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[PMID]:27888146
[Au] Autor:Kang TS; Wang W; Zhong HJ; Liang JX; Ko CN; Lu JJ; Chen XP; Ma DL; Leung CH
[Ad] Endereço:State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
[Ti] Título:A rhodium(III)-based inhibitor of autotaxin with antiproliferative activity.
[So] Source:Biochim Biophys Acta;1861(2):256-263, 2017 02.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Cancer of the skin is by far the most common of all cancers. Melanoma accounts for only about 1% of skin cancers but causes a large majority of skin cancer deaths. Autotaxin (ATX), also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), regulates physiological and pathological functions of lysophosphatidic acid (LPA), and is thus an important therapeutic target. METHODS: We synthesized ten metal-based complexes and a novel cyclometalated rhodium(III) complex 1 was identified as an ATX enzymatic inhibitor using multiple methods, including ATX enzymatic assay, thermal shift assay, western immunoblotting and so on. RESULTS: Protein thermal shift assays showed that 1 increased the melting temperature (T ) of ATX by 3.5°C. 1 also reduced ATX-LPA mediated downstream survival signal pathway proteins such as ERK and AKT, and inhibited the activation of the transcription factor nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3). 1 also exhibited strong anti-proliferative activity against A2058 melanoma cells (IC =0.58µM). Structure-activity relationship indicated that both the rhodium(III) center and the auxiliary ligands of complex 1 are important for bioactivity. CONCLUSIONS: 1 represents a promising scaffold for the development of small-molecule ATX inhibitors for anti-tumor applications. To our knowledge, complex 1 is the first metal-based ATX inhibitor reported to date. GENERAL SIGNIFICANCE: Rhodium complexes will have the increased attention in therapeutic and bioanalytical applications.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Proliferação Celular/efeitos dos fármacos
Inibidores Enzimáticos/farmacologia
Melanoma/tratamento farmacológico
Diester Fosfórico Hidrolases/metabolismo
Ródio/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Seres Humanos
Lisofosfolipídeos/farmacologia
Melanoma/metabolismo
Complexos Multienzimáticos/metabolismo
NF-kappa B/metabolismo
Fosfodiesterase I/metabolismo
Fator de Transcrição STAT3/metabolismo
Transdução de Sinais/efeitos dos fármacos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); 0 (Lysophospholipids); 0 (Multienzyme Complexes); 0 (NF-kappa B); 0 (STAT3 Transcription Factor); DMK383DSAC (Rhodium); EC 3.1.4.- (Phosphoric Diester Hydrolases); EC 3.1.4.1 (Phosphodiesterase I); EC 3.1.4.39 (alkylglycerophosphoethanolamine phosphodiesterase); PG6M3969SG (lysophosphatidic acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161127
[St] Status:MEDLINE


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[PMID]:26911851
[Au] Autor:Xin W; Li N; Fernandes VS; Chen B; Rovner ES; Petkov GV
[Ad] Endereço:Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina; and.
[Ti] Título:BK channel regulation by phosphodiesterase type 1: a novel signaling pathway controlling human detrusor smooth muscle function.
[So] Source:Am J Physiol Renal Physiol;310(10):F994-9, 2016 May 15.
