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  1 / 9806 MEDLINE  
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PMID:29268134
Autor:Plebanek E; Lescrinier E; Andrei G; Snoeck R; Herdewijn P; De Jonghe S
Endereço:Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49 - bus 1041, 3000 Leuven, Belgium.
Título:Emimycin and its nucleoside derivatives: Synthesis and antiviral activity.
Fonte:Eur J Med Chem; 144:93-103, 2018 Jan 20.
ISSN:1768-3254
País de publicação:France
Idioma:eng
Resumo:The synthesis of emimycin, 5-substituted emimycin analogues and the corresponding ribo- and 2'-deoxyribonucleoside derivatives is described. Emimycin, its 5-substituted congeners and the ribonucleoside derivatives are completely devoid of antiviral activity against RNA viruses. In contrast, some of the 2'-deoxyribosyl emimycin derivatives are potent inhibitors of the replication of herpes simplex virus-1 and varicella-zoster virus, lacking cytotoxicity.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Antiviral Agents); 0 (Nucleosides); 0 (Pyrazines); R14TE35LHD (emimycin)


  2 / 9806 MEDLINE  
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PMID:29441918
Autor:Wang S; Li A; Guo S
Título:Ligustrazine attenuates neuropathic pain by inhibition of JAK/STAT3 pathway in a rat model of chronic constriction injury.
Fonte:Pharmazie; 71(7):408-412, 2016 Jul 07.
ISSN:0031-7144
País de publicação:Germany
Idioma:eng
Resumo:AIM: Neuropathic pain is a common clinical complication of nerve injury, and the effective treatment of neuropathic pain is still challenging. Ligustrazine is mainly used for the treatment of cardiovascular disease and its role in neuropathic pain is less investigated. The purpose of our study was to explore the effects of ligustrazine on neuropathic pain, as well as the underlying molecular mechanism. METHODS: Neuropathic pain was induced by chronic constriction injury (CCI) of the right sciatic nerve in Sprague-Dawley (SD) rats. After CCI, rats received ligustrazine, IL-6, or both. Mechanical withdrawal threshold (MWT) and paw withdrawal thermal latency (PWTL) were assessed on days 1, 3, 7, and 14 after surgery. Expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-ß, IL-2, and phosphorylation of Signal Transducer and Activator of Transcription (STAT) 3 were analyzed. RESULTS: Our results showed that both MWT and PWTL were significantly decreased by CCI on days 1, 3, 7 and 14 compared to sham group, however, ligustrazine reversed this effects. Additionally, the elevated levels of TNF-α, IL-1ß, and IL-2 in CCI spinal cord were inhibited by ligustrazine. Quantitative real-time (qRT-PCR) and Western blotting analysis showed that the test substance reduced the elevated expression of pSTAT3 in the spinal cord induced by CCI, and while IL-6 administration reversed the levels as well as the behavior responses. CONCLUSION: Our results suggest that ligustrazine could effectively attenuate neuropathic pain by inhibition of Janus Kinase (JAK)/STAT3 pathway in CCI rats.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Cytokines); 0 (Pyrazines); 0 (STAT3 Transcription Factor); 0 (Stat3 protein, rat); V80F4IA5XG (tetramethylpyrazine)


  3 / 9806 MEDLINE  
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PMID:29270587
Autor:Tang X; Wang Z; Lei T; Zhou W; Chang S; Li D
Endereço:College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P. R. China. lidancps@zju.edu.cn.
Título:Importance of protein flexibility on molecular recognition: modeling binding mechanisms of aminopyrazine inhibitors to Nek2.
Fonte:Phys Chem Chem Phys; 20(8):5591-5605, 2018 Feb 21.
ISSN:1463-9084
País de publicação:England
Idioma:eng
Resumo:NIMA-related kinase 2 (Nek2) plays a significant role in cell cycle regulation, and overexpression of Nek2 has been observed in several types of carcinoma, suggesting it is a potential target for cancer therapy. In this study, we attempted to gain more insight into the binding mechanisms of a series of aminopyrazine inhibitors of Nek2 through multiple molecular modeling techniques, including molecular docking, molecular dynamics (MD) simulations and free energy calculations. The simulation results showed that the induced fit docking and ensemble docking based on multiple protein structures yield better predictions than conventional rigid receptor docking, highlighting the importance of incorporating receptor flexibility into the accurate predictions of the binding poses and binding affinities of Nek2 inhibitors. Additionally, we observed that the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations did not show better performance than the docking scoring to rank the binding affinities of the studied inhibitors, suggesting that MM/GBSA is system-dependent and may not be the best choice for the Nek2 systems. Moreover, the detailed information on protein-ligand binding was characterized by the MM/GBSA free energy decomposition, and a number of derivatives with improved docking scores were designed. It is expected that our study can provide valuable information for the future rational design of novel and potent inhibitors of Nek2.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Ligands); 0 (Protein Kinase Inhibitors); 0 (Pyrazines); EC 2.7.11.1 (NEK2 protein, human); EC 2.7.11.1 (NIMA-Related Kinases)


