Ruthenium(iii) complexes containing thiazole-based ligands that modulate amyloid-β aggregation
Alzheimer's Disease (AD) is a devastating neurodegenerative disorder where one of the commonly observed pathological hallmarks is extracellular deposits of the peptide amyloid-β (Aβ). These deposits contain a high concentration of metals and initially presented a promising target for therapy; however it has become increasingly evident that the soluble form of the peptide is neurotoxic, not the amyloidogenic species. Metal-based therapeutics are uniquely suited to target soluble Aβ and have shown considerable promise to prevent the aggregation and induced cytotoxicity of the peptide in vitro. Herein, we have prepared a small series of derivatives of two promising Ru(iii) complexes NAMI-A (imidazolium [trans-RuCl4(1H-imidazole)(dimethyl sulfoxide-S)]) and PMRU20 (2-aminothiazolium [trans-RuCl4(2-aminothiazole)2]), to determine structure-activity relationships (SAR) for Ru(iii) therapeutics for AD. Using the three complementary methods of Thioflavin T fluorescence, dynamic light scattering (DLS), and transmission electron microscopy (TEM), it was determined that the symmetry around the metal center did not significantly impact the activity of the complexes, but rather the attached thiazole ligand(s) mitigated Aβ aggregation. Across both families of Ru(iii) complexes the determined SAR for the functional groups on the thiazole ligands to modulate Aβ aggregation were NH2 > CH3 > H. These results highlight the importance of secondary interactions between the metallotherapeutic and the Aβ peptide where hydrogen-bonding has the greatest impact on modulating Aβ aggregation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Metallomics : integrated biometal science - 12(2020), 4 vom: 01. Apr., Seite 491-503 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Huffman, Samantha E [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 03.06.2021 Date Revised 03.06.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1039/d0mt00054j |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM308245660 |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Alzheimer's Disease (AD) is a devastating neurodegenerative disorder where one of the commonly observed pathological hallmarks is extracellular deposits of the peptide amyloid-β (Aβ). These deposits contain a high concentration of metals and initially presented a promising target for therapy; however it has become increasingly evident that the soluble form of the peptide is neurotoxic, not the amyloidogenic species. Metal-based therapeutics are uniquely suited to target soluble Aβ and have shown considerable promise to prevent the aggregation and induced cytotoxicity of the peptide in vitro. Herein, we have prepared a small series of derivatives of two promising Ru(iii) complexes NAMI-A (imidazolium [trans-RuCl4(1H-imidazole)(dimethyl sulfoxide-S)]) and PMRU20 (2-aminothiazolium [trans-RuCl4(2-aminothiazole)2]), to determine structure-activity relationships (SAR) for Ru(iii) therapeutics for AD. Using the three complementary methods of Thioflavin T fluorescence, dynamic light scattering (DLS), and transmission electron microscopy (TEM), it was determined that the symmetry around the metal center did not significantly impact the activity of the complexes, but rather the attached thiazole ligand(s) mitigated Aβ aggregation. Across both families of Ru(iii) complexes the determined SAR for the functional groups on the thiazole ligands to modulate Aβ aggregation were NH2 > CH3 > H. These results highlight the importance of secondary interactions between the metallotherapeutic and the Aβ peptide where hydrogen-bonding has the greatest impact on modulating Aβ aggregation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 7 | |a Amyloid beta-Peptides |2 NLM | |
| 650 | 7 | |a Coordination Complexes |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Peptide Fragments |2 NLM | |
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| 700 | 1 | |a Yawson, Gideon K |e verfasserin |4 aut | |
| 700 | 1 | |a Fisher, Samuel S |e verfasserin |4 aut | |
| 700 | 1 | |a Bothwell, Paige J |e verfasserin |4 aut | |
| 700 | 1 | |a Platt, David C |e verfasserin |4 aut | |
| 700 | 1 | |a Jones, Marjorie A |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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