CN103159665B - Isatin-5-amide inhibiting agent with inhibition effect against SARS coronavirus main protease - Google Patents
Isatin-5-amide inhibiting agent with inhibition effect against SARS coronavirus main protease Download PDFInfo
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- 108010055591 SARS coronavirus 3C-like protease Proteins 0.000 title claims abstract description 23
- 230000000694 effects Effects 0.000 title abstract description 13
- 230000002401 inhibitory effect Effects 0.000 title abstract description 8
- 230000005764 inhibitory process Effects 0.000 title abstract description 6
- 239000003795 chemical substances by application Substances 0.000 title abstract 2
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- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 claims abstract description 20
- -1 isatin-5-amide compound Chemical class 0.000 claims abstract description 15
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000002619 bicyclic group Chemical group 0.000 claims description 8
- 125000002950 monocyclic group Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 229940125673 3C-like protease inhibitor Drugs 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 3
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- LVNMAAGSAUGNIC-BQBZGAKWSA-N Cys-His Chemical compound SC[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CNC=N1 LVNMAAGSAUGNIC-BQBZGAKWSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
The invention provides an isatin-5-amide compound represented by a formula (1). The compound has an inhibition activity against SARS coronavirus main protease, and can be used as a SARS coronavirus main protease inhibiting agent, and can be applied in SARS treatment. The structural formula of the compound represented by the formula (1) is as the following.
Description
Technical Field
The invention relates to an isatin-5-amide inhibitor with an inhibiting effect on SARS coronavirus main protease, belonging to the field of pharmaceutical chemistry.
Background
SARS is a highly contagious Respiratory disease called Severe Acute Respiratory Syndrome (SARS) by the world health organization. SARS is mainly transmitted by close air droplets and close contact, and clinically manifests as pneumonia with significant accumulation in homes and hospitals. In 2003, atypical pneumonia (SARS) rolled up 32 countries around the world, causing a tremendous panic among people, and the warriors who originated this storm are SARS coronavirus.
At present, no medicine which is clinically proved to have special treatment effect exists in human beings and animals. During the SARS outbreak of 2003, only empirical therapy, supportive therapy and treatment methods to control complications were used clinically. The antiviral medicine, glucocorticoid, antibiotic, immunomodulator, etc. are used clinically in great amount and play important role in certain stage, but these medicines have their own demerits and interfere with the research of various signs of SARS patient and the observation of the normal disease course. Generally, no specific drug for SARS patients has been tested clinically. Although SARS is effectively controlled worldwide, people cannot guarantee that SARS storm will not be heavy enough, and in order to reduce the loss of life and property, it is of great significance to develop high-efficiency anti-SARS drugs aiming at the existing research results.
The Roron and Hospital laboratory successfully analyzed SARS coronavirus main protease (SARS CoVM) in 2003PROAlso known as SARS 3CL) at different pH values with a single inhibitor (hexapeptidyl CMK) which is a generalized serine protease with Cys-His as the active site, and which regulates the replication and transcription of the virus by hydrolyzing replicase polyprotein to release replicase PP1a and PP1ab, which provides greater possibilities for the development of specific and effective anti-SARS virus drugs.
Li Rung Chen et al synthesized a series of isatin derivatives (bioorg. Med. chem. Lett.15(2005), 3058-3062) in which there were two derivatives IC for SARS 3CL50Respectively reaches 0.98 mu M and 0.95 mu M, and the structures of the two derivatives are as follows:
IC50＝0.98μM
IC50＝0.95μM
a series of isatinamide derivatives (J.Med.chem.2006, 49, 3440-3443) were synthesized by Lu Zhou et al, the IC of the most active compound500.37. mu.M is achieved, and the compound has the following structure:
IC50＝0.37μM。
neither of the above documents describes the compound of the present invention, and there is no suggestion as to whether the compound obtained after the amino group of the 5-position acylamino group is substituted has SARS 3CL inhibitory activity.
Disclosure of Invention
The invention designs and synthesizes a series of isatin amide compounds which are not reported in literature and carries out SARSCoV M on the isatin amide compoundsPROActivity inhibition experiments, and experimental data prove that the compounds are used for SARS CoV MPROHas inhibitory effect on SARS coronavirus main protease. Nsp5 is the main protease of SARS coronavirus.