[Is] ISSN:1522-1466
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Large-conductance Ca(2+)-activated K(+) (BK) channels are critical regulators of detrusor smooth muscle (DSM) function. We aimed to investigate phosphodiesterase type 1 (PDE1) interactions with BK channels in human DSM to determine the mechanism by which PDE1 regulates human urinary bladder physiology. A combined electrophysiological, functional, and pharmacological approach was applied using human DSM specimens obtained from open bladder surgeries. The perforated whole cell patch-clamp technique was used to record transient BK currents (TBKCs) and the cell membrane potential in freshly isolated human DSM cells in combination with the selective PDE1 inhibitor, 8-methoxymethyl-3-isobutyl-1-methylxanthine (8MM-IBMX). Isometric DSM tension recordings were used to measure spontaneous phasic and electrical field stimulation-induced contractions in human DSM isolated strips. Selective pharmacological inhibition of PDE1 with 8MM-IBMX (10 µM) increased TBKC activity in human DSM cells, which was abolished by subsequent inhibition of protein kinase A (PKA) with H-89 (10 µM). The stimulatory effect of 8MM-IBMX on TBKCs was reversed upon activation of muscarinic acetylcholine receptors with carbachol (1 µM). 8MM-IBMX (10 µM) hyperpolarized the DSM cell membrane potential, an effect blocked by PKA inhibition. 8MM-IBMX significantly decreased spontaneous phasic and nerve-evoked contractions of human DSM isolated strips. The results reveal a novel mechanism that pharmacological inhibition of PDE1 attenuates human DSM excitability and contractility by activating BK channels via a PKA-dependent mechanism. The data also suggest interactions between PDE1 and muscarinic signaling pathways in human DSM. Inhibition of PDE1 can be a novel therapeutic approach for the treatment of overactive bladder associated with detrusor overactivity.
[Mh] Termos MeSH primário: Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo
Fosfodiesterase I/metabolismo
Bexiga Urinária Hiperativa/metabolismo
Xantinas/farmacologia
[Mh] Termos MeSH secundário: Idoso
Carbacol
Células Cultivadas
Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Avaliação Pré-Clínica de Medicamentos
Feminino
Seres Humanos
Técnicas In Vitro
Isoquinolinas
Masculino
Potenciais da Membrana/efeitos dos fármacos
Meia-Idade
Técnicas de Patch-Clamp
Fosfodiesterase I/antagonistas & inibidores
Transdução de Sinais/efeitos dos fármacos
Sulfonamidas
Bexiga Urinária Hiperativa/tratamento farmacológico
Xantinas/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (8-methoxymethyl-3-isobutyl-1-methylxanthine); 0 (Isoquinolines); 0 (Large-Conductance Calcium-Activated Potassium Channels); 0 (Sulfonamides); 0 (Xanthines); 8Y164V895Y (Carbachol); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 3.1.4.1 (Phosphodiesterase I); M876330O56 (N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170627
[Lr] Data última revisão:
170627
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160226
[St] Status:MEDLINE
[do] DOI:10.1152/ajprenal.00452.2015


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[PMID]:26669448
[Au] Autor:Daniels CM; Thirawatananond P; Ong SE; Gabelli SB; Leung AK
[Ad] Endereço:Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
[Ti] Título:Nudix hydrolases degrade protein-conjugated ADP-ribose.
[So] Source:Sci Rep;5:18271, 2015 Dec 16.
[Is] ISSN:2045-2322
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:ADP-ribosylation refers to the transfer of the ADP-ribose group from NAD(+) to target proteins post-translationally, either attached singly as mono(ADP-ribose) (MAR) or in polymeric chains as poly(ADP-ribose) (PAR). Though ADP-ribosylation is therapeutically important, investigation of this protein modification has been limited by a lack of proteomic tools for site identification. Recent work has demonstrated the potential of a tag-based pipeline in which MAR/PAR is hydrolyzed down to phosphoribose, leaving a 212 Dalton tag at the modification site. While the pipeline has been proven effective by multiple groups, a barrier to application has become evident: the enzyme used to transform MAR/PAR into phosphoribose must be purified from the rattlesnake Crotalus adamanteus venom, which is contaminated with proteases detrimental for proteomic applications. Here, we outline the steps necessary to purify snake venom phosphodiesterase I (SVP) and describe two alternatives to SVP-the bacterial Nudix hydrolase EcRppH and human HsNudT16. Importantly, expression and purification schemes for these Nudix enzymes have already been proven, with high-quality yields easily attainable. We demonstrate their utility in identifying ADP-ribosylation sites on Poly(ADP-ribose) Polymerase 1 (PARP1) with mass spectrometry and discuss a structure-based rationale for this Nudix subclass in degrading protein-conjugated ADP-ribose, including both MAR and PAR.
