Current understanding of metal-dependent amyloid-β aggregation and toxicity

Abstract

The discovery of effective therapeutics targeting amyloid-β (Aβ) aggregates for Alzheimer’s disease (AD) has been very challenging, which suggests its complicated etiology associated with multiple pathogenic elements. In AD-affected brains,...

Addressing the gaps in homeostatic mechanisms of copper and copper dithiocarbamate complexes in cancer therapy: a shift from classical platinum-drug mechanisms

“…This is because the energy required for the rearrangement between the copper (I) and copper(II) geometries (linear and square-planar, respectively) is very high. 136 It has also been suggested that the electron transfers during the metal-catalyzed ROS formation take place via a similar state, referred to as the catalytic in-between state. 136 Investigations by computational studies have shed light on the environment of copper in those states and its reactivity toward substrates (O 2 or H 2 O 2 ) 138 (Fig.…”

“…as well as the metal centres' responsiveness to ligand replacement and redox catalysis 136 (fig below). However, they often bind copper(II) in a square planar manner.…”

“…However, they often bind copper(II) in a square planar manner. 136,144 As shown in Fig. 6 (bottom) for component I, the copper(II) centre is coordinated to the N-terminal primary amine, two imidazole nitrogen (N) donor atoms from His-6 and His-13 or His-14, and the oxygen (O) donor atom from the backbone carbonyl group between asparagine 1 (Asp1) and alanine 2 (Ala2).…”

“…6 (bottom) for component I, the copper(II) centre is coordinated to the N-terminal primary amine, two imidazole nitrogen (N) donor atoms from His-6 and His-13 or His-14, and the oxygen (O) donor atom from the backbone carbonyl group between asparagine 1 (Asp1) and alanine 2 (Ala2). 136 Perhaps with a weakly attached carboxylate group from the side chain of Asp1, glutamine 3(Glu3), Asp7, or Glu11, or a water molecule at the apical position as a fifth ligand, d 9 copper(II)-Aβ complexes exhibit a deformed square planar or square pyramidal shape. A deprotonated backbone amide moiety between Asp1 and Ala2 is one of many accepted copper (II)-binding sites in component II that were indicated at somewhat high pH (ca.…”

“…pH ≥ 8). 136 A main anchoring ligand is the nitrogen-containing N-terminal amine. 145,146 Many other combinations of other groups can function as co-ligands, depending on the circumstances.…”