An isatin-5-amide compound represented by formula (1), the structural formula of which is as follows:
wherein,
R1is selected from C1-6Alkyl, aryl-methyl, aryl-heterocyclyl-methyl; the alkyl, aromatic ring, aromatic heterocyclic group is optionally substituted by one or more of the following groups: halogen, C1-4Alkyl, hydroxyl, nitro;
R2is a heterocyclic group containing at least one N atom, which heterocyclic group is connected to the acyl group at position 5 via the ring N, said heterocyclic group being optionally substituted with one or more of the following groups: halogen, C1-4Alkyl, aromatic, heteroaromatic, heterocyclic, aromatic-C1-4An alkyl group; or R2Is amino substituted with an aromatic ring group optionally substituted with one or more halogens;
the aromatic ring group is monocyclic or bicyclic 6-to 10-membered aromatic ring group,
the aromatic heterocyclic group is monocyclic or bicyclic, 6-10-membered, and contains one or more atoms selected from N, O or S,
the heterocyclic radical is monocyclic or bicyclic, 5-9-membered, saturated heterocyclic radical containing one or more atoms selected from N, O or S.
A preferred technical scheme of the invention is as follows:
the isatin-5-amide compound shown in the formula (1) has the structural formula shown in the specification,
wherein,
R1is selected from C1-6Alkyl, phenyl-methyl, naphthyl-methyl; the alkyl, phenyl, naphthyl groups are optionally substituted with one or more of the following groups: halogen, C1-4Alkyl, hydroxyl, nitro;
R2selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, said groups being linked to the acyl group at position 5 via the ring N and optionally substituted with one or more of the following groups: halogen, C1-4Alkyl, pyrrolidinyl, pyrrolyl, pyridyl, phenyl-C1-4An alkyl group; or R2Is amino substituted with phenyl, optionally substituted with one or more halogens.
The further preferable technical scheme of the invention is as follows:
the isatin-5-amide compound shown in the formula (1) has the structural formula shown in the specification,
wherein,
R1selected from:
n is an integer of 0 to 4;
R2selected from:
the further preferable technical scheme of the invention is as follows:
the isatin-5-amide compound shown in the formula (1) has the structural formula shown in the specification,
wherein: r1Selected from methyl, benzyl, 2-naphthylmethyl; r2Selected from morpholinyl, pyrrolidinyl, piperidinyl, 4-methylpiperidinyl.
The alkyl group in the present invention is a straight-chain or branched-chain saturated alkyl group, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, n-hexyl; halogen is preferably fluorine, chlorine, bromine, etc.; the aromatic ring group is a monocyclic or bicyclic 6-to 10-membered aromatic cyclic group, preferably phenyl, naphthyl, phenanthryl, etc.; the aromatic heterocyclic group is monocyclic or bicyclic, 6-to 10-membered, aromatic cyclic group containing one or more atoms selected from N, O or S, preferably pyrrolyl, pyridyl, quinolyl, isoquinolyl and the like; the heterocyclic group is a monocyclic or bicyclic, 5-to 9-membered, saturated cyclic group containing one or more atoms selected from N, O and S, and is preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and the like.
Preferred compounds of the invention are:
1-methyl-5- (4-morpholinoformyl) isatin (Compound 1),
1-benzyl-5- (1-pyrrolidinecarbonyl) isatin (compound 2),
1- (2-naphthylmethyl) -5- (1-pyrrolidinecarbonyl) isatin (compound 3),
1- (2-naphthylmethyl) -5- (1-piperidinecarboxyl) isatin (compound 4),
1- (2-Naphthalenylmethyl) -5- [ (4-methyl-1-piperidinyl) formyl ] isatin (Compound 5).
The compound of formula (1) of the invention is proved to have SARS coronavirus main protease inhibition effect by activity experiments, so the compound can be used for preparing a medicine composition for treating SARS, in particular for preparing SARS coronavirus main protease inhibitor, the medicine composition or the inhibitor contains the compound of formula (1) of the invention with effective treatment amount and pharmaceutic adjuvant, and the beneficial effect on SARS treatment is achieved by inhibiting the activity of SARS coronavirus main protease.
Detailed Description
The following examples are presented to enable those skilled in the art to more fully understand the present invention and are not intended to limit the invention in any way.
The general synthetic route for the compounds of formula (1) is as follows:
the first embodiment is as follows:
1-methyl-5- (4-morpholinoformyl) isatin (Compound 1)
The method comprises the following specific steps:
1. 21.6g (0.13mol) of chloral hydrate and 158g (1.10mol) of anhydrous sodium sulfate are added into a flask containing 440mL of water, the temperature is raised to 40 ℃, the mixture is stirred until the mixture is clear, and the prepared p-ethyl carbamate hydrochloric acid aqueous solution 1 (19.8 g (0.12mol) of p-ethyl carbamate is dissolved in 180mL of 2.5% hydrochloric acid) is dripped into the reaction solution and the addition is finished for 10-15 min. The reaction was continued for 0.5h to precipitate a large amount of white flocculent precipitate, and 16.7g (0.24mol) of hydroxylamine hydrochloride was added. The temperature was raised to 90 ℃. The solution turned pale yellow and reacted for 4 h. Cooled to room temperature and filtered with suction to obtain the product 2 as a yellow powder.
