Ruthenium(<scp>iii</scp>) complexes containing thiazole-based ligands that modulate amyloid-β aggregation

Huffman, Samantha E; Yawson, Gideon K.; Fisher, Samuel S.; Bothwell, Paige J; Platt, D; Jones, Marjorie A.; Hamaker, Christopher G.; Webb, Michael I.

doi:10.1039/d0mt00054j

Cited by 21 publications

(25 citation statements)

References 77 publications

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“…Electrospray ionization-mass spectrometry (ESI-MS) analysis, evidenced the formation of adducts formed upon reaction of the compound with the peptide and thioflavin T assay, revealed that the presence of the Ru complex greatly reduces peptide aggregation in vitro [ 15 ]. Derivatives of NAMI-A and PMRU20 exhibit enhanced affinity toward Aβ 1–40 [ 16 ]. The complex fac -[Ru(CO) 3 Cl 2 (N 1 -thz)] (thz = 1,3-thiazole) binds the 1–28 fragment of the β−amyloid peptide [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Modulation of Amyloidogenic Peptide Aggregation by Photoactivatable CO-Releasing Ruthenium(II) Complexes

et al. 2020

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Three Ru(II)-based CO-releasing molecules featuring bidentate benzimidazole and terpyridine derivatives as ligands were investigated for their ability to modulate the aggregation process of the second helix of the C-terminal domain of nucleophosmin 1, namely nucleophosmin 1 (NPM1)264–277, a model amyloidogenic system, before and after irradiation at 365 nm. Thioflavin T (ThT) binding assays and UV/Vis absorption spectra indicate that binding of the compounds to the peptide inhibits its aggregation and that the inhibitory effect increases upon irradiation (half maximal effective concentration (EC50) values in the high micromolar range). Electrospray ionization mass spectrometry data of the peptide in the presence of one of these compounds confirm that the modulation of amyloid aggregation relies on the formation of adducts obtained when the Ru compounds react with the peptide upon releasing of labile ligands, like chloride and carbon monoxide. This mechanism of action explains the subtle different behavior of the three compounds observed in ThT experiments. Overall, data support the hypothesis that metal-based CO releasing molecules can be used to develop metal-based drugs with potential application as anti-amyloidogenic agents.

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Section: Introductionmentioning

confidence: 99%

Modulation of Amyloidogenic Peptide Aggregation by Photoactivatable CO-Releasing Ruthenium(II) Complexes

et al. 2020

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“…31 Although all three complexes were found to impact the aggregation and toxicity of Aβ, PMRU20 emerged as a lead candidate. The subsequent preparation and evaluation of several azole-based derivatives of both NAMI-A and PMRU20 (Figure 1) 32,33 confirmed the importance of hydrogen bonding in coordinating and subsequently minimizing the aggregation of the peptide. Additionally, symmetry around the metal center was not a determining factor for activity, but rather the azole ligand itself governed the performance of the complex.…”

Section: ■ Introductionmentioning

confidence: 88%

“…This observation reflects previous studies of azole-containing Ru complexes, where the amino functional group was essential for activity. 32 By contrast, all remaining complexes had substantially lower absorbance readings relative to Ru-P9, with Ru-P8 having the next highest absorbance. Both Ru-P9 and Ru-P8 have terminal primary amines at the apical position on the pyridine ligand, suggesting that N−H hydrogen bonding with Aβ is responsible for their activity.…”

Section: ■ Introductionmentioning

confidence: 94%

“…Further investigation into identifying structure−activity relationships (SARs) determined that the amino functional group at the 2-position of the azole ring was critical for activity. 32 Comparatively, the importance of symmetry around the metal center was found to be dependent upon the nature of the azole ligand that was used. 33 Given these encouraging results, the current study expands the scope of Ru(III) therapeutics through the synthesis and evaluation of pyridine-based derivatives of NAMI-A for their ability to prevent Aβ aggregation.…”

Section: ■ Introductionmentioning

confidence: 99%

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Importance of Hydrogen Bonding: Structure–Activity Relationships of Ruthenium(III) Complexes with Pyridine-Based Ligands for Alzheimer’s Disease Therapy

et al. 2021

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Alzheimer’s disease (AD) is the most common form of dementia, where one of the pathological hallmarks of AD is extracellular protein deposits, the primary component of which is the peptide amyloid-β (Aβ). Recently, the soluble form of Aβ has been recognized as the primary neurotoxic species, making it an important target for therapeutic development. Metal-based drugs are promising candidates to target Aβ, as the interactions with the peptide can be tuned by ligand design. In the current study, 11 ruthenium complexes containing pyridine-based ligands were prepared, where the functional groups at the para position on the coordinated pyridine ligand were varied to determine structure–activity relationships. Overall, the complexes with terminal primary amines had the greatest impact on modulating the aggregation of Aβ and diminishing its cytotoxicity. These results identify the importance of specific intermolecular interactions and are critical in the advancement of metal-based drugs for AD therapy.

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“…This suggests that these compounds may not be as hazardous to mammalian cells. Short term incubation, with other compounds, has been shown previously to elicit acute cytotoxicity in glial cells [96]. A therapeutic use of these compounds targeted toward inhibiting Leishmania based infection should be further investigated.…”

Section: Detection Of Leishmania Nitric Oxide Using a Specific Fluorementioning

confidence: 98%

Synthesis of Polycyclic Ether-Benzopyrans and In Vitro Inhibitory Activity against Leishmania tarentolae

et al. 2020

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Construction of a focused library of polycyclic ether-benzopyrans was undertaken in order to discover new therapeutic compounds that affect Leishmania growth and infectivity. This is especially of interest since there are few drug therapies for leishmaniasis that do not have serious drawbacks such high cost, side effects, and emerging drug resistance. The construction of these polycyclic ether-benzopyrans utilized an acetoxypyranone-alkene [5+2] cycloaddition and the Suzuki-Miyaura cross-coupling. The multi-gram quantity of the requisite aryl bromide was obtained followed by effective Pd-catalyzed coupling with boronic acid derivatives. Compounds were tested in vitro using the parasitic protozoan, Leishmania tarentolae. Effects of concentration, time, and exposure to light were evaluated. In addition, the effects on secreted acid phosphatase activity and nitric oxide production were investigated, since both have been implicated in parasite infectivity. The data presented herein are indicative of disruption of the Leishmania tarentolae and thus provide impetus for the development and testing of a more extensive library.

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Ruthenium(iii) complexes containing thiazole-based ligands that modulate amyloid-β aggregation

Abstract: 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).

Cited by 21 publications

References 77 publications

Modulation of Amyloidogenic Peptide Aggregation by Photoactivatable CO-Releasing Ruthenium(II) Complexes

Modulation of Amyloidogenic Peptide Aggregation by Photoactivatable CO-Releasing Ruthenium(II) Complexes

Importance of Hydrogen Bonding: Structure–Activity Relationships of Ruthenium(III) Complexes with Pyridine-Based Ligands for Alzheimer’s Disease Therapy

Synthesis of Polycyclic Ether-Benzopyrans and In Vitro Inhibitory Activity against Leishmania tarentolae

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