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1.
Anal Methods ; 14(46): 4879-4885, 2022 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-36416170

RESUMEN

A previous study has shown that brassicasterol-d1 was detected in the serum of stroke-prone spontaneously hypertensive rats after oral administration of ergosterol-d1. To quantitatively evaluate the serum concentration of brassicasterol-d1, an ultra-high performance liquid chromatography-electrospray ionization-tandem mass spectrometry method was developed for the simultaneous determination of picolinyl ester-derivatized ergosterol-d1 and brassicasterol-d1. The separation was performed on an ODS column (Waters Acquity UPLC BEH C18) with a mobile phase consisting of methanol and water containing 0.1% acetic acid (95/5, v/v). Linear calibration curves in the presence of the serum were obtained in a concentration range of 0.04-8 µg mL-1. Recovery rates of 95.6-119% were obtained with an RSD (n = 6) of less than 7.5%. The method was applied to the determination of time-concentration curves of ergosterol-d1 and brassicasterol-d1 in stroke-prone spontaneously hypertensive rats, showing a pharmacokinetic profile of ergosterol-d1 where the peak serum concentration of brassicasterol-d1 was 3-fold higher than that of ergosterol-d1.


Asunto(s)
Ergosterol , Accidente Cerebrovascular , Animales , Ratas , Cromatografía Líquida de Alta Presión , Ratas Endogámicas SHR , Deuterio , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem
2.
Org Lett ; 21(8): 2606-2609, 2019 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-30924673

RESUMEN

An organocatalyzed method for synthesizing chiral γ,γ-disubstituted γ-butenolides via direct vinylogous aldol reactions of γ-substituted ß,γ-butenolides with aldehydes is reported. This reaction is catalyzed by a squaramide-sulfonamide organocatalyst to afford a range of anti-aldol adducts possessing vicinal quaternary and tertiary stereocenters with high to excellent enantioselectivities (reaching 95% ee). This is the first report of a successful stereoselective direct vinylogous aldol reaction of aldehydes with γ-substituted ß,γ-butenolides.

3.
Chirality ; 30(11): 1215-1224, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30211959

RESUMEN

In this study, stereoselective conjugate addition of ketones to alkylidene malonates using organocatalyst has been developed. The reaction in the presence of 20 mol% of a novel thiourea-sulfonamide organocatalyst afforded conjugate adducts in moderate to high yields (up to 81%) under mild reaction conditions. Excellent diastereoselectivity (up to 98:2 dr) and enantioselectivity (up to 88% ee) were achieved.

4.
Org Lett ; 20(18): 5569-5572, 2018 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-30199261

RESUMEN

The use of diaminomethylenemalononitrile (DMM) organocatalyst to promote the challenging 1,2-hydrophosphonylation of simple ketones and enones, which are also called α,ß-unsaturated ketones, is proposed and validated. This reaction provided the corresponding chiral α-hydroxy phosphonates in high to excellent yields and with enantioselectivity up to 96% ee.

5.
J Org Chem ; 83(4): 2402-2408, 2018 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-29333849

RESUMEN

A diaminomethylenemalononitrile organocatalyst efficiently catalyzed the asymmetric conjugate addition of α-cyanoketones to vinyl ketones to give the corresponding 1,5-dicarbonyl compounds, which bear an all-carbon quaternary stereogenic center with high enantioselectivities. This report is the first example of the asymmetric conjugate addition of α-cyanoketones to vinyl ketones using an organocatalyst.

6.
Chem Pharm Bull (Tokyo) ; 65(12): 1185-1190, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29199223

RESUMEN

The novel fluorous organocatalyst bearing a diaminomethylenemalononitrile motif is prepared. The fluorous organocatalyst efficiently promotes asymmetric conjugate additions of ketones to nitroalkenes and results in high yields of these addition products with excellent enantioselectivities under solvent-free conditions.


Asunto(s)
Alquenos/química , Cetonas/química , Nitrilos/química , Catálisis , Nitrocompuestos/química , Estereoisomerismo
7.
J Org Chem ; 82(13): 6986-6991, 2017 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-28605586

RESUMEN

The asymmetric conjugate addition of nitroalkanes to α,ß-unsaturated ketones in the presence of a catalytic amount of a novel sulfonamide-thiourea organocatalyst resulted in the corresponding γ-nitro carbonyl products in high yields with excellent enantioselectivities (up to 97% ee).