[Mh] Termos MeSH primário: Adenosina Difosfato Ribose/química
Proteínas de Bactérias/química
Venenos de Crotalídeos/química
Fosfodiesterase I/química
Pirofosfatases/química
[Mh] Termos MeSH secundário: Adenosina Difosfato Ribose/metabolismo
Animais
Proteínas de Bactérias/metabolismo
Venenos de Crotalídeos/enzimologia
Seres Humanos
Fosfodiesterase I/metabolismo
Proteômica
Pirofosfatases/metabolismo
Viperidae
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Crotalid Venoms); 20762-30-5 (Adenosine Diphosphate Ribose); EC 3.1.4.1 (Phosphodiesterase I); EC 3.6.1.- (Pyrophosphatases); EC 3.6.1.- (nudix hydrolases)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151217
[St] Status:MEDLINE
[do] DOI:10.1038/srep18271


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[PMID]:26498616
[Au] Autor:Gahan JM; Byrne MM; Hill M; Quinn EM; Murphy RT; Anney RJ; Ryan AW
[Ad] Endereço:Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland.
[Ti] Título:Detecting Allelic Expression Imbalance at Candidate Genes Using 5' Exonuclease Genotyping Technology.
[So] Source:Methods Mol Biol;1326:93-103, 2015.
[Is] ISSN:1940-6029
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Genetic variation along the length of a chromosome can influence the transcription of a gene. In a heterozygous individual, this may lead to one chromosome producing different levels of RNA, compared to its paired chromosome, for a given gene. Allelic differences in gene expression can offer insight into the role of variation in transcription, and subsequently infer a route to conferring disease risk. This phenomenon is known as allele expression imbalance or AEI, which may be assayed using a PCR-based method that includes the quantification of the relative dosage of each allele (e.g., 5' exonuclease assays, TaqMan™). Importantly, in heterozygous individuals the resolution of expression imbalance is performed within a controlled system; the comparison of the alternate allele is reported relative to the wild-type, as the experiment can be performed within a single sample, controlled for background genetic information. Alternative methods for the detection of AEI include Primer-extension MALDI-TOF (Sequenom MassARRAY(®)), Next-Generation Sequencing, and SNP genotyping arrays. Here we present the methods used for the TaqMan™ approach and include a description of the SNP identification, allele-specific PCR, and analytic methods to convert allele amplification metrics to relative allele dosage.
[Mh] Termos MeSH primário: Alelos
Genótipo
Fosfodiesterase I/metabolismo
[Mh] Termos MeSH secundário: Polimorfismo de Nucleotídeo Único
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 3.1.4.1 (Phosphodiesterase I)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151027
[St] Status:MEDLINE
[do] DOI:10.1007/978-1-4939-2839-2_10


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[PMID]:26002482
[Au] Autor:Kang L; Yang B; Zhang X; Cui L; Meng H; Mei L; Wu C; Ren S; Tan W
[Ad] Endereço:Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha, Hunan 410082, China.
[Ti] Título:Enzymatic cleavage and mass amplification strategy for small molecule detection using aptamer-based fluorescence polarization biosensor.
[So] Source:Anal Chim Acta;879:91-6, 2015 Jun 16.