  4 / 9806 MEDLINE  
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PMID:28465355
Autor:Lan L; Guo M; Ai Y; Chen F; Zhang Y; Xia L; Huang D; Niu L; Zheng Y; Suzuki CK; Zhang Y; Liu Y; Lu B
Endereço:Department of Biochemistry, Institute of Biophysics, Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Título:Tetramethylpyrazine blocks TFAM degradation and up-regulates mitochondrial DNA copy number by interacting with TFAM.
Fonte:Biosci Rep; 37(3), 2017 Jun 30.
ISSN:1573-4935
País de publicação:England
Idioma:eng
Resumo:The natural small molecule compound: 2,3,5,6-tetramethylpyrazine (TMP), is a major component of the Chinese medicine , which has wide clinical applications in dilating blood vessels, inhibiting platelet aggregation and treating thrombosis. Recent work suggests that TMP is also an antitumour agent. Despite its chemotherapeutic potential, the mechanism(s) underlying TMP action are unknown. Herein, we demonstrate that TMP binds to mitochondrial transcription factor A (TFAM) and blocks its degradation by the mitochondrial Lon protease. TFAM is a key regulator of mtDNA replication, transcription and transmission. Our previous work showed that when TFAM is not bound to DNA, it is rapidly degraded by the ATP-dependent Lon protease, which is essential for mitochondrial proteostasis. In cultured cells, TMP specifically blocks Lon-mediated degradation of TFAM, leading to TFAM accumulation and subsequent up-regulation of mtDNA content in cells with substantially low levels of mtDNA. protease assays show that TMP does not directly inhibit mitochondrial Lon, rather interacts with TFAM and blocks degradation. Pull-down assays show that biotinylated TMP interacts with TFAM. These findings suggest a novel mechanism whereby TMP stabilizes TFAM and confers resistance to Lon-mediated degradation, thereby promoting mtDNA up-regulation in cells with low mtDNA content.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (DNA, Mitochondrial); 0 (DNA-Binding Proteins); 0 (Mitochondrial Proteins); 0 (Pyrazines); 0 (TFAM protein, human); 0 (Transcription Factors); EC 3.4.- (Peptide Hydrolases); V80F4IA5XG (tetramethylpyrazine)


  5 / 9806 MEDLINE  
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PMID:29288949
Autor:Elkamhawy A; Park JE; Hassan AHE; Pae AN; Lee J; Park BG; Roh EJ
Endereço:Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Título:Synthesis and evaluation of 2-(3-arylureido)pyridines and 2-(3-arylureido)pyrazines as potential modulators of Aß-induced mitochondrial dysfunction in Alzheimer's disease.
Fonte:Eur J Med Chem; 144:529-543, 2018 Jan 20.
ISSN:1768-3254
País de publicação:France
Idioma:eng
Resumo:A series of 2-(3-arylureido)pyridines and 2-(3-benzylureido)pyridines were synthesized and evaluated as potential modulators for amyloid beta (Aß)-induced mitochondrial dysfunction in Alzheimer's disease (AD). The blocking activities of forty one small molecules against Aß-induced mitochondrial permeability transition pore (mPTP) opening were evaluated by JC-1 assay which measures the change of mitochondrial membrane potential (ΔΨm). The inhibitory activity of twenty five compounds against Aß-induced mPTP opening was superior to that of the standard cyclosporin A (CsA). Six hit compounds have been identified as likely safe in regards to mitochondrial and cellular safety and subjected to assessment for their protective effect against Aß-induced deterioration of ATP production and cytotoxicity. Among them, compound 7fb has been identified as a lead compound protecting neuronal cells against 67% of neurocytotoxicity and 43% of suppression of mitochondrial ATP production induced by 5 µM concentrations of Aß. Using CDocker algorithm, a molecular docking model presented a plausible binding mode for these compounds with cyclophilin D (CypD) receptor as a major component of mPTP. Hence, this report presents compound 7fb as a new nonpeptidyl mPTP blocker which would be promising for further development of Alzheimer's disease (AD) therapeutics.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Amyloid beta-Peptides); 0 (Mitochondrial Membrane Transport Proteins); 0 (Pyrazines); 0 (Pyridines); 0 (mitochondrial permeability transition pore)


