New Metal Chelators for Chelation Therapy in Neurodegenerative Diseases

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In this thesis, a series of four new metal chelating compounds (MS1-4) based on the cyclen macrocycle that bear pendant arms to modify the molecules’ properties are evaluated as candidate drugs for Alzheimer's disease. These compounds have been designed to bind to the misregulated metals associated with Alzheimer’s disease. The corresponding Cu²⁺, Zn²⁺ and Ni²⁺ complexes were 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 Aβ₄₀ was also examined. The results show that the cyclen compounds have the ability to effectively chelate Cu²⁺ and Zn²⁺ metal ions and de-aggregate Aβ₄₀ that has been aggregated due to the presence of these ions. The antioxidant properties of the cyclen compounds were tested using the DPPH scavenging assay, and the results show that some of the compounds can decrease oxidative stress especially MS1 with IC₅₀ equals to 71 μM. Molecular modelling studies revealed the behaviour of the cyclen compounds within the E2 domain of APP and its interaction with Cu and Zn. Pharmacokinetics parameters were also promising for the compounds. Overall, these compounds exhibit promising properties as candidates for the treatment of Alzheimer’s disease. A study of drug candidates for Parkinson's disease investigated a series of new iron chelating compounds based on deferiprone and 8-hydroxyquinoline that have amphetamine-like structures. This work addresses a significant problem in Parkinson’s disease research, the issue of targeted delivery of chelating compounds into dopaminergic cells where iron may accumulate. The corresponding Fe²⁺ complexes were synthesised and characterised to examine the ability of the chelators to bind to metal centres. Thermodynamic parameters between the chelators and iron were calculated by using Isothermal titration calorimetry. The results show that 8-hydroxyquinoline-based compounds are more potent chelators than deferiprone-based compounds. N27 dopaminergic cell culture study was conducted to investigate whether the chelators can be transported within cells to prevent dopaminergic cell death caused by iron toxicity. The 8-hydroxyquinoline-based compounds showed the most promising results to rescue dopaminergic cells from iron-induced stress. The antioxidant properties of the compounds were tested using the DPPH scavenging assay, and the results show that 8-hydroxyquinoline-based compounds were superior in decreasing oxidative stress compared to the deferiprone-based compounds. Overall, 8-hydroxyquinoline-based compounds showed favourable properties as candidates for future Parkinson's disease research.
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