Conjugates of desferrioxamine and aromatic amines improve markers of iron-dependent neurotoxicity

Rodrigo R.V. Carvalho; Tanara V. Peres; Cleber W. Liria; M. Teresa Machini; Michael Aschner; Breno P. Espósito

doi:10.1007/s10534-020-00277-7

Conjugates of desferrioxamine and aromatic amines improve markers of iron-dependent neurotoxicity

Rodrigo R.V. Carvalho, Tanara V. Peres, Cleber W. Liria, M. Teresa Machini, Michael Aschner, Breno P. Espósito

Molecular Pharmacology

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Abstract: Alzheimer’s Disease (AD) is a complex neurodegenerative disorder associated in some instances with dyshomeostasis of redox-active metal ions, such as copper and iron. In this work, we investigated whether the conjugation of various aromatic amines would improve the pharmacological efficacy of the iron chelator desferrioxamine (DFO). Conjugates of DFO with aniline (DFOANI), benzosulfanylamide (DFOBAN), 2-naphthalenamine (DFONAF) and 6-quinolinamine (DFOQUN) were obtained and their properties examined. DFOQUN had good chelating activity, promoted a significant increase in the inhibition of β-amyloid peptide aggregation when compared to DFO, and also inhibited acetylcholinesterase (AChE) activity both in vitro and in vivo (Caenorhabditis elegans). These data indicate that the covalent conjugation of a strong iron chelator to an AChE inhibitor offers a powerful approach for the amelioration of iron-induced neurotoxicity symptoms. Graphic abstract: [Figure not available: see fulltext.]

Original language	English (US)
Pages (from-to)	259-275
Number of pages	17
Journal	BioMetals
Volume	34
Issue number	2
DOIs	https://doi.org/10.1007/s10534-020-00277-7
State	Published - Apr 2021

Keywords

Acetylcholinesterase
Alzheimer’s disease
Beta amyloid
Caenorhabditis elegans
Desferrioxamine
Iron

ASJC Scopus subject areas

Biomaterials
Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
Metals and Alloys

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10.1007/s10534-020-00277-7

Cite this

@article{e371ddb374b54ab1bc09bf7f44b7f1e6,

title = "Conjugates of desferrioxamine and aromatic amines improve markers of iron-dependent neurotoxicity",

abstract = "Abstract: Alzheimer{\textquoteright}s Disease (AD) is a complex neurodegenerative disorder associated in some instances with dyshomeostasis of redox-active metal ions, such as copper and iron. In this work, we investigated whether the conjugation of various aromatic amines would improve the pharmacological efficacy of the iron chelator desferrioxamine (DFO). Conjugates of DFO with aniline (DFOANI), benzosulfanylamide (DFOBAN), 2-naphthalenamine (DFONAF) and 6-quinolinamine (DFOQUN) were obtained and their properties examined. DFOQUN had good chelating activity, promoted a significant increase in the inhibition of β-amyloid peptide aggregation when compared to DFO, and also inhibited acetylcholinesterase (AChE) activity both in vitro and in vivo (Caenorhabditis elegans). These data indicate that the covalent conjugation of a strong iron chelator to an AChE inhibitor offers a powerful approach for the amelioration of iron-induced neurotoxicity symptoms. Graphic abstract: [Figure not available: see fulltext.]",

keywords = "Acetylcholinesterase, Alzheimer{\textquoteright}s disease, Beta amyloid, Caenorhabditis elegans, Desferrioxamine, Iron",

author = "Carvalho, {Rodrigo R.V.} and Peres, {Tanara V.} and Liria, {Cleber W.} and Machini, {M. Teresa} and Michael Aschner and Esp{\'o}sito, {Breno P.}",

note = "Funding Information: This work was supported by FAPESP (2016/03709-9 and 2018/19684-0 to BPE and 2015/14360-4 to MTM) and CAPES (Brazilian agencies). MA was supported in part by grants from the National Institute of Environmental Health Science (NIEHS) R01ES07331 and R01ES10563. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature B.V. part of Springer Nature.",

year = "2021",

month = apr,

doi = "10.1007/s10534-020-00277-7",

language = "English (US)",

volume = "34",

pages = "259--275",

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TY - JOUR

T1 - Conjugates of desferrioxamine and aromatic amines improve markers of iron-dependent neurotoxicity

AU - Carvalho, Rodrigo R.V.

AU - Peres, Tanara V.

AU - Liria, Cleber W.

AU - Machini, M. Teresa

AU - Aschner, Michael

AU - Espósito, Breno P.

N1 - Funding Information: This work was supported by FAPESP (2016/03709-9 and 2018/19684-0 to BPE and 2015/14360-4 to MTM) and CAPES (Brazilian agencies). MA was supported in part by grants from the National Institute of Environmental Health Science (NIEHS) R01ES07331 and R01ES10563. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature B.V. part of Springer Nature.

PY - 2021/4

Y1 - 2021/4

N2 - Abstract: Alzheimer’s Disease (AD) is a complex neurodegenerative disorder associated in some instances with dyshomeostasis of redox-active metal ions, such as copper and iron. In this work, we investigated whether the conjugation of various aromatic amines would improve the pharmacological efficacy of the iron chelator desferrioxamine (DFO). Conjugates of DFO with aniline (DFOANI), benzosulfanylamide (DFOBAN), 2-naphthalenamine (DFONAF) and 6-quinolinamine (DFOQUN) were obtained and their properties examined. DFOQUN had good chelating activity, promoted a significant increase in the inhibition of β-amyloid peptide aggregation when compared to DFO, and also inhibited acetylcholinesterase (AChE) activity both in vitro and in vivo (Caenorhabditis elegans). These data indicate that the covalent conjugation of a strong iron chelator to an AChE inhibitor offers a powerful approach for the amelioration of iron-induced neurotoxicity symptoms. Graphic abstract: [Figure not available: see fulltext.]

AB - Abstract: Alzheimer’s Disease (AD) is a complex neurodegenerative disorder associated in some instances with dyshomeostasis of redox-active metal ions, such as copper and iron. In this work, we investigated whether the conjugation of various aromatic amines would improve the pharmacological efficacy of the iron chelator desferrioxamine (DFO). Conjugates of DFO with aniline (DFOANI), benzosulfanylamide (DFOBAN), 2-naphthalenamine (DFONAF) and 6-quinolinamine (DFOQUN) were obtained and their properties examined. DFOQUN had good chelating activity, promoted a significant increase in the inhibition of β-amyloid peptide aggregation when compared to DFO, and also inhibited acetylcholinesterase (AChE) activity both in vitro and in vivo (Caenorhabditis elegans). These data indicate that the covalent conjugation of a strong iron chelator to an AChE inhibitor offers a powerful approach for the amelioration of iron-induced neurotoxicity symptoms. Graphic abstract: [Figure not available: see fulltext.]

KW - Acetylcholinesterase

KW - Alzheimer’s disease

KW - Beta amyloid

KW - Caenorhabditis elegans

KW - Desferrioxamine

KW - Iron

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Conjugates of desferrioxamine and aromatic amines improve markers of iron-dependent neurotoxicity

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