Cyclen-based chelators for the inhibition of Aβ aggregation: Synthesis, anti-oxidant and aggregation evaluation

Abstract

The aggregation of the protein amyloid-β in the brain has been associated with neurodegenerative diseases such as Alzheimer's disease. Such aggregation of amyloid-β can be induced by misregulated metal ions such as Cu 2+ and Zn 2+. Here we present a series of four metal chelating compounds based on the cyclen macrocycle that bears pendant arms to provide additional anti-oxidant activity. The corresponding Cu 2+ , Zn 2+ and Ni 2+ complexes have been synthesized and characterized to examine the ability of the chelators to bind to the metal centres. Aβ40 de-aggregation by the cyclen compounds was assessed using turbidometry and the re-solubilization of the Aβ40 was also examined. Our results show that the cyclen compounds have the ability to effectively chelate Cu 2+ and Zn 2+ metal ions and thus de-aggregate Aβ40 that has been aggregated due to the presence of these ions. The antioxidant properties of the cyclen compounds was tested by using the DPPH scavenging assay and the results show that some of the compounds can decrease oxidative stress.

Enhancement of the Antioxidant Activity and Neurotherapeutic Features through Pyridol Addition to Tetraazamacrocyclic Molecules

“…The strong correlation between uncontrolled oxidative stress and the development of neurodegenerative diseases has led to the study of a range of antioxidant small molecules and was the premise for the exploration of L4 . DPPH • (λ max = 520 nm) was used to assay the radical scavenging activity of L4 compared to L2 . − A radical scavenging molecule can quench DPPH • , and the corresponding color change from purple to clear yellow can be monitored spectrophotometrically to evaluate the radical reactivity (Scheme S2). − The concentrations of L2 (one pyridol moiety) and L4 (two pyridol moieties) were studied over the range of 1–1500 μM (Figure ).…”

“…DPPH • (λ max = 520 nm) was used to assay the radical scavenging activity of L4 compared to L2 . − A radical scavenging molecule can quench DPPH • , and the corresponding color change from purple to clear yellow can be monitored spectrophotometrically to evaluate the radical reactivity (Scheme S2). − The concentrations of L2 (one pyridol moiety) and L4 (two pyridol moieties) were studied over the range of 1–1500 μM (Figure ). 2,6-Di- tert -butyl-4-methylphenol, or butylated hydroxytoluene (BHT), was used as a positive control and resulted in a rapid decrease in the DPPH • absorbance band. , Likewise, L4 showed a strong, concentration-dependent antioxidant response beginning at 100 μM (Figure ).…”

The Synthesis of a Bis(thiosemicarbazone) Macrocyclic Ligand and the Mn(II), Co(II), Zn(II) and 68Ga(III) Complexes

“…While most sixcoordinate complexes have a distinct octahedral preference over trigonal prismatic, high-spin d 5 and d 10 electron-configurations have no octahedral preference due to the absence of crystal field stabilisation energy, and high-spin d 7 configurations have only a marginal preference [78]. A trigonal prismatic geometry can be forced upon Co 2+ com- Several instances of trigonal prismatic high-spin 3d 5 Mn 2+ , high-spin 3d 7 Co 2+ and 3d 10 Zn 2+ azamacrocyclic complexes have been reported [72][73][74][75][76][77]. While most six-coordinate complexes have a distinct octahedral preference over trigonal prismatic, high-spin d 5 and d 10 electron-configurations have no octahedral preference due to the absence of crystal field stabilisation energy, and high-spin d 7 configurations have only a marginal preference [78].…”

“…H 2 L is the first example of an azamacrocyclic N 5 S donor for Mn 2+ . A trigonal prismatic Zn 2+ complex has been previously reported with a N 5 O ligand containing a single pendant arm [75].…”