[Is] ISSN:1873-4324
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Fluorescence polarization (FP) assays incorporated with fluorophore-labeled aptamers have attracted great interest in recent years. However, detecting small molecules through the use of FP assays still remains a challenge because small-molecule binding only results in negligible changes in the molecular weight of the fluorophore-labeled aptamer. To address this issue, we herein report a fluorescence polarization (FP) aptamer assay that incorporates a novel signal amplification strategy for highly sensitive detection of small molecules. In the absence of adenosine, our model target, free FAM-labeled aptamer can be digested by nuclease, resulting in the release of FAM-labeled nucleotide segments from the dT-biotin/streptavidin complex with weak background signal. However, in the presence of target, the FAM-labeled aptamer-target complex protects the FAM-labeled aptamer from nuclease cleavage, allowing streptavidin to act as a molar mass amplifier. The resulting increase in molecular mass and FP intensity of the aptamer-target complex provides improved sensitivity for concentration measurement. The probe could detect adenosine from 0.5 µM to 1000 µM, with a detection limit of 500 nM, showing that the sensitivity of the probe is superior to aptamer-based FP approaches previously reported for adenosine. Importantly, FP could resist environmental interferences, making it useful for complex biological samples without any tedious sample pretreatments. Our results demonstrate that this dual-amplified, aptamer-based strategy can be used to design fluorescence polarization probes for rapid, sensitive, and selective measurement of small molecules in complicated biological environment.
[Mh] Termos MeSH primário: Adenosina/análise
Aptâmeros de Nucleotídeos/química
Técnicas Biossensoriais/métodos
Polarização de Fluorescência/métodos
Corantes Fluorescentes/química
[Mh] Termos MeSH secundário: Animais
Aptâmeros de Nucleotídeos/metabolismo
Crotalus
Limite de Detecção
Fosfodiesterase I/metabolismo
Proteínas de Répteis/metabolismo
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aptamers, Nucleotide); 0 (Fluorescent Dyes); 0 (Reptilian Proteins); EC 3.1.4.1 (Phosphodiesterase I); K72T3FS567 (Adenosine)
[Em] Mês de entrada:1602
[Cu] Atualização por classe:150524
[Lr] Data última revisão:
150524
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150524
[St] Status:MEDLINE


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[PMID]:25817770
[Au] Autor:Niaz H; Kashtoh H; Khan JA; Khan A; Wahab AT; Alam MT; Khan KM; Perveen S; Choudhary MI
[Ad] Endereço:H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
[Ti] Título:Synthesis of diethyl 4-substituted-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylates as a new series of inhibitors against yeast α-glucosidase.
[So] Source:Eur J Med Chem;95:199-209, 2015 May 05.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:1,4-Dihydropyridine-3,5-dicarboxylate derivatives (1-25) were synthesized in high yields via Hantzsch reaction and evaluated for their α-glucosidase inhibitory activity. Compounds 1, 2, 6-8, 11, 13-15, and 23-25 showed a potent inhibitory activity against yeast α-glucosidase with IC50 values in the range of 35.0-273.7 µM, when compared with the standard drug acarbose (IC50 = 937 ± 1.60 µM). Their structures were characterized by different spectroscopic techniques. The kinetics, selectivity, and toxicity studies on these compounds were also carried out. The kinetic studies on most active compounds 14 and 25 determined their modes of inhibition and dissociation constants Ki. Compound 14 was found to be a non-competitive inhibitor with Ki = 25.0 ± 0.06, while compound 25 was identified as a competitive inhibitor with Ki = 66.0 ± 0.07 µM.
