Alzheimer's Disease (AD), the most prevalent neurodegenerative disease, still lacks effective therapeutic and early diagnostic tools. High concentrations of copper are found within amyloid peptide deposits in AD-affected brains. Research suggests that Cu(II) stabilizes soluble Aβ oligomers and enhances the neurotoxicity of the most neurotoxic Aβ peptide alloform, Aß42. Herein, we use organic synthesis to develop 1,4,7-triazacyclononane ligands for potential use as 64Cu PET imaging agents with high affinity for Aβ. Additionally, previously synthesized therapeutic ligands were used for an Alamar blue assay to prevent copper toxicity in vitro. Ligand precursors, ditosyl ethylene glycol and tritosyl diethylenetriamine were synthesized and combined to produce tritosyl-1,4,7-triazacyclononane (Ts3-TACN). Ditosyl-1,4,7-triazacyclononane (Ts2-TACN) and monotosyl-1,4,7-triazacyclononane (Ts-TACN) were synthesized by reaction of tritosyl-1,4,7-triazacyclononane in hydrobromic and glacial acetic acid. Ts2-TACN, 2-bromopropane, and sodium carbonate reacted to produce 7-isopropyl-1,4-ditosyl-1,4,7-triazacyclononane (Ts2iPr-TACN). Additionally, Ts2-TACN, formaldehyde, and formic acid were combined to produce 7-methyl-1,4-ditosyl-1,4,7-triazacyclononane (Ts2Me-TACN). Previous derivatization of Ts2-TACN and Ts3-TACN was necessary to provide the triisopropyl (iPr3-TACN), diisopropyl (iPr2-TACN), trimethyl (Me3-TACN), and dimethyl (Me2-TACN) TACN ligands for an Alamar blue assay. Analysis of N2A cell viability upon treatment with CuCl2 and ligand showed that low ligand concentration has minimal effect on cell viability.
School:
Howard University
Department:
Chemistry
Research Advisor:
Dr. Liviu Mirica
Department of Research Advisor:
Chemistry
Year of Publication:
2022