8.
Biochem Biophys Res Commun ; 490(3): 849-854, 2017 08 26.
Artículo en Inglés | MEDLINE | ID: mdl-28648599

RESUMEN

2,3-Butandione 2-monoxime (BDM) is a widely used myosin inhibitor with an unclear mode of action. In this report, we investigated the mechanism of BDM oxime group nucleophilic reactivity on the phosphoester bond of ATP. BDM increased the ATPase activity of skeletal myosin subfragment 1 (S1) under conditions in which ATP cleavage is the rate-limiting step (K+, EDTA-ATPase activity of native S1 and Mg2+-ATPase activity of trinitrophenylated S1 and partially unfolded S1). Furthermore, the effect of BDM on the S1-bound adenosine 5'-(ß,γ-imido) triphosphate (AMPPNP) 31P NMR spectrum suggests that BDM changes the microenvironment around the phosphorus atoms of myosin-bound nucleotide. A computational search for the BDM-binding site in the adenosine 5'-[γ-thio] triphosphate (myosin-ATPγS) complex predicted that BDM is located adjacent to the nucleotide on myosin. Therefore, we propose that the BDM oxime group catalytically assists in ATP cleavage, thereby enhancing the ATPase activity of myosin in a manner analogous to pralidoxime-mediated reactivation of organophosphate-inactivated acetylcholinesterase. This is the first study suggesting that oxime provides catalytic assistance for ATP cleavage by an ATP-hydrolyzing enzyme.


Asunto(s)
Adenosina Trifosfato/metabolismo , Miosina Tipo II/antagonistas & inhibidores , Miosina Tipo II/metabolismo , Oximas/química , Oximas/farmacología , Adenosina Trifosfatasas/metabolismo , Animales , ATPasa de Ca(2+) y Mg(2+)/metabolismo , Simulación del Acoplamiento Molecular , Subfragmentos de Miosina/metabolismo , Conejos
9.
J Org Chem ; 82(9): 4661-4667, 2017 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-28394134

RESUMEN

Asymmetric direct vinylogous aldol reactions of furan-2(5H)-one with aldehydes in the presence of a catalytic amount of novel squaramide-sulfonamide organocatalyst resulted in the corresponding addition products with high to excellent enantioselectivities. This is the first successful report illustrating an example of highly stereoselective reactions using a squaramide-sulfonamide organocatalyst.

10.
Int J Mycobacteriol ; 6(1): 61-69, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28317807

RESUMEN

OBJECTIVE/BACKGROUND: Mycobacterium tuberculosis thymidine monophosphate kinase (mtTMPK) is a potential enzymatic target for the treatment of tuberculosis (TB). MATERIALS AND METHODS: In this study, we performed pharmacophore-based in silico screening, targeting mtTMPK with a compound library of 461,383 chemicals. We evaluated the candidate compounds for inhibitory effects on the growth of the model mycobacteria, Mycobacterium smegmatis. RESULTS: The compound KTP3 completely inhibited the growth of M. smegmatis at 100 µM. A similarity search and rescreening with the structure of compound KTP3 using a web-based database identified two similar compounds (KTPS1 and KTPS2) with improved potency. The KTP3 analogs, KTPS1 and KTPS2, exhibited strong growth inhibitory effects with half-maximal inhibitory concentration values of 8.04 µM and 17.1 µM, respectively, against M. smegmatis. Moreover, the most potent chemical compound, KTPS1, did not exhibit toxic effects on the model enterobacteria and several mammalian cells. Two active chemicals, KTPS1 and KTPS2, inhibited mtTMPK activity by 18% and 36%, respectively, suggesting that these compounds have off-target activities against Mycobacterium. CONCLUSION: Structural and biological information on these chemicals is likely to be useful for the development of novel antibiotics for the treatment of TB.


Asunto(s)
Antituberculosos/farmacología , Furanos/farmacología , Mycobacterium smegmatis/efectos de los fármacos , Nucleósido-Fosfato Quinasa/antagonistas & inhibidores , Pirimidinonas/farmacología , Antituberculosos/química , Simulación por Computador , Descubrimiento de Drogas , Furanos/química , Ensayos Analíticos de Alto Rendimiento , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Mycobacterium smegmatis/crecimiento & desarrollo , Mycobacterium tuberculosis/efectos de los fármacos , Pirimidinonas/química , Relación Estructura-Actividad , Tuberculosis/tratamiento farmacológico
11.
Chem Pharm Bull (Tokyo) ; 64(12): 1781-1784, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27904086

RESUMEN

Diaminomethylenemalononitrile organocatalysts promote the asymmetric chlorination of simple cyclic ß-keto esters such as methyl, ethyl, and benzyl esters of 1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid. This affords the corresponding chiral α-chlorinated carbonyl products in excellent yields with high enantioselectivities.