[Mh] Termos MeSH primário: Ácidos Carboxílicos/síntese química
Ácidos Carboxílicos/farmacologia
Proliferação Celular/efeitos dos fármacos
Fibroblastos/efeitos dos fármacos
Inibidores de Glicosídeo Hidrolases/síntese química
Inibidores de Glicosídeo Hidrolases/farmacologia
Piridinas/síntese química
Piridinas/farmacologia
Saccharomyces cerevisiae/enzimologia
alfa-Glucosidases/química
[Mh] Termos MeSH secundário: Animais
Anidrase Carbônica II/antagonistas & inibidores
Inibidores da Anidrase Carbônica/síntese química
Inibidores da Anidrase Carbônica/farmacologia
Células Cultivadas
Relação Dose-Resposta a Droga
Fibroblastos/citologia
Cinética
Estrutura Molecular
Fosfodiesterase I/antagonistas & inibidores
Inibidores de Fosfodiesterase/síntese química
Inibidores de Fosfodiesterase/farmacologia
Ratos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carbonic Anhydrase Inhibitors); 0 (Carboxylic Acids); 0 (Glycoside Hydrolase Inhibitors); 0 (Phosphodiesterase Inhibitors); 0 (Pyridines); 0 (diethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate); 0 (diethyl 2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate); EC 3.1.4.1 (Phosphodiesterase I); EC 3.2.1.20 (alpha-Glucosidases); EC 4.2.1.- (Carbonic Anhydrase II)
[Em] Mês de entrada:1602
[Cu] Atualização por classe:150420
[Lr] Data última revisão:
150420
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150331
[St] Status:MEDLINE


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[PMID]:25475204
[Au] Autor:Fujita H; Nakajima K; Kasahara Y; Ozaki H; Kuwahara M
[Ad] Endereço:Graduate School of Science and Technology, Gunma University, 1-5-1 Tenjin-cho, Kiryu, Gunma 376-8515, Japan.
[Ti] Título:Polymerase-mediated high-density incorporation of amphiphilic functionalities into DNA: enhancement of nuclease resistance and stability in human serum.
[So] Source:Bioorg Med Chem Lett;25(2):333-6, 2015 Jan 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Modified oligodeoxyribonucleotides (mdODNs) bearing multiple copies of an amphiphilic functional group were enzymatically synthesized by simultaneous incorporation of base-modified 5'-triphosphate analogs of 2'-deoxyguanosine (dG(am)TP), 2'-deoxyuridine (dU(am)TP), 2'-deoxyadenosine (dA(am)TP), and 2'-deoxycytosine (dC(am)TP). The amphiphilic functionality, that is, (E)-38,53-dioxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39,52-diazapentapentacont-54-en-55-yl group, consists of the water soluble dodeca(ethylene glycol) chain and the hydrophobic dodecyl chain. An enzymatically synthesized ODN, composed of a 20-mer 5'-terminal segment containing 2'-O,4'-C-methylene-bridged/linked bicyclic ribonucleotide (B/L nucleotide) and a 12-mer 3'-terminal segment containing the nucleobase-modified analogs, exhibits very high resistance against phosphodiesterase I and is stable in human serum for a longer period when compared with ODN, where the 12-mer 3'-terminal segment contains unmodified nucleotides.
[Mh] Termos MeSH primário: DNA Polimerase Dirigida por DNA/metabolismo
DNA/química
Oligodesoxirribonucleotídeos/química
Fosfodiesterase I/metabolismo
Soro/química
[Mh] Termos MeSH secundário: Seres Humanos
Estrutura Molecular
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Oligodeoxyribonucleotides); 9007-49-2 (DNA); EC 2.7.7.7 (DNA-Directed DNA Polymerase); EC 3.1.4.1 (Phosphodiesterase I)
[Em] Mês de entrada:1509
[Cu] Atualização por classe:141226
[Lr] Data última revisão:
141226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141206
[St] Status:MEDLINE


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[PMID]:25470505
[Au] Autor:Saad SM; Saleem M; Perveen S; Alam MT; Khan KM; Choudhary MI
[Ti] Título:Synthesis and Biological Potential Assessment of 2-Substituted Quinazolin-4(3H)-ones as Inhibitors of Phosphodiesterase-I and Carbonic Anhydrase-II.
[So] Source:Med Chem;11(4):336-41, 2015.
