01 is difference highly significant.
2. experimental result
Toxicity of 2.1 GY001-GY004 to 2 cell of HepG
GY001-GY004 is detected in vitro to the toxicity of HepG2 cell by mtt assay, the results showed that GY001-GY004 pairs
The toxicity of HepG2 cell is smaller, wherein CC50 > 1000 μM of GY002, and the CC50 of GY001 and GY003 are respectively 963.69 μM
With 994.49 μM, the toxicity of GY004 compares slightly larger (table 2).
2 GY001-GY004 of table is in vitro to the toxicity of HepG2 cell
Compared with blank control group, P < 0.01 * P < 0.05, * *
Inhibiting effect of 2.2 GY001-GY004 to HepG2.2.15 cell and HepGRL1 cell HBV antigen
Using wild type HepG2.2.15 cell as model, Lamivudine (3TC) is positive control, ELISA method detection
Inhibiting effect of the GY001-GY004 to HBV antigen.The results are shown in Table 3, and 1 μM of GY001-GY004 is to HepG2.2.15 cell
The inhibiting effect of HBV antigen is suitable with 20 μM of positive drug Lamivudine effect, and the inhibiting rate secreted to HBsAg and HBeAg is equal
10% or so, wherein GY004 is respectively 12.5% (P < 0.05) and 10.12% (P to the inhibiting rate of HBsAg and HBeAg antigen
<0.05)。
Using the HepGRL1 cell to lamivudine resistance as model, Lamivudine (3TC) is positive control, detection
Inhibiting effect of the GY001-GY004 to drug-resistant type HBV antigen.The results are shown in Table 3, and GY001-GY004 is to persister HBeAg's
Secretion has inhibiting effect.
To sum up, GY001-GY004 has inhibiting effect to HepG2.2.15 cell and HepGRL1 cell HBV antigen.
3 GY001-GY004 of table makees the inhibition of HBsAg and HBeAg after acting on HepG2.2.15 and HepGRL1 cell 6 days
With
Compared with blank control group, P < 0.01 * P < 0.05, * *, compared with positive controls,&P<0.05,□P<0.01
Inhibiting effect of 2.3 GY001-GY004 to HepG2.2.15 cell and HepGRL1 cell HBV DNA
Q-PCR method is the results show that GY001-GY004 administration group can significantly reduce cell supernatant and intracellular HBVDNA water
It is flat, and be in concentration dependent to the inhibiting rate of its copy number.After HepG2.2.15 cell medication 6 days, 1 μM of GY001-
GY004 GY001-GY004 at 75% or so, 0.2 μM average to the inhibiting rate of cell conditioned medium HBV DNA copy number is to supernatant
The average inhibiting rate of HBV DNA copy number in 35% or so, 3TC group is 76% to its inhibiting rate, illustrate administration group concentration only
For 3TC concentration 1/20th when just show the effect of the same intracellular HBV DNA of inhibition therewith.GY001-GY002
It is not much different in supernatant with intracellular inhibiting rate, but GY003-GY004 will be slightly to the inhibiting effect of HBV DNA in supernatant
Better than intracellular (table 4).It more can intuitively compare the inhibiting rate trend of tetra- compounds of GY001-GY004 from Fig. 2.
To after HepGRL1 cell (lamivudine resistance) medication 6 days, GY001-GY004 HBV DNA's intracellular to supernatant
Apparent concentration dependent is all presented in inhibiting effect.The inhibiting rate of positive drug Lamivudine obvious drop compared with wild strain first
Low, it is then 22.16% to HBV DNA intracellular that the inhibiting rate to HBV DNA in supernatant, which is 16.65%, but GY001-GY004
3TC is above to the inhibiting effect of persister, and does not show apparent drug resistance.More can intuitively it compare from Fig. 3
The inhibiting rate trend of tetra- compounds of GY001-GY004.
In conclusion GY001-GY004 is to cell conditioned medium and cell in HepG2.2.15 cell and HepGRL1 cell
Interior HBV DNA has extraordinary inhibiting effect, and effect is better than 3TC, and does not show apparent drug resistance.
The inhibiting effect of 4 GY001-GY004 of table effect HepG2.2.15 cell (wild type HBV) HBV DNA after 6 days
Compared with blank control group, P < 0.01 * P < 0.05, * *, compared with positive controls,&P<0.05,□P<0.01
The inhibition of 5 GY001-GY004 of table effect HepGRL1 cell (lamivudine resistance type HBV) HBV DNA after 6 days is made
With
Compared with blank control group, P < 0.01 * P < 0.05, * *, compared with positive controls,&P<0.05,□P<0.01。
Claims (3)
1. the medicinal usage with the 4- amino acid substitution Pyrmidine nucleoside derivatives of logical formula (I) structure, which is characterized in that as work
Property ingredient, be used for preparation and treat or prevent or alleviate virus causing the drug of disease,
In formula, R1=H, CH3, CH2CH3,K,Na；
R2=H, CH3, CH2CH3,K,Na
And R1、R2It is not simultaneously CH3。
2. the medicinal usage of 4- amino acid substitution Pyrmidine nucleoside derivatives as described in claim 1, which is characterized in that the disease
Poison is anti-hepatitis B virus (HBV).
3. the medicinal usage of 4- amino acid substitution Pyrmidine nucleoside derivatives as claimed in claim 1 or 2, which is characterized in that choosing
One of following compound:
。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351931A (en) * | 2010-09-07 | 2012-02-15 | 河南省科学院高新技术研究中心 | Pyrimidine nucleoside derivatives as well as synthesis method and application thereof in preparation of anti-tumor and antiviral drugs |
| CN103709220A (en) * | 2014-01-13 | 2014-04-09 | 河南省科学院高新技术研究中心 | 3-methyluridine and 4-methylcytidine nucleosides compound and synthesis method and pharmaceutical application thereof |
| CN109265504A (en) * | 2018-11-08 | 2019-01-25 | 河南省科学院高新技术研究中心 | 4- amino acid substitution pyrimidine nucleoside compound and its medicinal usage |
-
2019
- 2019-06-14 CN CN201910513608.7A patent/CN110169975A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351931A (en) * | 2010-09-07 | 2012-02-15 | 河南省科学院高新技术研究中心 | Pyrimidine nucleoside derivatives as well as synthesis method and application thereof in preparation of anti-tumor and antiviral drugs |
| CN103709220A (en) * | 2014-01-13 | 2014-04-09 | 河南省科学院高新技术研究中心 | 3-methyluridine and 4-methylcytidine nucleosides compound and synthesis method and pharmaceutical application thereof |
| CN109265504A (en) * | 2018-11-08 | 2019-01-25 | 河南省科学院高新技术研究中心 | 4- amino acid substitution pyrimidine nucleoside compound and its medicinal usage |
Non-Patent Citations (1)
| Title |
|---|
| YUAN LIU等: "Design, synthesis, and biological evaluation of new 1,2,3-triazolo-20-deoxy-20-fluoro- 40-azido nucleoside derivatives as potent anti-HBV agents", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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Application publication date: 20190827 |