Resurrection of Organophosphorus-Aged Acetylcholinesterase via Mannich Bases Derived from Proline
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The Ohio State University / OhioLINK
2019
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=osu1565714137331736 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu15657141373317362021-08-03T07:12:24Z Resurrection of Organophosphorus-Aged Acetylcholinesterase via Mannich Bases Derived from Proline Ward, Nathan Andrew Biochemistry Chemistry Organic Chemistry organophosphorus resurrection proline Mannich bases resurrection of acetylcholinesterase organophosphorus-aged OP-aged AChE Organophosphorus (OP) compounds are responsible for an estimated 220,000 deaths annually. OP compounds inhibit the enzyme acetylcholinesterase (AChE) via phosphylation of a serine residue within the active site. Upon inhibition of AChE, acetylcholine accumulates in neuromuscular junctions, resulting in a cholinergic crisis and, if not treated immediately, can lead to death. Along with management of symptoms, current medical countermeasures for OP poisoning utilize nucleophilic oximes, which can displace the phosphorus moiety from the serine residue, reactivating AChE to its native state. However, following inhibition, a spontaneous O-dealkylation of the phosphylated serine residue can occur, resulting in an anionic phosphylated serine residue; this process is known as aging. There is currently no approved therapeutic that is capable of restoring OP-aged AChE to its native state (a process referred to as resurrection). Previous studies by our group have shown that a class of compounds called quinone methide precursors (QMPs) both resurrect OP-aged AChE and reactivate OP-inhibited AChE back to its native state.A previous lead QMP from the Hadad group featured a pyrrolidine leaving group, while the current lead QMP features an (R)-2-methylpyrrolidine leaving group. Thus, the addition of a methyl group at the 2-position of the pyrrolidine ring with the (R)-configuration increased the resurrection efficacy of OP-aged AChE. This work describes the synthesis of novel QMPs that have been derived from proline. Proline was derivatized to vary the functional group at the 2-position of the pyrrolidine ring in an effort to further increase the resurrection efficacy of OP-aged AChE.More specifically, proline was derivatized to feature ester, amide, alcohol, ether, and amine functional groups. Then, the QMPs were synthesized via a Mannich reaction between 3-hydroxypyridine and the proline derivatives. The QMPs were screened against OP-aged AChE and the resurrection efficacy was measured via Ellman’s assay. 2019 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1565714137331736 http://rave.ohiolink.edu/etdc/view?acc_num=osu1565714137331736 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. |
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NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Biochemistry Chemistry Organic Chemistry organophosphorus resurrection proline Mannich bases resurrection of acetylcholinesterase organophosphorus-aged OP-aged AChE |
| spellingShingle |
Biochemistry Chemistry Organic Chemistry organophosphorus resurrection proline Mannich bases resurrection of acetylcholinesterase organophosphorus-aged OP-aged AChE Ward, Nathan Andrew Resurrection of Organophosphorus-Aged Acetylcholinesterase via Mannich Bases Derived from Proline |
| author |
Ward, Nathan Andrew |
| author_facet |
Ward, Nathan Andrew |
| author_sort |
Ward, Nathan Andrew |
| title |
Resurrection of Organophosphorus-Aged Acetylcholinesterase via Mannich Bases Derived from Proline |
| title_short |
Resurrection of Organophosphorus-Aged Acetylcholinesterase via Mannich Bases Derived from Proline |
| title_full |
Resurrection of Organophosphorus-Aged Acetylcholinesterase via Mannich Bases Derived from Proline |
| title_fullStr |
Resurrection of Organophosphorus-Aged Acetylcholinesterase via Mannich Bases Derived from Proline |
| title_full_unstemmed |
Resurrection of Organophosphorus-Aged Acetylcholinesterase via Mannich Bases Derived from Proline |
| title_sort |
resurrection of organophosphorus-aged acetylcholinesterase via mannich bases derived from proline |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2019 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1565714137331736 |
| work_keys_str_mv |
AT wardnathanandrew resurrectionoforganophosphorusagedacetylcholinesteraseviamannichbasesderivedfromproline |
| _version_ |
1719456336816635904 |