[PMID]: | 29195795 |
[Au] Autor: | Kozarski M; Kubacka D; Wojtczak BA; Kasprzyk R; Baranowski MR; Kowalska J |
[Ad] Endereço: | University of Warsaw, Faculty of Physics, Institute of Experimental Physics, Division of Biophysics, Pasteura 5, 02-093 Warsaw, Poland. |
[Ti] Título: | 7-Methylguanosine monophosphate analogues with 5'-(1,2,3-triazoyl) moiety: Synthesis and evaluation as the inhibitors of cNIIIB nucleotidase. |
[So] Source: | Bioorg Med Chem;26(1):191-199, 2018 01 01. |
[Is] ISSN: | 1464-3391 |
[Cp] País de publicação: | England |
[La] Idioma: | eng |
[Ab] Resumo: | The hydrolysis of nucleoside 5'-monophosphates to the corresponding nucleosides and inorganic phosphate is catalysed by 5'-nucleotidases, thereby contributing to the control of endogenous nucleotide turnover and affecting the fate of exogenously delivered nucleotide- and nucleoside-derived therapeutics in cells. A recently identified nucleotidase cNIIIB shows preference towards 7-methylguanosine monophosphate (m GMP) as a substrate, which suggests its potential involvement in mRNA degradation. However, the extent of biological functions and the significance of cNIIIB remains to be elucidated. Here, we synthesised a series of m GMP analogues carrying a 1,2,3-triazole moiety at the 5' position as the potential inhibitors of human cNIIIB. The compounds were synthesised by using the copper-catalysed azide-alkyne cycloaddition (CuAAC) between 5'-azido-5'-deoxy-7-methylguanosine and different phosphate or phosphonate derivatives carrying terminal alkyne. The analogues were evaluated as cNIIIB inhibitors using HPLC and malachite green assays, demonstrating that compound 1a, carrying a 1,2,3-triazoylphosphonate moiety, inhibits cNIIIB activity at micromolar concentrations (IC 87.8 ±â€¯7.5 µM), while other analogues showed no activity. In addition, compound 1d was identified as an artifical substrate for cNIIIB. Further characterization of inhibitor 1a revealed that it is poorly recognised by other m G-binding proteins, eIF4E and DcpS, indicating its selectivity towards cNIIIB. The first inhibitor (1a) and unnatural substrate (1d) of cNIIIB, identified here, can be used as molecular probes for the elucidation of biological roles of cNIIIB, including the verification of its proposed function in mRNA metabolism. |
[Mh] Termos MeSH primário: |
5´-Nucleotidase/antagonistas & inibidores Inibidores Enzimáticos/farmacologia Análogos de Capuz de RNA/farmacologia Triazóis/farmacologia
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[Mh] Termos MeSH secundário: |
5'-Nucleotidase/metabolismo Relação Dose-Resposta a Droga Inibidores Enzimáticos/síntese química Inibidores Enzimáticos/química Seres Humanos Estrutura Molecular Análogos de Capuz de RNA/síntese química Análogos de Capuz de RNA/química Relação Estrutura-Atividade Triazóis/química
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[Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (Enzyme Inhibitors); 0 (RNA Cap Analogs); 0 (Triazoles); 10162-58-0 (7-methylguanosine-5'-monophosphate); EC 3.1.3.5 (5'-Nucleotidase) |
[Em] Mês de entrada: | 1801 |
[Cu] Atualização por classe: | 180106 |
[Lr] Data última revisão:
| 180106 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 171203 |
[St] Status: | MEDLINE |
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