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Doctoral Thesis
DOI
Document
Author
Full name
Rodrigo Rodrigues Victor de Carvalho
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2019
Supervisor
Committee
Esposito, Breno Pannia (President)
Corbi, Pedro Paulo
Hernández, Raúl Bonne
Marzorati, Liliana
Title in Portuguese
Quelantes bifuncionais para o tratamento de neurodisfunções associadas ao ferro
Keywords in Portuguese
Acetilcolinesterase
Beta amilóide
Conjugação
Desferrioxamina
Doença de alzheimer
Ferro
Abstract in Portuguese
Ferro é o metal de transição mais abundante da Terra. Quando se encontra na presença de substratos biológicos como o peróxido, Fe(II) o reduz ao radical hidroxila através da reação de Fenton. Os riscos associados a desordens neurodegenerativas aumentam devido à presença das espécies reativas de oxigênio, em alguns casos geradas por intermédio de reações com ferro. Uma das desordens mais graves entre estas é a Doença de Alzheimer (DA). Diferentes fármacos foram desenvolvidas ao longo dos anos para tratamento da DA. O tratamento da sobrecarga de Fe é baseado na terapia de quelação. Um dos quelantes amplamente empregados é a desferrioxamina (DFO). Nos últimos anos, um novo paradigma tem surgido na química medicinal, a estratégia MTDL (Multiple- target- directed ligand; ligante direcionado a múltiplos alvos). Propomos neste trabalho a conjugação de diferentes aminas aromáticas inspiradas em moléculas anti-Alzheimer com DFO, a fim de melhorar as propriedades farmacológicas deste quelante. Os novos quelantes, conjugados de DFO com anilina (DFOANI), benzosulfanilamida (DFOBAN), 2-aminonaftaleno(DFONAF) e 6-aminoquinolina (DFOQUN) foram obtidos. DFOQUN apresenta atividade quelante comparável à da DFO, enquanto os demais conjugados parecem menos eficientes. Ensaio antioxidante com dihidrorodamina (DHR) mostra que os conjugados (exceto DFONAF) apresentam comportamento similar ao da DFO, o que era esperado em função do ambiente de coordenação envolvido. DFOQUN promoveu significativo aumento de inibição de agregação de beta amilóide (βA) quando comparado com DFO, devido ao anel quinolínico em sua estrutura. Estudos com a enzima acetilcolinesterase (AChE) realizados in vitro e in vivo (Caenorhabditis elegans) mostraram que a atividade de AChE decaiu na presença de DFOQUN. Estudos comportamentais demonstraram aumento no número de curvaturas dos vermes tratado com Fe na presença de DFO e DFOQUN. Além disso, verificou-se aumento de permeabilidade celular de DFOQUN e DFOANI comparado com DFO, sem decaimento da viabilidade dos conjugados na presença de Fe. Concluímos que DFOQUN demonstra características importantes como novo candidato a fármaco anti-DA.
Title in English
Bifunctional chelators for the treatment of neurodysfunctions associated with iron
Keywords in English
β-amyloid
Acetylcholinesterase
Alzheimer's disease
Conjugation
Desferrioxamine
Iron
Abstract in English
Iron is the most abundant transition metal on Earth. In the presence of biological substrates such as peroxide, Fe(II) generates hydroxyl radical through the Fenton reaction. The risks associated with neurodegenerative disorders increase due to the presence of reactive oxygen species, in some cases catalyzed by iron. One of the most serious disorders among these is Alzheimer's Disease (AD). Different drugs have been developed over the years for the treatment of AD. The treatment of iron overload is based on chelation therapy. One of the widely used chelators is desferrioxamine (DFO). In recent years, a new paradigm has emerged in medicinal chemistry, the MTDL (Multiple Target-directed ligand) strategy. We propose in this work the conjugation of different aromatic amines inspired in anti-Alzheimer molecules with DFO to improve the pharmacological properties of this chelator.The novel chelators, DFO conjugate with aniline (DFOANI), benzosulfanilamide (DFOBAN), 2-naphtylamine (DFONAF) and 6-quinolinamine (DFOQUN) were obtained. DFOQUN has comparable chelating activity to that of DFO, while the other conjugates appear to be less efficient. Antioxidant tests with dihydrorhodamine (DHR) showed that, except for DFONAF, the conjugates exhibit similar behavior as DFO, due to the coordination environment involved. DFOQUN promoted a significant increase in inhibition of beta amyloid (Aβ) aggregation when compared to DFO, because of the quinoline ring in its structure. Studies with the enzyme acetylcholinesterase (AChE) performed in vitro and in vivo (Caenorhabditis elegans) showed that AChE activity declined in the presence of DFOQUN. Behavioral studies showed an increase in the number of bends of the worms treated with Fe in the presence of DFO and DFOQUN. In addition, increased cell permeability of DFOQUN and DFOANI compared to DFO was observed, without decreased cell viability caused by the conjugates in the presence of Fe. We conclude that DFOQUN showed important characteristics for a new anti-AD drug candidate.
 
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Publishing Date
2019-08-20
 
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