Design, selection, and characterization of thioflavin-based intercalation compounds with metal chelating properties for application in alzheimer's disease
Rodríguez-Rodríguez, Cristina (Universitat Autònoma de Barcelona. Departament de Química)
Sánchez de Groot, Natalia (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Rimola Gibert, Albert (Universitat Autònoma de Barcelona. Departament de Química)
Alvarez-Larena, Angel (Universitat Autònoma de Barcelona. Servei de Difracció de Raigs X)
Lloveras Monserrat, Vega (Institut de Ciència de Materials de Barcelona)
Vidal-Gancedo, José (Institut de Ciència de Materials de Barcelona)
Ventura, Salvador (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Vendrell i Roca, Josep (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Sodupe Roure, Mariona (Universitat Autònoma de Barcelona. Departament de Química)
González Duarte, Pilar (Universitat Autònoma de Barcelona. Departament de Química)

Data:	2009
Resum:	Metal chelation is considered a rational therapeutic approach for interdicting Alzheimer's amyloid pathogenesis. At present, enhancing the targeting and efficacy of metal-ion chelating agents through ligand design is a main strategy in the development of the next generation of metal chelators. Inspired by the traditional dye Thioflavin-T, we have designed new multifunctional molecules that contain both amyloid binding and metal chelating properties. In silico techniques have enabled us to identify commercial compounds that enclose the designed molecular framework (M1), include potential antioxidant properties, facilitate the formation of iodine-labeled derivatives, and can be permeable through the blood-brain barrier. lodination reactions of the selected compounds, 2-(2-hydroxyphenyl)benzoxazole (HBX), 2-(2-hydroxyphe- nyl)benzothiazole (HBT), and 2-(2-aminophenyl)-1 H-benzimidazole (BM), have led to the corresponding iodinated derivatives HBXI, HBTI, and BMI, which have been characterized by X-ray diffraction. The chelating properties of the latter compounds toward Cu(ll) and Zn(ll) have been examined in the solid phase and in solution. The acidity constants of HBXI, HBTI, and BMI and the formation constants of the corresponding ML and ML2 complexes [M = Cu(ll), Zn(ll)] have been determined by UV-vis pH titrations. The calculated values for the overall formation constants for the ML 2 complexes indicate the suitability of the HBXI, HBTI, and BMI ligands for sequestering Cu(ll) and Zn(ll) metal ions present in freshly prepared solutions of β-amyloid (Aβ) peptide. This was confirmed by Aβ aggregation studies showing that these compounds are able to arrest the metal-promoted increase in amyloid fibril buildup. The fluorescence features of HBX, HBT, BM, and the corresponding iodinated derivatives, together with fluorescence microscopy studies on two types of pregrown fibrils, have shown that HBX and HBT compounds could behave as potential markers for the presence of amyloid fibrils, whereas HBXI and HBTI may be especially suitable for radioisotopic detection of Aβ deposits. Taken together, the results reported in this work show the potential of new multifunctional thioflavin-based chelating agents as Alzheimer's disease therapeutics.
Ajuts:	Ministerio de Educación y Ciencia BIO2007-68046 Agència de Gestió d'Ajuts Universitaris i de Recerca 2005/SGR-01037 Agència de Gestió d'Ajuts Universitaris i de Recerca 2005/SGR-00896 Agència de Gestió d'Ajuts Universitaris i de Recerca 2005/SGR-00244
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Llengua:	Anglès
Document:	Article ; recerca ; Versió sotmesa a revisió
Matèria:	Fluorescence ; Ligands ; Metals ; Nanofibers ; Peptides and proteins
Publicat a:	Journal of the American Chemical Society, Vol. 131, issue 4 (February 2009) , p. 1436-1451, ISSN 1520-5126

DOI: 10.1021/ja806062g

Preprint 51 p, 2.3 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut de Biotecnologia i de Biomedicina (IBB)
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