| Autor: |
Zhuang Q, Franjesevic AJ, Corrigan TS, Coldren WH, Dicken R, Sillart S, DeYong A, Yoshino N, Smith J, Fabry S, Fitzpatrick K, Blanton TG; Department of Chemistry and Biochemistry , The Ohio State University-Marion , Marion , Ohio 43302 , United States., Joseph J, Yoder RJ; Department of Chemistry and Biochemistry , The Ohio State University-Marion , Marion , Ohio 43302 , United States., McElroy CA, Ekici ÖD; Department of Chemistry and Biochemistry , The Ohio State University-Newark , Newark , Ohio 43055 , United States., Callam CS, Hadad CM |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2018 Aug 23; Vol. 61 (16), pp. 7034-7042. Date of Electronic Publication: 2018 Jun 20. |
| DOI: |
10.1021/acs.jmedchem.7b01620 |
| Abstrakt: |
After the inhibition of acetylcholinesterase (AChE) by organophosphorus (OP) nerve agents, a dealkylation reaction of the phosphylated serine, referred to as aging, can occur. When aged, known reactivators of OP-inhibited AChE are no longer effective. Realkylation of aged AChE may provide a route to reversing aging. We designed and synthesized a library of quinone methide precursors (QMPs) as proposed realkylators of aged AChE. Our lead compound (C8) from an in vitro screen successfully resurrected 32.7 and 20.4% of the activity of methylphosphonate-aged and isopropyl phosphate-aged electric-eel AChE, respectively, after 4 days. C8 displays properties of both resurrection (recovery from the aged to the native state) and reactivation (recovery from the inhibited to the native state). Resurrection of methylphosphonate-aged AChE by C8 was significantly pH-dependent, recovering 21% of activity at 4 mM and pH 9 after only 1 day. C8 is also effective against isopropyl phosphate-aged human AChE. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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