Please use this identifier to cite or link to this item:
Title: Ametantrone-based compounds as potential regulators of Tau pre-mRNA alternative splicing
Author: Artigas Solé, Gerard
López-Senín, Paula
González, Carlos
Escaja Sánchez, Nuria
Marchán Sancho, Vicente
Keywords: RNA
Issue Date: 22-Oct-2014
Publisher: Royal Society of Chemistry
Abstract: We describe the synthesis and characterization of ametantrone-containing RNA ligands based on the derivatization of this intercalator with two neamine moieties (Amt-Nea,Nea) or with one azaquinolone heterocycle and one neamine (Amt-Nea,Azq) as well as its combination with guanidinoneamine (Amt-NeaG4). Biophysical studies revealed that guanidinylation of the parent ligand (Amt-Nea) had a positive effect on the binding of the resulting compound for Tau pre-mRNA target as well as on the stabilization upon complexation of some of the mutated RNA sequences associated with the development of tauopathies. Further studies by NMR revealed the existence of a preferred binding site in the stem-loop structure, in which ametantrone intercalates in the characteristic bulged region. Regarding doubly-functionalized ligands, binding affinity and stabilizing ability of Amt-Nea,Nea were similar to those of the guanidinylated ligand, but the two aminoglycoside fragments seem to interfere with its accommodation in a single binding site. However, Amt-Nea,Azq binds at the bulged region in a similar way than Amt-NeaG4. Overall, these results provide new insights on fine-tuning RNA binding properties of ametantrone by single or double derivatization with other RNA recognition motifs, which could help in the future design of new ligands with improved selectivity for disease-causing RNA molecules.
Note: Versió postprint del document publicat a:
It is part of: Organic & Biomolecular Chemistry, 2014, vol. 13, p. 452-464
Related resource:
ISSN: 1477-0520
Appears in Collections:Articles publicats en revistes (Química Inorgànica i Orgànica)

Files in This Item:
File Description SizeFormat 
644340.pdf932.76 kBAdobe PDFView/Open

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.