Role of the Metal Center in the Modulation of the Aggregation Process of Amyloid Model Systems by Square Planar Complexes Bearing 2-(2′-pyridyl)benzimidazole Ligands

Florio, Daniele; Iacobucci, Ilaria; Ferraro, Giarita; Mansour, Ahmed M.; Morelli, Giancarlo; Monti, Maria; Merlino, Antonello; Marasco, Daniela

doi:10.3390/ph12040154

Cited by 26 publications

(25 citation statements)

References 46 publications

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“…Aβ 21–40 formed an adduct with one molecule of Pt-terpy ( Figure 3 D), losing the only chloride present, as demonstrated by the presence of the double charged ion at m / z 1176.57 Da. Moreover, in the ESI-MS acquiring conditions, the isolated Aβ 21–40 peptide provided an in-source fragmentation phenomena, generating b series fragments ( Figure 3 A), as previously reported [ 26 ]. The fragmentation of free Aβ 21–40 peptide persisted also in the presence of Pt-phen ( Figure 3 B) and Pt-terpy ( Figure 3 D), since a large amount of peptide was unbound.…”

Section: Resultssupporting

confidence: 70%

“…Very recently, we carried out several studies focusing on the effects of several metallo-drugs on the aggregation of several peptide sequences assumed as amyloid models [ 20 , 21 , 22 , 23 , 24 , 25 ]. The fragment spanning 21–40 residues of the C-terminal domain of Aβ 1–40 (Aβ 21–40 , Table 1 ) was tested with Pd(II)-, Pt(II)- and Au(III) compounds featuring 2-(2′-pyridyl)benzimidazole [ 26 ], Pt(II) complexes with β-hydroxy dithiocinnamic esters [ 9 ] and Ru(II)-based CO-releasing molecules featuring bidentate benzimidazole and terpyridine derivatives [ 27 ]. They all revealed able to modulate self-assembly of different amyloid sequences employing coordination or oxidative mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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A Comparative Study of the Effects of Platinum (II) Complexes on β-Amyloid Aggregation: Potential Neurodrug Applications

Manna

Florio

Iacobucci

et al. 2021

IJMS

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Herein the effects of three platinum complexes, namely (SP-4-2)-(2,2′-bipyridine)dichloridoplatinum(II), Pt-bpy, (SP-4-2)-dichlorido(1,10-phenanthroline) platinum(II), Pt-phen, and (SP-4-2)-chlorido(2,2′:6′,2′′-terpyridine)platinum(II) chloride, Pt-terpy, on the aggregation of an amyloid model system derived from the C-terminal domain of Aβ peptide (Aβ21–40) were investigated. Thioflavin T (ThT) binding assays revealed the ability of Pt(II) compounds to repress amyloid aggregation in a dose-dependent way, whereas the ability of Aβ21–40 peptide to interfere with ligand field of metal complexes was analyzed through UV-Vis absorption spectroscopy and electrospray ionization mass spectrometry. Spectroscopic data provided micromolar EC50 values and allowed to assess that the observed inhibition of amyloid aggregation is due to the formation of adducts between Aβ21–40 peptide and complexes upon the release of labile ligands as chloride and that they can explore different modes of coordination toward Aβ21–40 with respect to the entire Aβ1–40 polypeptide. In addition, conformational studies through circular dichroism (CD) spectroscopy suggested that Pt-terpy induces soluble β-structures of monomeric Aβ21–40, thus limiting self-recognition. Noticeably, Pt-terpy demonstrated the ability to reduce the cytotoxicity of amyloid peptide in human SH-SY5Y neuroblastoma cells. Presented data corroborate the hypothesis to enlarge the application field of already known metal-based agents to neurodegenerative diseases, as potential neurodrugs.

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Section: Resultssupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

A Comparative Study of the Effects of Platinum (II) Complexes on β-Amyloid Aggregation: Potential Neurodrug Applications

Manna

Florio

Iacobucci

et al. 2021

IJMS

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“…This finding suggests a modulation of peptide self-aggregation. At t = 0, the non–zero values and the different fluorescence intensities of ThT, in the presence of the three compounds, suggest a potential quenching/direct binding between metal complexes and the fluorescent probe [ 54 ]. At the early stage of aggregative process, compounds 1 and 2 already act as modulators of the aggregation, while compound 3 exhibits suppression of aggregation only after 20 min of stirring.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2020

Self Cite

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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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“…The observed increase of Cotton effect for Aβ 1-42 in the presence of CO at 24 h ( Fig. 3 ) can be ascribed to a stabilization of these secondary structures [ [73] , [74] , [75] , [76] , [77] , [78] ]. When comparing the CD spectra of Aβ 1-42 in the presence of all three compounds after 24 h, it became apparent that the presence of the three isoquinoline alkaloids induced differences in the structural organization of Aβ 1-42 ( Fig.…”

Section: Resultsmentioning

confidence: 96%

Plant isoquinoline alkaloids as potential neurodrugs: A comparative study of the effects of benzo[c]phenanthridine and berberine-based compounds on β-amyloid aggregation

Marasco

Vicidomini

Krupa

et al. 2021

Chemico-Biological Interactions

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Herein we present a comparative study of the effects of isoquinoline alkaloids belonging to benzo [ c ]phenanthridine and berberine families on β-amyloid aggregation. Results obtained using a Thioflavine T (ThT) fluorescence assay and circular dichroism (CD) spectroscopy suggested that the benzo [ c ]phenanthridine nucleus, present in both sanguinarine and chelerythrine molecules, was directly involved in an inhibitory effect of Aβ 1–42 aggregation. Conversely, coralyne, that contains the isomeric berberine nucleus, significantly increased propensity for Aβ 1–42 to aggregate. Surface Plasmon Resonance (SPR) experiments provided quantitative estimation of these interactions: coralyne bound to Aβ 1–42 with an affinity (K D = 11.6 μM) higher than benzo [ c ]phenanthridines. Molecular docking studies confirmed that all three compounds are able to recognize Aβ 1–42 in different aggregation forms suggesting their effective capacity to modulate self-recognition mechanism. Molecular dynamics simulations indicated that coralyne increased the β-content of Aβ 1–42 , in early stages of aggregation, consistently with fluorescence-based promotion of self-recognition mechanism by this alkaloid. At the same time, sanguinarine seemed to determine an increase of helical conformation corroborating its ability to delay aggregation as experimentally proved in vitro . Investigated compounds demonstrated to interfere with aggregation of Aβ 1–42 applying as starting leads in neurodegenerative diseases.

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Role of the Metal Center in the Modulation of the Aggregation Process of Amyloid Model Systems by Square Planar Complexes Bearing 2-(2′-pyridyl)benzimidazole Ligands

Cited by 26 publications

References 46 publications

A Comparative Study of the Effects of Platinum (II) Complexes on β-Amyloid Aggregation: Potential Neurodrug Applications

A Comparative Study of the Effects of Platinum (II) Complexes on β-Amyloid Aggregation: Potential Neurodrug Applications

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

Plant isoquinoline alkaloids as potential neurodrugs: A comparative study of the effects of benzo[c]phenanthridine and berberine-based compounds on β-amyloid aggregation

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