2. 60mL of concentrated sulfuric acid was heated to 60 ℃ and 2.0g of product 2 were added in portions, stirred and warmed to 80 ℃. And reacting for 4 h. And cooling to room temperature. The reaction solution was slowly poured into 300mL of ice water and stirred. And (5) extracting with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was spin dried to give isatin-5-carboxylic acid, red powder product 3.
3. 355mg (1.86mmol) of product 3 was dissolved in dry tetrahydrofuran (10mL) under a nitrogen atmosphere, 300mg (1.86mmol) of N, N' -carbonyldiimidazole was added, and the mixture was stirred at room temperature until no bubble was released. Triethylamine 0.52mL (3.72mmol) and morpholine 323mg (3.72mmol) were added. Stirring at room temperature for 10h, adding water for treatment, and extracting with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed. Column chromatography purification with dichloromethane to methanol at 150: 1 afforded product 4.
4. 260mg (1mmol) of the product 4 is dissolved in 5ml of anhydrous DMF, 36mg (1.5mmol) of NaH is added for reaction for 15min, 213mg (1.5mmol) of iodomethane is dissolved in 1ml of DMF, the solution is dripped into the reaction solution and reacted for 1h at room temperature, ethyl acetate and water are used for extraction, the organic phase is collected, the solvent is removed, and the mixture is purified by a column, wherein dichloromethane and methanol are 100: 1, so that a yellow solid 5 is obtained. The yield thereof is 73 percent,1HNMR(400MHz，DMSO-d6，in ppm)：3.17(s，3H)，3.65(t，J＝4.8Hz，4H)，3.51(t，J＝4.8Hz，4H)，7.21(d，J＝8.8Hz，1H)，7.44(s，1H)，8.18(d，J＝8.8Hz，1H)；ESI-MS m/z 275.10([M+H+])。
the following compounds were synthesized by the same method as that for the synthesis of compound 1, using the corresponding starting materials:
1-benzyl-5- (1-pyrrolidinecarbonyl) isatin (Compound 2)
Yellow solid, yield 81%.1H NMR(400MHz，DMSO-d6，in ppm)：1.98(t，J＝5.6Hz，2H)，3.49(t，J＝5.6Hz，2H)，4.94(s，2H)，7.03(d，J＝8.8Hz，1H)，7.27-7.45(m，6H)，8.10(d，J＝8.8Hz，1H)；ESI-MS m/z 335.13([M+H+])。
1- (2-Naphthalenylmethyl) -5- (1-pyrrolidinecarbonyl) isatin (Compound 3)
Orange solid, yield 78%.1H NMR(400MHz，DMSO-d6，in ppm)：1.96(t，J＝5.6Hz，2H)，3.43(t，J＝5.6Hz，2H)，5.14(s，2H)，6.91(d，J＝8.4Hz，1H)，7.27-7.45(m，8H)，8.15(d，J＝8.4Hz，1H)；ESI-MS m/z 385.13([M+H+])。
1- (2-Naphthalenylmethyl) -5- (1-piperidinecarbonyl) isatin (Compound 4)
Orange solid, yield 78%.1H NMR(400MHz，DMSO-d6，in ppm)：1.80(m，4H)，1.66(m，2H)，3.43(t，J＝5.6Hz，4H)，5.04(s，2H)，6.87(d，J＝8.4Hz，1H)，7.24-7.48(m，8H)，8.13(d，J＝8.4Hz，1H)；；ESI-MS m/z 399.16([M+H+])。
1- (2-Naphthalenylmethyl) -5- [ (4-methyl-1-piperidinyl) formyl ] isatin (Compound 5)
Yellow solid, yield 76%.1H NMR(400MHz，DMSO-d6，in ppm)：0.98(d，J＝7.2Hz，3H)，1.67(m，1H)，1.33-1.58(m，4H)，3.28-3.42(m，4H)5.07(s，2H)，6.91(d，J＝8.4Hz，1H)，7.31-7.65(m，8H)，8.24(d，J＝8.4Hz，1H)；ESI-MS m/z 413.18([M+H+])。
The pharmacological activity test method of the invention is as follows:
expression and purification of SARS coronavirus main protease
Expression and purification of the SARS coronavirus main protease were carried out according to the literature (Yang H et al Proc Natl Acad Sci.2003 Nov; 100 (23): 13190-5). The specific method comprises the following steps:
1.1 the construction of the expression vector of SARS coronavirus main protease, which comprises the following steps:
a. the cDNA library of SARS virus strain numbered BJ01 provided by Beijing Hua large gene center is used for in vitro amplification by PCR technology;
a forward primer: 5'-CGGGATCCAGTGGTTTTAGGAAAATG-3'
Reverse primer: 5'-CCGCTCGAGTCATTGGAAGGTAACACCAGA-3'
b. After the gene fragment amplified by PCR is cut by BamHI and XhoI double enzymes, the fragment with the size of about 1kb is recovered by agarose gel electrophoresis;
