Kinetics Are Crucial When Targeting Copper Ions to Fight Alzheimer's Disease: An Illustration with Azamacrocyclic Ligands

Conte-Daban, Amandine; Beyler, Maryline; Tripier, Raphaël; Hureau, Christelle

doi:10.1002/chem.201801520

Cited by 19 publications

(34 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is known that the Cu 2+ -Aβ42 species can promote the formation of ROS that have deleterious effect in AD. 66 Herein, we performed an ascorbate consumption assay to evaluate the ability of LS-4 to suppress the Cu 2+ -ascorbate redox cycling. In the absence of LS-4, the consumption of ascorbate in the presence of Cu 2+ is rapid (Figure 7a, black); however, if Cu 2+ is premixed with 2 eq of LS-4, the ascorbate consumption is virtually eliminated (Figure 7a, red), indicating that LS-4 can bind tightly to Cu 2+ and mitigate the redox cycling.…”

Section: Cu 2+ -Induced Ascorbate Consumption Assaymentioning

confidence: 99%

Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for the Soluble Amyloid-β Oligomers in Alzheimer’s Disease

Sun¹,

Cho²,

Sen³

et al. 2021

Preprint

View full text Add to dashboard Cite

Alzheimer’s Diseases (AD) is the most common neurodegenerative disease, but efficient therapeutic and early diagnosis agents for this neurological disorder are still lacking. <a>Herein, we report the development of a novel amphiphilic compound, LS-4, generated linking a hydrophobic amyloid fibril-binding fragment with a hydrophilic azamacrocycle that can dramatically increase the binding affinity towards various amyloid β (Aβ) peptide aggregates. The developed compound exhibits uncommon fluorescence turn-on and high binding affinity for Aβ aggregates, especially for soluble Aβ oligomers. Moreover, upon the administration of LS-4 to 5xFAD mice, fluorescence imaging of the LS-4-treated brain sections reveals that LS-4 can readily penetrate the blood-brain-barrier (BBB) and bind to the Aβ oligomers in vivo, as confirmed by immunostaining with an Aβ oligomer-specific antibody. In addition, the treatment of 5xFAD mice with LS-4 significantly reduces the amount of both amyloid plaques and associated phosphorylated tau (p-tau) aggregates vs. the vehicle-treated 5xFAD mice, while microglia activation is also reduced. Furthermore, molecular dynamics simulations corroborate the observation that introducing a hydrophilic moiety into the molecular structure can significantly enhance the electrostatic interactions with the polar residues of the Aβ peptide species. Finally, taking advantage of the strong Cu-chelating property of the azamacrocycle, we performed a series of radioimaging and biodistribution studies that show the 64Cu-LS-4 complex binds to the amyloid plaques and can accumulate a significantly larger extent in the 5xFAD mice brains vs. the WT controls. Overall, these in vitro and in vivo studies illustrate that the novel strategy to employ an amphiphilic molecule containing a hydrophilic fragment attached to a hydrophobic amyloid fibril-binding fragment </a><a>can increase the binding affinity of these compounds for the soluble Aβ oligomers and can thus be used </a>to detect and regulate the soluble Aβ species in AD.

show abstract

Section: Cu 2+ -Induced Ascorbate Consumption Assaymentioning

confidence: 99%

Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for the Soluble Amyloid-β Oligomers in Alzheimer’s Disease

Sun¹,

Cho²,

Sen³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…For L1, the two highest protonation constants (log K1H = 11.17 3 =10.36(1)). 64 The two other protonation constants of the macrocyclic cyclam scaffold (i.e. the two tertiary amines) were estimated to be lower than 2.5 (e.g.…”

Section: Complex Synthesis and Structural Propertiesmentioning

confidence: 99%

Formation of Heteropolynuclear Lanthanide Complexes Using Macrocyclic Phosphonated Cyclam-Based Ligands

et al. 2020

Self Cite

View full text Add to dashboard Cite

Ligands L1 and L2, respectively based on a cyclam and a cross-bridged cyclam scaffold functionalised at N1 and N8 by 6-phosphonic-2-methylene pyridyl groups are described. While 2 complexation of lanthanide (Ln) cations with L2 was not possible, a family of complexes has been prepared with L1, of the general formulae [LnL1D2]Cl (Ln 3+ = Lu, Tb, Yb) or [LnL1D] (Ln 3+ = Eu). The solution, structural, potentiometric and photophysical data for these novel ligands and their complexes have been investigated, including solid-state study by X-ray diffraction (L1, L2 and [EuL1H]), 1 H NMR complexation investigations (Lu 3+) as well as UV-Vis absorption and luminescence spectroscopy in water and D2O (pH ≈ 7). L1 forms 1:1 metal-ligand stoichiometric octadentate complexes in solution. Importantly the pyridyl phosphonate functions are capable of simultaneous chelation to the metal centre and of interaction with a second metal centre. 1 H NMR (Lu 3+) and spectrophotometric titrations of the isolated [TbL1]complex by EuCl3 salts demonstrated the formation of high order (hetero)polymetallic species in aqueous solution (H2O, pH = 7). Global analysis of the luminescence titration experiment points to the formation of 4:1, 3:1, and 3:2 [TbL1]:Eu heteropolynuclear assemblies, exhibiting a strong preference to forming [TbL1]3Eu2 at increased europium concentrations, with energy transfer occurring between the kinetically inert terbium complex and added europium cations.

show abstract

“…The lability is the appropriate term if the ligandmetal interaction is kinetically controlled, measured as the life time of the ligand's association with the metal ion or the rate constant of ligand substitution [204]. The thermodynamic (Kd) and kinetic (lifetime) definitions of pathological metal ions thus potentially differ, as indicated by some recent studies [205]. For high-affinity copper sites in proteins, kinetic control of copper pools may arise from barriers to release copper depending on the steric and electronic nature of the ligands.…”

mentioning

confidence: 99%

Copper imbalance in Alzheimer’s disease: Convergence of the chemistry and the clinic

Kepp

Squitti

2019

Coordination Chemistry Reviews

View full text Add to dashboard Cite

Content 1. Introduction 2. The amyloid hypothesis and its main problems 3. Brain copper homeostasis 4. The critical Kd of CuAD 5. Clinical evidence: Copper dyshomeostasis in AD 6. Biochemical evidence: APP/Aβ and copper transport 7. Molecular mechanisms of copper toxicity in CuAD 8. Analogies to other Cu-related diseases 9. Combining the facts into a simple model of AD due to copper dyshomeostasis 10. Conclusions

show abstract

Kinetics Are Crucial When Targeting Copper Ions to Fight Alzheimer's Disease: An Illustration with Azamacrocyclic Ligands

Cited by 19 publications

References 52 publications

Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for the Soluble Amyloid-β Oligomers in Alzheimer’s Disease

Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for the Soluble Amyloid-β Oligomers in Alzheimer’s Disease

Formation of Heteropolynuclear Lanthanide Complexes Using Macrocyclic Phosphonated Cyclam-Based Ligands

Copper imbalance in Alzheimer’s disease: Convergence of the chemistry and the clinic

Contact Info

Product

Resources

About