Novel multi-target compounds in the quest for new chemotherapies against Alzheimer's disease : An experimental and theoretical study
(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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- author
- Martínez, Alberto ; Zahran, Mai ; Gomez, Miguel ; Cooper, Coreen ; Guevara, Johnny ; Ekengard, Erik LU ; Nordlander, Ebbe LU ; Alcendor, Ralph and Hambleton, Sarah
- organization
- publishing date
- 2018-09-15
- 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
-
- pmid:30181028
- 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
- 2024-04-01 11:34:37
@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}},
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}},
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}},
doi = {{10.1016/j.bmc.2018.08.019}},
volume = {{26}},
year = {{2018}},
}