Asunto(s)
Diaminas/química , Ésteres/química , Halogenación , Hidrocarburos Clorados/síntesis química , Nitrilos/química , Catálisis , Hidrocarburos Clorados/química , Estructura Molecular , Estereoisomerismo
12.
Eur J Med Chem ; 94: 378-85, 2015 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-25778993

RESUMEN

The Mycobacterium tuberculosis (M. tuberculosis) enoyl-acyl carrier protein reductase (mtInhA) is an attractive enzyme and a thoroughly studied target for tuberculosis therapy. In this study, to identify novel structure-activity relationships (SARs) of mtInhA inhibitors, a series of diphenyl ether derivatives were designed based on the matched molecular pair (MMP) method, and the binding energies of these compounds were subsequently estimated by in silico structure-based drug screening (SBDS) to provide more useful data. Consequently, the 10 unique candidate compounds (KEM1-KEM10) were identified and assessed for the inhibition of mtInhA enzymatic activity, in vitro antibiotic effects against model mycobacteria and toxicity level on both intestinal bacteria and mammalian cells. Among the compounds tested, phenyl group (KEM4) and 2-fluorobenzyl group (KEM7) substitutions produced preferable inhibitory effects on mtInhA enzymatic activity relative to those provided by a furyl group (KES4: base compound) at the terminal of the compound, and KEM7 inhibited the growth of the mycobacteria strain with a lower IC50 value. Moreover, most of the candidate compounds exhibited neither inhibition of the growth of enterobacteria nor toxic effects on mammalian cells, though KEM10 exhibited toxicity against cultured MDCK cells. The structural and experimental information concerning these mtInhA inhibitors identified through MMP-based in silico screening will likely contribute to the lead optimisation of novel antibiotics for M. tuberculosis.


Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Descubrimiento de Drogas , Mycobacterium smegmatis/efectos de los fármacos , Oxidorreductasas/antagonistas & inhibidores , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Proteínas Bacterianas/metabolismo , Línea Celular , Perros , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Mycobacterium smegmatis/crecimiento & desarrollo , Oxidorreductasas/metabolismo , Relación Estructura-Actividad
13.
J Chem Inf Model ; 54(4): 1242-53, 2014 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-24655350

RESUMEN

The emergence of multidrug-resistant Staphylococcus aureus (S. aureus) makes the treatment of infectious diseases in hospitals more difficult and increases the mortality of the patients. In this study, we attempted to identify novel potent antibiotic candidate compounds against S. aureus dihydrofolate reductase (saDHFR). We performed three-step in silico structure-based drug screening (SBDS) based on the crystal structure of saDHFR using a 154,118 chemical compound library. We subsequently evaluated whether candidate chemical compounds exhibited inhibitory effects on the growth of the model bacterium: Staphylococcus epidermidis (S. epidermidis). The compound KB1 showed a strong inhibitory effect on the growth of S. epidermidis. Moreover, we rescreened chemical structures similar to KB1 from a 461,397 chemical compound library. Three of the four KB1 analogs (KBS1, KBS3, and KBS4) showed inhibitory effects on the growth of S. epidermidis and enzyme inhibitory effects on saDHFR. We performed structure-activity relationship (SAR) analysis of active chemical compounds and observed a correlative relationship among the IC50 values, interaction residues, and structure scaffolds. In addition, the active chemical compounds (KB1, KBS3, and KBS4) had no inhibitory effects on the growth of model enterobacteria (E. coli BL21 and JM109 strains) and no toxic effects on cultured mammalian cells (MDCK cells). Results obtained from Protein Ligand Interaction Fingerprint (PLIF) and Ligand Interaction (LI) analyses suggested that all of the active compounds exhibited potential inhibitory effects on mutated saDHFR of the drug-resistant strains. The structural and experimental information concerning these novel chemical compounds will likely contribute to the development of new antibiotics for both wild-type and drug-resistant S. aureus.