c. connecting the recovered fragment with a T vector, then transforming Escherichia coli DH5 alpha competent cells with the connection product, coating the competent cells on an LB plate (containing 100mg/L ampicillin), and culturing overnight;
d. a plurality of single colonies were picked up from the plate, inoculated into tubes containing about 5mL of LB (ampicillin was added to the LB solution so that the final concentration was 100mg/L), and cultured overnight. Then extracting plasmids by using a plasmid extraction kit (B type plasmid small-quantity rapid extraction kit of Boda Taike company), carrying out enzyme digestion by using BamHI and XhoI, and then recovering a target gene fragment with the size of about 1kb by using agarose gel;
e. the target vector pGEX-4T-1 (purchased from Pharmacia) was digested with BamHI and XhoI, and then the digested fragment was recovered by agarose gel;
f. and (3) connecting the fragments obtained in the step (d) and the fragment obtained in the step (e) (mixing the target gene fragment and the target vector fragment which are recovered by enzyme digestion according to the molar ratio of 3: 1-6: 1, reacting for 30 minutes-18 hours at 16 ℃ according to the requirement of Takara DNA Ligation), transforming the competent cells of the Escherichia coli DH5 alpha, and coating the competent cells on an LB plate (containing 100mg/L ampicillin) for overnight culture. The positive clones screened were used for identification and sequencing. The sequencing result shows that the coding gene of the main protease of SARS coronavirus has been correctly cloned into pGEX-4T-1 vector.
1.2 expression and purification of SARS coronavirus main protease, which comprises the following steps:
a. transforming Escherichia coli BL21(DE3) strain with pGEX-4T-1 vector containing SARS coronavirus main protease gene obtained in the step 1.1, and screening positive clone with LB plate (containing 100mg/L ampicillin);
b. positive clones (single colonies grown on LB plates containing ampicillin) were picked up on LB plates as described in a, cultured overnight, and then transferred to 1L of LB medium (containing 100mg/L ampicillin) when OD was reached600Adding about 1mM IPTG when the concentration reaches 0.6-0.8, and culturing at 16 deg.C for about 12 hr;
centrifuging at 5000-8000 rpm for 10-15min to collect cells, and then ultrasonically breaking the bacteria in ice bath for 20-30 min; centrifuging the bacterium breaking solution at 13000-15000 rpm for 20-40 min, and collecting the supernatant;
d. the supernatant was added to a GST affinity column (GE) pre-equilibrated with PBS, and 20-30 bed volumes were eluted with PBS to remove contaminating proteins. Finally, adding about 2mL of human rhinovirus 3C protease with the concentration of about 0.1mg/mL, carrying out enzyme digestion at 4 ℃ for 12-20 hours, and then collecting protein;
e. and (3) purifying the protein obtained in the last step d by using Mono Q (GE company) anion exchange chromatography to obtain the SARS coronavirus main protease with higher purity.
Screening method of SARS coronavirus main protease inhibitor
The method for screening SARS coronavirus main protease inhibitor adopted by the invention is a screening method disclosed in CN101418334A, and the specific method is as follows:
the activity of SARS coronavirus main protease was measured by using the fluorogenic substrate MCA-AVLQSGFR-Lys (Dnp) -Lys-NH2 (purity: 95% or more, Gill Biochemical Co., Ltd., Shanghai). The amino acid sequence of the fluorescent substrate is derived from the N-terminal self-cleavage sequence of SARS coronavirus main protease.
The instrument used for the fluorescence intensity measurement was a Fluoraskan Ascent fluorometer (ThermoLabsystems, Helsinki, Finland), and the wavelengths of the excitation light and the emission light were 320nm and 405nm, respectively.
