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Novel multi-target compounds in the quest for new chemotherapies against Alzheimer's disease : An experimental and theoretical study

Martínez, Alberto; Zahran, Mai; Gomez, Miguel; Cooper, Coreen; Guevara, Johnny; Ekengard, Erik LU ; Nordlander, Ebbe LU ; Alcendor, Ralph and Hambleton, Sarah (2018) In Bioorganic and Medicinal Chemistry 26(17). p.4823-4840
Abstract

The lack of any effective therapy along with the aging world population anticipates a growth of the worldwide incidence of Alzheimer's disease (AD) to more than 100 million cases by 2050. Accumulation of extracellular amyloid-β (Aβ) plaques, intracellular tangles in the brain, and formation of reactive oxygen species (ROS) are the major hallmarks of the disease. In the amyloidogenic process, a β-secretase, known as BACE 1, plays a fundamental role in the production of Aβ fragments, and therefore, inhibition of such enzymes represents a major strategy for the rational design of anti-AD drugs. In this work, a series of four multi-target compounds (1–4), inspired by previously described ionophoric polyphenols, have been synthesized and... (More)

The lack of any effective therapy along with the aging world population anticipates a growth of the worldwide incidence of Alzheimer's disease (AD) to more than 100 million cases by 2050. Accumulation of extracellular amyloid-β (Aβ) plaques, intracellular tangles in the brain, and formation of reactive oxygen species (ROS) are the major hallmarks of the disease. In the amyloidogenic process, a β-secretase, known as BACE 1, plays a fundamental role in the production of Aβ fragments, and therefore, inhibition of such enzymes represents a major strategy for the rational design of anti-AD drugs. In this work, a series of four multi-target compounds (1–4), inspired by previously described ionophoric polyphenols, have been synthesized and studied. These compounds have been designed to target important aspects of AD, including BACE 1 enzymatic activity, Aβ aggregation, toxic concentrations of Cu2+ metal ions and/or ROS production. Two other compounds (5 and 6), previously reported by some of us as antimalarial agents, have also been studied because of their potential as multi-target species against AD. Interestingly, compounds 3 and 5 showed moderate to good ability to inhibit BACE 1 enzymatic activity in a FRET assay, with IC50′s in the low micromolar range (4.4 ± 0.3 and 1.7 ± 0.3 μM, respectively), comparable to other multi-target species, and showing that the observed activity was in part due to a competitive binding of the compounds at the active site of the enzyme. Theoretical docking calculations overall agreed with FRET assay results, displaying the strongest binding affinities for 3 and 5 at the active site of the enzyme. In addition, all compounds selectively interacted with Cu2+ metal ions forming 2:1 complexes, inhibited the production of Aβ-Cu2+ catalyzed hydroxyl radicals up to a ∼100% extent, and scavenged AAPH-induced peroxyl radical species comparably to resveratrol, a compound used as reference in this work. Our results also show good anti-amyloidogenic ability: compounds 1–6 inhibited both the Cu2+-induced and self-induced Aβ(1–40) fibril aggregation to an extent that ranged from 31% to 77%, while they disaggregated pre-formed Aβ(1–40) mature fibrils up to a 37% and a 69% extent in absence and presence of Cu2+, respectively. Cytotoxicity was additionally studied in Tetrahymena thermophila and HEK293 cells, and compared to that of resveratrol, showing that compounds 1–6 display lower toxicity than that of resveratrol, a well-known non-toxic polyphenol.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
Alzheimer's disease, Amyloid-beta aggregation, Antioxidant, BACE1, Docking, Ionophoric compound, Molecular design, Multi-target compound, Polyphenol, Reactive oxygen species, Tetrahymena, β-secretase inhibitor
in
Bioorganic and Medicinal Chemistry
volume
26
issue
17
pages
18 pages
publisher
Elsevier
external identifiers
  • scopus:85052742587
ISSN
0968-0896
DOI
10.1016/j.bmc.2018.08.019
language
English
LU publication?
yes
id
8d17ee59-8d7e-45a6-a4bd-8b058f785004
date added to LUP
2018-10-05 12:11:01
date last changed
2019-03-19 04:00:19
@article{8d17ee59-8d7e-45a6-a4bd-8b058f785004,
  abstract     = {<p>The lack of any effective therapy along with the aging world population anticipates a growth of the worldwide incidence of Alzheimer's disease (AD) to more than 100 million cases by 2050. Accumulation of extracellular amyloid-β (Aβ) plaques, intracellular tangles in the brain, and formation of reactive oxygen species (ROS) are the major hallmarks of the disease. In the amyloidogenic process, a β-secretase, known as BACE 1, plays a fundamental role in the production of Aβ fragments, and therefore, inhibition of such enzymes represents a major strategy for the rational design of anti-AD drugs. In this work, a series of four multi-target compounds (1–4), inspired by previously described ionophoric polyphenols, have been synthesized and studied. These compounds have been designed to target important aspects of AD, including BACE 1 enzymatic activity, Aβ aggregation, toxic concentrations of Cu<sup>2+</sup> metal ions and/or ROS production. Two other compounds (5 and 6), previously reported by some of us as antimalarial agents, have also been studied because of their potential as multi-target species against AD. Interestingly, compounds 3 and 5 showed moderate to good ability to inhibit BACE 1 enzymatic activity in a FRET assay, with IC<sub>50</sub>′s in the low micromolar range (4.4 ± 0.3 and 1.7 ± 0.3 μM, respectively), comparable to other multi-target species, and showing that the observed activity was in part due to a competitive binding of the compounds at the active site of the enzyme. Theoretical docking calculations overall agreed with FRET assay results, displaying the strongest binding affinities for 3 and 5 at the active site of the enzyme. In addition, all compounds selectively interacted with Cu<sup>2+</sup> metal ions forming 2:1 complexes, inhibited the production of Aβ-Cu<sup>2+</sup> catalyzed hydroxyl radicals up to a ∼100% extent, and scavenged AAPH-induced peroxyl radical species comparably to resveratrol, a compound used as reference in this work. Our results also show good anti-amyloidogenic ability: compounds 1–6 inhibited both the Cu<sup>2+</sup>-induced and self-induced Aβ(1–40) fibril aggregation to an extent that ranged from 31% to 77%, while they disaggregated pre-formed Aβ(1–40) mature fibrils up to a 37% and a 69% extent in absence and presence of Cu<sup>2+</sup>, respectively. Cytotoxicity was additionally studied in Tetrahymena thermophila and HEK293 cells, and compared to that of resveratrol, showing that compounds 1–6 display lower toxicity than that of resveratrol, a well-known non-toxic polyphenol.</p>},
  author       = {Martínez, Alberto and Zahran, Mai and Gomez, Miguel and Cooper, Coreen and Guevara, Johnny and Ekengard, Erik and Nordlander, Ebbe and Alcendor, Ralph and Hambleton, Sarah},
  issn         = {0968-0896},
  keyword      = {Alzheimer's disease,Amyloid-beta aggregation,Antioxidant,BACE1,Docking,Ionophoric compound,Molecular design,Multi-target compound,Polyphenol,Reactive oxygen species,Tetrahymena,β-secretase inhibitor},
  language     = {eng},
  month        = {09},
  number       = {17},
  pages        = {4823--4840},
  publisher    = {Elsevier},
  series       = {Bioorganic and Medicinal Chemistry},
  title        = {Novel multi-target compounds in the quest for new chemotherapies against Alzheimer's disease : An experimental and theoretical study},
  url          = {http://dx.doi.org/10.1016/j.bmc.2018.08.019},
  volume       = {26},
  year         = {2018},
}