Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) are fatal. No successful treatments are currently available, even after decades of research. Although the specific mechanisms of these diseases remain unclear, it is believed that autophagy, a cytoplasmic degradation process, becomes overwhelmed and/or impaired in these, and other, neurodegenerative diseases. The naturally occurring, sulfur-containing amino acid metabolite, lanthionine ketenamine (LK) and its brain-permeable, synthetic, 5-ethyl ester (LKE) have been shown to exhibit neuroprotective, neurotrophic and anti-neuroinflammatory properties. LKE also stimulates cellular autophagy in multiple cell types. Based on the study on LKE and its autophagy stimulation, as well as its neuroprotective activities, we hypothesized that small molecules mimicking the structure of lanthionine ketenamine can stimulate autophagy and can be used as treatments for neurodegenerative diseases. The goal of my studies has been to develop new agents to protect against diseases involving dysregulated autophagy and a synthetic strategy was employed to create new LKE-like molecules with increased efficacy and potency as autophagy stimulators. Using medicinal chemistry techniques, a panel of 17 compounds was designed and synthesized. The synthetic strategy combined multiple reactions into “one-pot” to afford products in high yield and purity. All compounds were characterized by 1H nuclear magnetic resonance (NMR) spectroscopy, 13C NMR, 31P NMR and ultraperformance liquid chromatography tandem ultraviolet spectrophotometry high-resolution mass spectrometry (UPLC-UV-HRMS). The synthesized compounds were evaluated in vitro for cytotoxicity. The lead compound arising from this panel, 2-n-hexyl-LKE-P, was further evaluated for autophagy stimulation in vitro by Western blot analysis. 2-n-hexyl-LKE-P was also tested in multiple Drosophila melanogaster models for neuroprotective activity via oral administration. Life span, mobility, sleep pattern and other relevant phenotypes were evaluated in Drosophila models of ALS, PD and Alzheimer’s disease (AD). 2-n-hexyl-LKE-P reversed the induced “neurodegenerative eye” and sleep phenotypes in multiple ALS models. 2-n-hexyl-LKE-P also significantly enhanced life span, recovered a visible “crushed thorax” phenotype and improved impaired mobility in the PINK1B9 model of PD. In addition, this paradigm can be applied as an in vivo, structure activity relationship development tool for the refinement of novel drug candidates for the treatment of neurodegenerative diseases.
|Advisor:||Denton, Travis T|
|Commitee:||Lazarus, Philip, Wang, Zhenjia, Padowski, Jeannie M, Chen, Gang|
|School:||Washington State University|
|School Location:||United States -- Washington|
|Source:||DAI-B 82/3(E), Dissertation Abstracts International|
|Subjects:||Pharmaceutical sciences, Organic chemistry, Pharmacology, Neurosciences|
|Keywords:||ALS, Autophagy, Drosophila, Lanthionine ketimine, Neurodegenerative disease, Parkinson's disease|
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