A Dual-Pronged Approach : A Ruthenium(III) Complex That Modulates Amyloid-β Aggregation and Disrupts Its Formed Aggregates
Alzheimer's disease (AD) is a devastating neurological disorder for which soluble oligomers of the peptide amyloid-β (Aβ) are now recognized as the neurotoxic species. Metal-based therapeutics are uniquely suited to target Aβ, with ruthenium-based (Ru) complexes emerging as propitious candidates. Recently, azole-based Ru(III) complexes were observed to modulate the aggregation of Aβ in solution, where the inclusion of a primary amine proximal to the ligand coordination site improved the activity of the complexes. To advance these structure-activity relationships, a series of oxazole-based Ru complexes were prepared and evaluated for their ability to modulate Aβ aggregation. From these studies, a lead candidate, Oc, emerged that had superior activity relative to its azole predecessors in modulating the aggregation of soluble Aβ and diminishing its cytotoxicity. Further evaluation of Oc demonstrated its ability to disrupt formed Aβ aggregates, resulting in smaller amorphous species. Because altering both sides of the aggregation equilibrium for Aβ has not been previously suggested for metal-based complexes for AD, this work represents an exciting new avenue for improved therapeutic success.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:61 |
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| Enthalten in: |
Inorganic chemistry - 61(2022), 6 vom: 14. Feb., Seite 2733-2744 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yawson, Gideon K [VerfasserIn] |
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| Links: |
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| Themen: |
7UI0TKC3U5 |
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| Anmerkungen: |
Date Completed 21.02.2022 Date Revised 21.02.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.inorgchem.1c01651 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM336364369 |
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| 100 | 1 | |a Yawson, Gideon K |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A Dual-Pronged Approach |b A Ruthenium(III) Complex That Modulates Amyloid-β Aggregation and Disrupts Its Formed Aggregates |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Alzheimer's disease (AD) is a devastating neurological disorder for which soluble oligomers of the peptide amyloid-β (Aβ) are now recognized as the neurotoxic species. Metal-based therapeutics are uniquely suited to target Aβ, with ruthenium-based (Ru) complexes emerging as propitious candidates. Recently, azole-based Ru(III) complexes were observed to modulate the aggregation of Aβ in solution, where the inclusion of a primary amine proximal to the ligand coordination site improved the activity of the complexes. To advance these structure-activity relationships, a series of oxazole-based Ru complexes were prepared and evaluated for their ability to modulate Aβ aggregation. From these studies, a lead candidate, Oc, emerged that had superior activity relative to its azole predecessors in modulating the aggregation of soluble Aβ and diminishing its cytotoxicity. Further evaluation of Oc demonstrated its ability to disrupt formed Aβ aggregates, resulting in smaller amorphous species. Because altering both sides of the aggregation equilibrium for Aβ has not been previously suggested for metal-based complexes for AD, this work represents an exciting new avenue for improved therapeutic success | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Amyloid beta-Peptides |2 NLM | |
| 650 | 7 | |a Coordination Complexes |2 NLM | |
| 650 | 7 | |a Neuroprotective Agents |2 NLM | |
| 650 | 7 | |a Oxazoles |2 NLM | |
| 650 | 7 | |a Protein Aggregates |2 NLM | |
| 650 | 7 | |a Ruthenium |2 NLM | |
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| 700 | 1 | |a Will, Mark F |e verfasserin |4 aut | |
| 700 | 1 | |a Huffman, Samantha E |e verfasserin |4 aut | |
| 700 | 1 | |a Strandquist, Evan T |e verfasserin |4 aut | |
| 700 | 1 | |a Bothwell, Paige J |e verfasserin |4 aut | |
| 700 | 1 | |a Oliver, Ethan B |e verfasserin |4 aut | |
| 700 | 1 | |a Apuzzo, C Fiore |e verfasserin |4 aut | |
| 700 | 1 | |a Platt, David C |e verfasserin |4 aut | |
| 700 | 1 | |a Weitzel, Christopher S |e verfasserin |4 aut | |
| 700 | 1 | |a Jones, Marjorie A |e verfasserin |4 aut | |
| 700 | 1 | |a Ferrence, Gregory M |e verfasserin |4 aut | |
| 700 | 1 | |a Hamaker, Christopher G |e verfasserin |4 aut | |
| 700 | 1 | |a Webb, Michael I |e verfasserin |4 aut | |
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