  6 / 9806 MEDLINE  
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PMID:29218345
Autor:Yang X; Li Z; Jiang T; Du L; Li M
Endereço:Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China. mli@sdu.edu.cn.
Título:A coelenterazine-type bioluminescent probe for nitroreductase imaging.
Fonte:Org Biomol Chem; 16(1):146-151, 2017 Dec 19.
ISSN:1477-0539
País de publicação:England
Idioma:eng
Resumo:Novel coelenterazine-type bioluminescent probes have been designed and synthesized to detect nitroreductase (NTR) in hypoxic tumors. The design strategy is that NTR catalyzes the reduction of the nitrobenzyl moiety to the aniline group with an electron donor, thus resulting in 1,4 or 1,6-rearrangement-elimination to release coelenterazine analogues, which can be catalyzed by Renilla luciferase to emit bioluminescence. After careful evaluation, almost all probes had a 3-fold greater response for NTR over other biologically relevant substances at >100-fold dose more than NTR. In the dose-independent and selectivity study, probes A1, A2 and A5 presented a high selectivity in a dose-dependent manner. Overall, among all molecules, probe A5 showed high sensitivity, low cytotoxicity and good compatibility, so as to be successfully applied for assessing the hypoxic status in cellulo and in vivo as the first coelenterazine-type bioluminescent probe.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Fluorescent Dyes); 0 (Imidazoles); 0 (Pyrazines); 3O1CB88RRD (coelenterazine); EC 1.7.- (Nitroreductases)


  7 / 9806 MEDLINE  
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PMID:28465146
Autor:Tokunaga T; Yamamoto Y; Sakai M; Tomonaga K; Honda T
Endereço:Laboratory of RNA Viruses, Department of Virus Research, Institute for Frontier Life and Medical Sciences (InFRONT), Kyoto University, Kyoto, Japan; Department of Mammalian Regulatory Network, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
Título:Antiviral activity of favipiravir (T-705) against mammalian and avian bornaviruses.
Fonte:Antiviral Res; 143:237-245, 2017 07.
ISSN:1872-9096
País de publicação:Netherlands
Idioma:eng
Resumo:Bornaviruses, non-segmented, negative-strand RNA viruses, are emerging agents with the potential for causing various types of neurological symptoms. Previous studies have shown that ribavirin, a nucleic acid analog with broad-spectrum antiviral activity, has a potent antiviral effect on infections with a mammalian bornavirus, Borna disease virus (BoDV-1), as well as avian bornaviruses. However, ribavirin-based treatment does not eliminate bornaviruses from persistently infected cells and viral replication resumes after treatment cessation. Therefore, the development of a novel effective anti-bornavirus treatment is needed. To identify such agents, we screened nucleoside/nucleotide mimetics for agents with anti-bornavirus activity. We used Vero cells infected with recombinant BoDV-1 carrying Gaussia luciferase to monitor BoDV-1 replication and found that favipiravir (T-705) is a potent inhibitor of BoDV-1 replication. T-705 suppressed BoDV-1 replication in a dose- and time-dependent manner during the observation period of 4 weeks. Notably, no increase in luciferase activity or in the number of BoDV-1-positive cells was detected in the at least 4 weeks following T-705 removal. Finally, we demonstrated that T-705 effectively suppressed viral replication of both BoDV-1 and an avian bornavirus, suggesting that T-705 may have a strong antiviral activity against a broad range of bornaviruses. Our findings provide a novel and effective option for treating persistent bornavirus infection.
Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Nome de substância:0 (Amides); 0 (Antiviral Agents); 0 (Pyrazines); 0 (RNA, Viral); EW5GL2X7E0 (favipiravir)