Asunto(s)
Antibacterianos/farmacología , Staphylococcus/efectos de los fármacos , Tetrahidrofolato Deshidrogenasa/efectos de los fármacos , Bacterias/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Pruebas de Sensibilidad Microbiana
14.
Curr Top Med Chem ; 14(1): 176-88, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24236720

RESUMEN

Tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis and is a common infectious disease with high mortality and morbidity. The increasing prevalence of drug-resistant strains of TB presents a major public health problem. Due to the lack of effective drugs to treat these drug-resistant strains, the discovery or development of novel anti-TB drugs is important. Computer-aided drug design has become an established strategy for the identification of novel active chemicals through a combination of several drug design tools. In this review, we summarise the current chemotherapy for TB, describe attractive target proteins for the development of antibiotics against TB, and detail several computational drug design strategies that may contribute to the further identification of active chemicals for the treatment of not only TB but also other diseases.


Asunto(s)
Antituberculosos/química , Antituberculosos/farmacología , Química Farmacéutica/métodos , Diseño de Fármacos , Antituberculosos/uso terapéutico , Humanos , Terapia Molecular Dirigida , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología
15.
Molecules ; 18(12): 14529-42, 2013 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-24287989

RESUMEN

Asymmetric conjugate additions of branched aldehydes to vinyl sulfones promoted by sulfonamide organocatalyst 6 or 7 have been developed, allowing facile synthesis of the corresponding adducts with all-carbon quaternary stereocenters in excellent yields with up to 95% ee.


Asunto(s)
Aldehídos/química , Sulfonamidas/química , Sulfonas/química , Catálisis , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular
16.
J Chem Inf Model ; 53(5): 1200-12, 2013 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-23600706

RESUMEN

To identify novel antibiotics against Mycobacterium tuberculosis, we performed a hierarchical structure-based drug screening (SBDS) targeting the enoyl-acyl carrier protein reductase (InhA) with a compound library of 154,118 chemicals. We then evaluated whether the candidate hit compounds exhibited inhibitory effects on the growth of two model mycobacterial strains: Mycobacterium smegmatis and Mycobacterium vanbaalenii. Two compounds (KE3 and KE4) showed potent inhibitory effects against both model mycobacterial strains. In addition, we rescreened KE4 analogs, which were identified from a compound library of 461,383 chemicals through fingerprint analysis and genetic algorithm-based docking simulations. All of the KE4 analogs (KES1-KES5) exhibited inhibitory effects on the growth of M. smegmatis and/or M. vanbaalenii. Based on the predicted binding modes, we probed the structure-activity relationships of KE4 and its analogs and found a correlative relationship between the IC50 values and the interaction residues/LogP values. The most potent inhibitor, compound KES4, strongly and stably inhibited the long-term growth of the model bacteria and showed higher inhibitory effects (IC50 = 4.8 µM) than isoniazid (IC50 = 5.4 µM), which is a first-line drug for tuberculosis therapy. Moreover, compound KES4 did not exhibit any toxic effects that impede cell growth in several mammalian cell lines and enterobacteria. The structural and experimental information of these novel chemical compounds will likely be useful for the development of new anti-TB drugs. Furthermore, the methodology that was used for the identification of the effective chemical compound is also likely to be effective in the SBDS of other candidate medicinal drugs.


Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Simulación del Acoplamiento Molecular , Mycobacterium smegmatis/efectos de los fármacos , Animales , Antibacterianos/metabolismo , Antibacterianos/toxicidad , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Línea Celular Tumoral , Perros , Evaluación Preclínica de Medicamentos , Escherichia coli/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Dosificación Letal Mediana , Células de Riñón Canino Madin Darby , Mycobacterium smegmatis/enzimología , Oxidorreductasas/antagonistas & inhibidores , Oxidorreductasas/química , Oxidorreductasas/metabolismo , Conformación Proteica , Ratas , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/toxicidad
17.
Eur J Med Chem ; 60: 333-9, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23314046