To a buffer solution (50mM Tris-HCl (pH 7.3), 1mM EDTA (with or without DTT)) was added SARS coronavirus main protease (final concentration 0.5. mu.M), DMSO lysate of compound (to make the final concentration: 500. mu.g/mL, substrate concentration 20. mu.M, after 10 minutes at 298K, fluorescently labeled substrate (MCA-AVLQSGFRL(DNP) L-NH2, 20 μ M final) was added rapidly, negative controls were set: the compound is not added to the reaction mixture, the other conditions are the same, the excitation wavelength and the emission wavelength are respectively 320nm and 405nm, the temperature is kept at 298K, the fluorescence reading is recorded every 10 seconds, 10 points are totally determined, the time is taken as an X axis, the fluorescence value is taken as a Y axis to plot to obtain an enzyme activity mechanical curve, the initial speed V of the reaction can be obtained by calculating the slope through the numerical values of the first two points on the graph, and the initial speed of the reaction of the negative control is defined as V.0The initial rate of reaction of the added compound is defined as ViTo calculate the residual activity of the host protease after addition of the corresponding compound (V)i/V0) The inhibition ratio of the corresponding compound is (1-V)i/V0). When the remaining activity of the host protease is less than 20% (or the inhibition rate is greater than 80%), the IC of the compound is further determined50The value is obtained.
3. IC of compound for inhibiting SARS coronavirus main proteinase activity50Determination of value
The compounds were dissolved in 95% DMSO respectively50mol/mL of the solution. 10. mu.L of the solution was diluted with 95% DMSO in a gradient of 2 times to obtain about 12 sample solutions. The residual activity of the main protease was tested at various chemical concentrations using the assay described above. The diluted compound concentrations were divided by the molecular weights of the corresponding compounds and the corresponding residual activity values were plotted on the X-axis against the base 10 logarithmic values and on the Y-axis against GraphPad Prism 5(GraphPad software Inc.) and the corresponding IC's were calculated50The value is obtained.
Example two:
determination of IC of Compounds (1) to (5) according to the above-mentioned pharmacological Activity test method50The values are shown in Table 2.
TABLE 2 Activity data Table of Compounds (1) to (5)
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (8)
1. An isatin-5-amide compound represented by formula (1), the structural formula of which is as follows:
wherein,
R1is an aromatic ring radical-CH2-; said aromatic ring group being substituted with one or more groups selected from: halogen, C1-4An alkyl group;
R2is at least oneA heterocyclic group of N atoms which is attached to the acyl group at position 5 through the ring N, said heterocyclic group being substituted with one or more groups selected from: halogen, C1-4An alkyl group;
the aromatic ring group is monocyclic or bicyclic 6-to 10-membered aromatic ring group,
the heterocyclic radical is monocyclic or bicyclic, 5-9-membered, saturated heterocyclic radical containing one or more atoms selected from N, O or S.
2. A compound of formula (1) according to claim 1, characterized in that: r1Selected from benzyl,
3. A compound of formula (1) according to claim 1, characterized in that: r2Is selected from
4. A compound of formula (1) according to any one of claims 1 to 3, which is:
5. a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (1) according to any one of claims 1 to 4, together with a pharmaceutically acceptable adjuvant.
6. Pharmaceutical composition according to claim 5, characterized in that it is a SARS coronavirus main protease inhibitor.
7. Use of a compound of formula (1) according to any one of claims 1 to 4 in the manufacture of a pharmaceutical composition for the treatment of SARS.
8. Use according to claim 7, characterized in that the pharmaceutical composition is a SARS coronavirus main protease inhibitor.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999065875A1 (en) * | 1998-06-17 | 1999-12-23 | Geron Corporation | Telomerase inhibitors |
| CN101128424A (en) * | 2005-02-25 | 2008-02-20 | 小野药品工业株式会社 | Indole compound and use thereof |
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| WO1999065875A1 (en) * | 1998-06-17 | 1999-12-23 | Geron Corporation | Telomerase inhibitors |
| CN101128424A (en) * | 2005-02-25 | 2008-02-20 | 小野药品工业株式会社 | Indole compound and use thereof |
Non-Patent Citations (3)
| Title |
|---|
| Isatin Compounds as Noncovalent SARS Coronavirus 3C-like Protease Inhibitors;Lu Zhou，等;《J. Med. Chem.》;20060516(第49期);3440-3443 * |
| Preparation of substituted oxindole derivatives for use as CB2 agonists;WYETH LLC;《CA》;20101231;第153:174836卷;RN号1234340-10-3和1234340-06-7 * |
| Synthesis and evaluation of isatin derivatives as effective SARS coronavirus 3CL protease inhibitors;第15期;《Bioorganic & Medicinal Chemistry Letters》;20050517;3058-3062 * |
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