[Is] ISSN:1875-6638
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:A library of twenty-five derivatives of 2-substituted quinazolin-4(3H)-ones 1-25 was synthesized and evaluated against phosphodiesterase-I (PDE) and carbonic anhydrase-II (CA). Compounds 17 (IC50 = 210.7 ± 2.62 µM), 16 (IC50 = 301.6 ± 1.18 µM), and 13 (IC50 = 458.13 ± 3.60 µM), selectively exhibited PDE inhibition while compounds 22 (IC50 = 61.33 ± 2.38 µM), 1 (IC50 = 108.30 ± 0.93 µM), and 21 (IC50 = 191.93 ± 2.72 µM), discriminatingly exhibited CA inhibition as compared to standards EDTA (IC50 = 277.69 ± 2.52 µM) and acetazolamide (IC50 = 0.12 ± 0.03 µM), for PDE and CA inhibitions, respectively. However, compound 15 was found to be active against both enzymes with the IC50 values 344.33 ± 4.32 µM and 20.94 ± 0.58 µM, for PDE and CA inhibitions, respectively. Remaining compounds were found to be inactive against both the enzymes. Structure-activity relationship studies are discussed herein.
[Mh] Termos MeSH primário: Anidrase Carbônica II/antagonistas & inibidores
Inibidores da Anidrase Carbônica/síntese química
Fosfodiesterase I/antagonistas & inibidores
Inibidores de Fosfodiesterase/síntese química
Quinazolinonas/síntese química
Bibliotecas de Moléculas Pequenas/síntese química
[Mh] Termos MeSH secundário: Acetazolamida/química
Animais
Anidrase Carbônica II/química
Anidrase Carbônica II/isolamento & purificação
Inibidores da Anidrase Carbônica/química
Desenho de Drogas
Ácido Edético/química
Ensaios Enzimáticos
Estrutura Molecular
Fosfodiesterase I/química
Fosfodiesterase I/isolamento & purificação
Inibidores de Fosfodiesterase/química
Quinazolinonas/química
Bibliotecas de Moléculas Pequenas/química
Serpentes/metabolismo
Soluções
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carbonic Anhydrase Inhibitors); 0 (Phosphodiesterase Inhibitors); 0 (Quinazolinones); 0 (Small Molecule Libraries); 0 (Solutions); 9G34HU7RV0 (Edetic Acid); EC 3.1.4.1 (Phosphodiesterase I); EC 4.2.1.- (Carbonic Anhydrase II); O3FX965V0I (Acetazolamide)
[Em] Mês de entrada:1602
[Cu] Atualização por classe:150508
[Lr] Data última revisão:
150508
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141204
[St] Status:MEDLINE


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[PMID]:25151088
[Au] Autor:Kashtoh H; Hussain S; Khan A; Saad SM; Khan JA; Khan KM; Perveen S; Choudhary MI
[Ad] Endereço:Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21412, Saudi Arabia.
[Ti] Título:Oxadiazoles and thiadiazoles: novel α-glucosidase inhibitors.
[So] Source:Bioorg Med Chem;22(19):5454-65, 2014 Oct 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Oxadiazoles and thiadiazoles 1-37 were synthesized and evaluated for the first time for their α-glucosidase inhibitory activities. As a result, fifteen of them 1, 4, 5, 7, 8, 13, 17, 23, 25, 30, 32, 33, 35, 36 and 37 were identified as potent inhibitors of the enzyme. Kinetic studies of the most active compounds (oxadiazoles 1, 23 and 25, and thiadiazoles 35 and 37) were carried out to determine their mode of inhibition and dissociation constants Ki. The most potent compound of the oxadiazole series (compound 23) was found to be a non-competitive inhibitor (Ki=4.36±0.017 µM), while most potent thiadiazole 35 was identified as a competitive inhibitor (Ki=6.0±0.059 µM). The selectivity and toxicity of these compounds were also studied by evaluating their potential against other enzymes, such as carbonic anhydrase-II and phosphodiesterase-I. Cytotoxicity was evaluated against rat fibroblast 3T3 cell line. Interestingly, these compounds were found to be inactive against other enzymes, exhibiting their selectivity towards α-glucosidase. Inhibition of α-glucosidase is an effective strategy for controlling post-prandial hyperglycemia in diabetic patients. α-Glucosidase inhibitors can also be used as anti-obesity and anti-viral drugs. Our study identifies two novel series of potent α-glucosidase inhibitors for further investigation.