RESUMEN

The increasing prevalence of drug-resistant tuberculosis, which is resistant to effective multiple antibiotic, presents a major global health threat. The thymidine monophosphate kinase (TMPK) of Mycobacterium tuberculosis (M. tuberculosis), which is an essential enzyme for the maintenance of the thymidine triphosphate pools, is considered an attractive target for the development of effective antibiotics against tuberculosis. In this study, we attempted to identify novel chemical compounds that specifically target the M. tuberculosis TMPK (mtTMPK). We performed in silico structure-based drug screening using the crystal structure data of mtTMPK and a large-scale virtual compound library, which is composed of 6,192,930 chemicals. Through a three-step screening method using the DOCK and GOLD, we identified ten chemical compounds that were predicted to have high binding affinity to the active site cleft of the mtTMPK. We then evaluated the antibiotic effects of these chemical compounds on model mycobacteria strains. As a result, we found that a chemical compound, K10, completely inhibited the growth of Mycobacterium vanbaalenii (M. vanbaalenii) and Mycobacterium smegmatis (M. smegmatis). Moreover, K10 does not exhibit any toxic effects on the growth of enterobacteria and mammalian cells. The structural and experimental information regarding this novel chemical compound, K10, is likely to be useful for the hit-to-lead optimization of new antibiotics for the treatment of tuberculosis.


Asunto(s)
Antibacterianos/farmacología , Inhibidores Enzimáticos/farmacología , Mycobacterium/efectos de los fármacos , Nucleósido-Fosfato Quinasa/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Línea Celular , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Células de Riñón Canino Madin Darby , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Molecular , Mycobacterium/enzimología , Mycobacterium/crecimiento & desarrollo , Nucleósido-Fosfato Quinasa/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad
18.
Eur J Med Chem ; 46(5): 1849-56, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21397998

RESUMEN

The enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis (MTB) is a key enzyme of the type II fatty acid synthesis system. It is involved in the production of mycolic acid and is a known target for isoniazid, an effective antibiotic for tuberculosis treatment. The increasing prevalence of tuberculosis in many areas of the world, which is associated with the rise of drug-resistant MTB strains, presents a major global health threat. In this study, we attempted to identify novel antibiotics specifically targeting the MTB enoyl-acyl carrier protein reductase. We performed in silico structure-based drug screening using the crystal structure data for the MTB enoyl-acyl carrier protein reductase (PDB code; 2H7I) and a virtual compound library, which includes 152,102 chemicals. By a two-step screening method using DOCK (first screening) and GOLD (second screening), we identified 5 chemical compounds expected to have high binding affinity to the active center of the MTB enoyl-acyl carrier protein reductase. Moreover, we examined the antibiotic effects of these chemical compounds on model bacterial strains by in vitro experiments. We found that a chemical compound, which has a basic skeleton comprised of dibenzofuran, acetoamide, trizol, furyl and methylphenyl groups, completely inhibited the growth of Mycobacterium vanbaalenii and had no toxic effects on enterobacteria and cultured mammalian cells. Therefore, the chemical compound is likely to be useful in the research and development of new antibiotics for tuberculosis.


Asunto(s)
Antibacterianos/farmacología , Tuberculosis/tratamiento farmacológico , Animales , Antibacterianos/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Perros , Evaluación Preclínica de Medicamentos , Enoil-ACP Reductasa (NADH)/antagonistas & inhibidores , Enoil-ACP Reductasa (NADH)/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Mycobacterium/efectos de los fármacos , Mycobacterium/enzimología , Mycobacterium/crecimiento & desarrollo , Rhodococcus/efectos de los fármacos , Rhodococcus/crecimiento & desarrollo , Bibliotecas de Moléculas Pequeñas , Estereoisomerismo , Relación Estructura-Actividad
19.
Org Lett ; 4(6): 885-8, 2002 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-11893177

RESUMEN

[reaction: see text] Novel synthesis of cephalotaxine 1 based on tertiary N-acyliminium ion chemistry starting from alkynylamide 2 was achieved. The key steps include the preparation of pyrroloisoquinoline 4 from alkynylamide 2, the ring expansion of pyrroloisoquinoline 4 to pyrrolobenzazepine 12, and the construction of cyclopentapyrrolobenzazepine ring system 6, all of which are derived from N-acyliminium ion intermediates.


Asunto(s)
Harringtoninas/síntesis química , Harringtoninas/química , Homoharringtonina , Estructura Molecular
20.
J Org Chem ; 63(20): 6797-6801, 1998 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-11672297

RESUMEN

Tilivalline 1, a metabolite from Klebsiella pneumoniae var. ocytoca, was easily synthesized in five steps from (S)-proline and 3-(benzyloxy)isatoic anhydride 4g. This synthesis is based on modified Curtius reactions of 3-substituted phthalic anhydrides 11 to 3-substituted isatoic anhydrides 4, conversion of lactams 6 to the acyliminium precursors 7 and stereoselective introduction of indole from the less hindered side of 7.

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