Search

Abstract: Alzheimer's disease and oxidative stress are connected. In the present communication, we report the use of a MnII‐based superoxide dismutase (SOD) mimic ([MnII(L)]+, 1+) as a pro‐drug candidate to target CuII‐associated events, namely, CuII‐induced formation of reactive oxygen species (ROS) and modulation of the amyloid‐β (Aβ) peptide aggregation. Complex 1+ is able to remove CuII from Aβ, stop ROS and prevent alteration of Aβ aggregation as would do the corresponding free ligand LH. Using 1+ instead of LH in further biological applications would have the double advantage to avoid the cell toxicity of LH and to benefit from its proved SOD‐like activity. [ABSTRACT FROM AUTHOR]

The pseudopeptide L, derived from a nitrilotriacetic acid scaffold and functionalized with three histidine moieties, is reminiscent of the amino acid side chains encountered in the Alzheimer's peptide (Aβ). Its synthesis and coordination properties for CuΙ and CuΙΙ are described. L efficiently complex CuΙΙ in a square-planar geometry involving three imidazole nitrogen atoms and an amidate-Cu bond. By contrast, CuΙ is coordinated in a tetrahedral environment. The redox behavior is irreversible and follows an ECEC mechanism in accordance with the very different environments of the two redox states of the Cu center. This is in line with the observed resistance of the CuΙ complex to oxidation by oxygen and the CuΙΙ complex reduction by ascorbate. The affinities of L for CuΙΙ and CuΙ at physiological pH are larger than that reported for the Aβ peptide. Therefore, due to its peculiar Cu coordination properties, the ligand L is able to target both redox states of Cu, redox silence them and prevent reactive oxygen species production by the CuAβ complex. Because reactive oxygen species contribute to the oxidative stress, a key issue in Alzheimer's disease, this ligand thus represents a new strategy in the long route of finding molecular concepts for fighting Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Targeting copper ions to either remove or redistribute them is currently viewed as a possible therapeutic strategy in the context of Alzheimer's disease (AD). Thermodynamic parameters, as for instance the copper(II) affinity of the drug candidate or the copper(II) over zinc(II) selectivity, are considered in the design of the drug candidate. In contrast, kinetic factors have been overlooked despite their probable high importance. In the present article, we use a series of azamacrocyclic ligands to demonstrate that kinetic issues must be taken into account when designing copper-targeting drug candidates in the context of AD., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Alzheimer's disease and oxidative stress are connected. In the present communication, we report the use of a Mn II -based superoxide dismutase (SOD) mimic ([Mn II (L)] + , 1 + ) as a pro-drug candidate to target Cu II -associated events, namely, Cu II -induced formation of reactive oxygen species (ROS) and modulation of the amyloid-β (Aβ) peptide aggregation. Complex 1 + is able to remove Cu II from Aβ, stop ROS and prevent alteration of Aβ aggregation as would do the corresponding free ligand LH. Using 1 + instead of LH in further biological applications would have the double advantage to avoid the cell toxicity of LH and to benefit from its proved SOD-like activity., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The pseudopeptide L, derived from a nitrilotriacetic acid scaffold and functionalized with three histidine moieties, is reminiscent of the amino acid side chains encountered in the Alzheimer's peptide (Aβ). Its synthesis and coordination properties for Cu Ι and Cu ΙΙ are described. L efficiently complex Cu ΙΙ in a square-planar geometry involving three imidazole nitrogen atoms and an amidate-Cu bond. By contrast, Cu Ι is coordinated in a tetrahedral environment. The redox behavior is irreversible and follows an ECEC mechanism in accordance with the very different environments of the two redox states of the Cu center. This is in line with the observed resistance of the Cu Ι complex to oxidation by oxygen and the Cu ΙΙ complex reduction by ascorbate. The affinities of L for Cu ΙΙ and Cu Ι at physiological pH are larger than that reported for the Aβ peptide. Therefore, due to its peculiar Cu coordination properties, the ligand L is able to target both redox states of Cu, redox silence them and prevent reactive oxygen species production by the CuAβ complex. Because reactive oxygen species contribute to the oxidative stress, a key issue in Alzheimer's disease, this ligand thus represents a new strategy in the long route of finding molecular concepts for fighting Alzheimer's disease., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

While metal ions such as copper and zinc are essential in biology, they are also linked to several amyloid-related diseases, including Alzheimer's disease (AD). Zinc and copper can indeed modify the aggregation pathways of the amyloid-β (Aβ) peptide, the key component encountered in AD. In addition, the redox active copper ions do produce Reactive Oxygen Species (ROS) when bound to the Aβ peptide. While Cu(i) or Cu(ii) or Zn(ii) coordination to the Aβ has been extensively studied in the last ten years, characterization of hetero-bimetallic Aβ complexes is still scarce. This is also true for the metal induced Aβ aggregation and ROS production, for which studies on the mutual influence of the copper and zinc ions are currently appearing. Last but not least, zinc can strongly interfere in therapeutic approaches relying on copper detoxification. This will be exemplified with a biological lead, namely metallothioneins, and with synthetic ligands.