[Mh] Termos MeSH primário: Inibidores de Glicosídeo Hidrolases/farmacologia
Oxidiazóis/farmacologia
Tiadiazóis/farmacologia
alfa-Glucosidases/metabolismo
[Mh] Termos MeSH secundário: Células 3T3
Animais
Inibidores da Anidrase Carbônica/síntese química
Inibidores da Anidrase Carbônica/química
Inibidores da Anidrase Carbônica/farmacologia
Anidrases Carbônicas/metabolismo
Relação Dose-Resposta a Droga
Inibidores de Glicosídeo Hidrolases/síntese química
Inibidores de Glicosídeo Hidrolases/química
Camundongos
Estrutura Molecular
Oxidiazóis/síntese química
Oxidiazóis/química
Fosfodiesterase I/antagonistas & inibidores
Fosfodiesterase I/metabolismo
Inibidores de Fosfodiesterase/síntese química
Inibidores de Fosfodiesterase/química
Inibidores de Fosfodiesterase/farmacologia
Relação Estrutura-Atividade
Tiadiazóis/síntese química
Tiadiazóis/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carbonic Anhydrase Inhibitors); 0 (Glycoside Hydrolase Inhibitors); 0 (Oxadiazoles); 0 (Phosphodiesterase Inhibitors); 0 (Thiadiazoles); EC 3.1.4.1 (Phosphodiesterase I); EC 3.2.1.20 (alpha-Glucosidases); EC 4.2.1.1 (Carbonic Anhydrases)
[Em] Mês de entrada:1504
[Cu] Atualização por classe:140922
[Lr] Data última revisão:
140922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140825
[St] Status:MEDLINE


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[PMID]:24983883
[Au] Autor:Guenther DC; Kumar P; Anderson BA; Hrdlicka PJ
[Ad] Endereço:Department of Chemistry, University of Idaho, 875 Perimeter Drive MS2343, Moscow, ID 83844-2343, USA. hrdlicka@uidaho.edu.
[Ti] Título:C5-amino acid functionalized LNA: positively poised for antisense applications.
[So] Source:Chem Commun (Camb);50(64):9007-9, 2014 Aug 18.
[Is] ISSN:1364-548X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Incorporation of positively charged C5-amino acid functionalized LNA uridines into oligodeoxyribonucleotides (ONs) results in extraordinary RNA affinity, binding specificity and stability towards 3'-exonucleases.
[Mh] Termos MeSH primário: Oligodesoxirribonucleotídeos Antissenso/química
Oligonucleotídeos/química
Uridina/química
[Mh] Termos MeSH secundário: Células 3T3-L1
Aminoácidos/química
Animais
Exonucleases/química
Luciferases de Vaga-Lume/genética
Camundongos
Oligodesoxirribonucleotídeos Antissenso/farmacologia
Oligonucleotídeos/farmacologia
Fosfodiesterase I/química
RNA/química
RNA/genética
Uridina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Amino Acids); 0 (Oligodeoxyribonucleotides, Antisense); 0 (Oligonucleotides); 0 (locked nucleic acid); 63231-63-0 (RNA); EC 1.13.12.7 (Luciferases, Firefly); EC 3.1.- (Exonucleases); EC 3.1.16.1 (spleen exonuclease); EC 3.1.4.1 (Phosphodiesterase I); EC 3.1.4.1 (phosphodiesterase I, snake venom); WHI7HQ7H85 (Uridine)
[Em] Mês de entrada:1505
[Cu] Atualização por classe:140715
[Lr] Data última revisão:
140715
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140702
[St] Status:MEDLINE
[do] DOI:10.1039/c4cc03623a



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