Synthetic Efforts Towards Small Molecule Solutions for Organophosphorus Nerve AgentPoisoning and Protease Inhibition
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2017
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu14939937190153322021-08-03T07:02:19Z Synthetic Efforts Towards Small Molecule Solutions for Organophosphorus Nerve AgentPoisoning and Protease Inhibition Corrigan, Thomas S. Chemistry A strong healthcare system is not only an ethical responsibility for a developed society, but a prerequisite to the advancement and prosperity of the human race as a whole. The field of medicinal chemistry, capitalizing on the synergistic effects of the collaboration between chemistry, pharmacology, biology, and enzymology, has time and time again presented elegant solutions to the general population for human health issues, both small and large. From medicines to alleviate symptoms of the common cold, to the eradication of pandemic diseases such as smallpox, scientists have been at the forefront of ensuring comfort in both the present, and future through the development of therapeutics. The research presented in this thesis was conducted with the hope that it will make a positive impact, large or small, towards the quality of life for humankind. Small molecules have long played a critical role in the development of advanced therapeutics. A successful synthetic organic chemist in the field of medicinal chemistry must combine a highly refined arsenal of synthesis techniques with an understanding for the intended interactions of small molecules at the interface of their medicinal targets. The work presented within this document will highlight advances made to develop practical solutions to health challenges facing today’s society in the form of the rational design and synthesis of small molecules.The first three chapters will introduce organophosphorus (OP) nerve agent molecules, address the deadly threats that these chemical warfare agent and pesticide compounds pose to both developed and undeveloped societies, and present two approaches for combatting their toxic effects. The first, a preventative approach, involves the design and synthesis of small molecule mimics for the destructive hydrolysis pathway of OPs, with a goal to raise antibodies capable of destroying the deadly OP compounds before their toxic effects take hold. The second approach addresses a serious problem that occurs after inhibition of the OP target enzyme acetylcholinesterase (AChE), in a process known as “aging”. In this project, the exploration of quinone methide precursors (QMPs), including their design, synthesis, and evaluation as potential realkylators for the aged AChE enzyme in an effort to revive the enzyme’s critical function of hydrolyzing the neurotransmitter acetylcholine (ACh) is presented in detail.The fourth chapter will present a new class of small molecule protease inhibitors, which were designed and synthesized, with the ability to be synthetically tuned for a variety of target protease enzymes. These small molecule inhibitors are presented with the intention of therapeutic use for the treatment of a variety of diseases, with an initial emphasis on developing a suitable drug candidate for the treatment of multiple myeloma by inhibition of the proteasome enzyme, a key component of the ubiquitin proteasome pathway (UPP). Here, the inhibitor design, synthesis and initial evaluation of the inhibitors will be discussed. 2017-10-12 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1493993719015332 http://rave.ohiolink.edu/etdc/view?acc_num=osu1493993719015332 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Chemistry |
| spellingShingle |
Chemistry Corrigan, Thomas S. Synthetic Efforts Towards Small Molecule Solutions for Organophosphorus Nerve AgentPoisoning and Protease Inhibition |
| author |
Corrigan, Thomas S. |
| author_facet |
Corrigan, Thomas S. |
| author_sort |
Corrigan, Thomas S. |
| title |
Synthetic Efforts Towards Small Molecule Solutions for Organophosphorus Nerve AgentPoisoning and Protease Inhibition |
| title_short |
Synthetic Efforts Towards Small Molecule Solutions for Organophosphorus Nerve AgentPoisoning and Protease Inhibition |
| title_full |
Synthetic Efforts Towards Small Molecule Solutions for Organophosphorus Nerve AgentPoisoning and Protease Inhibition |
| title_fullStr |
Synthetic Efforts Towards Small Molecule Solutions for Organophosphorus Nerve AgentPoisoning and Protease Inhibition |
| title_full_unstemmed |
Synthetic Efforts Towards Small Molecule Solutions for Organophosphorus Nerve AgentPoisoning and Protease Inhibition |
| title_sort |
synthetic efforts towards small molecule solutions for organophosphorus nerve agentpoisoning and protease inhibition |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2017 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1493993719015332 |
| work_keys_str_mv |
AT corriganthomass syntheticeffortstowardssmallmoleculesolutionsfororganophosphorusnerveagentpoisoningandproteaseinhibition |
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1719452456948072448 |