  8 / 9806 MEDLINE  
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PMID:27773231
Autor:Yu H; Seow YX; Ong PK; Zhou W
Endereço:Food Science & Technology Programme, c/o Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore.
Título:Effects of high-intensity ultrasound on Maillard reaction in a model system of d-xylose and l-lysine.
Fonte:Ultrason Sonochem; 34:154-163, 2017 01.
ISSN:1873-2828
País de publicação:Netherlands
Idioma:eng
Resumo:This study compared the effects of high-intensity ultrasound on Maillard reaction (MR) with those of thermally produced MR using a model system of d-xylose and l-lysine. The ultrasonic MR process had higher depletion rates of reactants and higher generation rates of intermediate MR products (MRPs) and melanoidins under relatively low processing temperatures (55 and 60°C). However, the rates were lower for ultrasonic MR than thermal MR when the processing temperature increased to 65, 70 and 75°C. Overall, ultrasonic MR had relatively low activation energy (E ) compared to thermal MR (e.g. 55.59 vs. 80.42kJmol for d-xylose depletion). Moreover, ultrasonic MR could produce at least one N-containing pyrazine (3-ethyl-2,5-dimethylpyrazine), one N-containing amine (butyl amine) and one O-containing volatile compound (maltol) that were absent from thermal MR. The difference in flavour generation might be a result of the extremely high, albeit momentary, temperature and pressure condition produced by high-intensity ultrasound.
Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Nome de substância:0 (Pyrazines); A1TA934AKO (Xylose); K3Z4F929H6 (Lysine)


  9 / 9806 MEDLINE  
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PMID:29283993
Autor:Chinello P; Petrosillo N; Pittalis S; Biava G; Ippolito G; Nicastri E; INMI Ebola Team
Endereço:Lazzaro Spallanzani National Institute for Infectious Diseases (INMI), IRCCS, Rome, Italy.
Título:QTc interval prolongation during favipiravir therapy in an Ebolavirus-infected patient.
Fonte:PLoS Negl Trop Dis; 11(12):e0006034, 2017 12.
ISSN:1935-2735
País de publicação:United States
Idioma:eng
Tipo de publicação: CASE REPORTS; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Nome de substância:0 (Amides); 0 (Antiviral Agents); 0 (Pyrazines); 6GNT3Y5LMF (Levofloxacin); EC 2.7.7.48 (RNA Replicase); EW5GL2X7E0 (favipiravir)


  10 / 9806 MEDLINE  
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PMID:29193819
Autor:Denton CP; Hachulla É; Riemekasten G; Schwarting A; Frenoux JM; Frey A; Le Brun FO; Herrick AL; Raynaud Study Investigators
Endereço:Royal Free Hospital, London, UK.
Título:Efficacy and Safety of Selexipag in Adults With Raynaud's Phenomenon Secondary to Systemic Sclerosis: A Randomized, Placebo-Controlled, Phase II Study.
Fonte:Arthritis Rheumatol; 69(12):2370-2379, 2017 12.
ISSN:2326-5205
País de publicação:United States
Idioma:eng
Resumo:OBJECTIVE: To determine the effect of selexipag, an oral, selective IP prostacyclin receptor agonist, on the frequency of attacks of Raynaud's phenomenon (RP) in patients with systemic sclerosis (SSc). METHODS: Patients with SSc-related RP were randomized 1:1 to placebo (n = 38) or selexipag (n = 36) in individualized doses (maximum of 1,600 µg twice daily) during a 3-week titration period. The primary end point was the weekly average number of RP attacks during the study maintenance period, analyzed using a Bayesian approach with a negative binomial model adjusted for baseline number of RP attacks. Other outcome measures included Raynaud's Condition Score (RCS), RP attack duration, and treatment-emergent adverse events (AEs). RESULTS: Baseline characteristics were comparable between treatment groups. For 83.3% of patients, the individualized maintenance dosage of selexipag was ≤800 µg twice daily. No significant difference was observed between placebo and selexipag in weekly average number of electronic diary (eDiary)-recorded RP attacks during the maintenance period (14.2 attacks during the maintenance period and 21.5 attacks during the baseline week in the placebo group [n = 32] versus 18.0 attacks during the maintenance period and 22.4 attacks during the baseline week in the selexipag group [n = 27]; adjusted mean treatment difference of 3.4 in favor of placebo). No significant treatment effect was observed on RCS or RP attack duration. In the double-blind period, 86.8% of placebo-treated patients and 100% of selexipag-treated patients reported ≥1 AE; 55.3% and 91.7%, respectively, reported ≥1 prostacyclin-associated AE. CONCLUSION: Treatment with selexipag did not reduce the number of RP attacks compared with placebo. The safety profile of selexipag was similar to that previously reported. This study provides important information about the feasibility of eDiary reporting of RP attacks in clinical trials.
Tipo de publicação: CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T
Nome de substância:0 (Acetamides); 0 (Antihypertensive Agents); 0 (Pyrazines); 5EXC0E384L (selexipag)



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