Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 May 8;8(6):622-627.
doi: 10.1021/acsmedchemlett.7b00037. eCollection 2017 Jun 8.

Study of para-Quinone Methide Precursors toward the Realkylation of Aged Acetylcholinesterase

Ryan J Yoder  1 , Qinggeng Zhuang  2 , Jeremy M Beck  2 , Andrew Franjesevic  2 , Travis G Blanton  1 , Sydney Sillart  2 , Tyler Secor  2 , Leah Guerra  2 , Jason D Brown  2 , Carolyn Reid  2 , Craig A McElroy  3 , Özlem Doğan Ekici  4 , Christopher S Callam  2 , Christopher M Hadad  2
Affiliations

Study of para-Quinone Methide Precursors toward the Realkylation of Aged Acetylcholinesterase

Ryan J Yoder et al. ACS Med Chem Lett. .

Abstract

Acetylcholinesterase (AChE) is an essential enzyme that can be targeted by organophosphorus (OP) compounds, including nerve agents. Following exposure to OPs, AChE becomes phosphylated (inhibited) and undergoes a subsequent aging process where the OP-AChE adduct is dealkylated. The aged AChE is unable to hydrolyze acetylcholine, resulting in accumulation of the neurotransmitter in the central nervous system (CNS) and elsewhere. Current therapeutics are only capable of reactivating inhibited AChE. There are no known therapeutic agents to reverse the aging process or treat aged AChE. Quinone methides (QMs) have been shown to alkylate phosphates under physiological conditions. In this study, a small library of novel quinone methide precursors (QMPs) has been synthesized and examined as potential alkylating agents against model nucleophiles, including a model phosphonate. Computational studies have been performed to evaluate the affinity of QMPs for the aged AChE active site, and preliminary testing with electric eel AChE has been performed.

Keywords: Acetylcholinesterase; organophosphorus chemical nerve agents; quinone methide.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Inhibition, Aging and Realkylation of AChE
The leaving group X is substituted during inhibition. The alkyl group R is lost during aging.
Scheme 2
Scheme 2. Potential Quinone Methide Precursor (QMP) Prodrug and Quinone Methide Intermediate
Figure 1
Figure 1
Target quinone methide precursors.
Scheme 3
Scheme 3. Reductive Amination for the Preparation of QMPs
Scheme 4
Scheme 4. Alkylation of Model Nucleophiles by QMPs
Scheme 5
Scheme 5. Reactions between 1 or 1-HCl and the Model Phosphonate (a)
Protonation states are not specified.
Figure 2
Figure 2
Docked pose of 3-HCl in the aged AChE active site, displaying the putative reactive orientation of the benzylic carbon being less than 5 Å from aged serine residue.
Figure 3
Figure 3
Result of AChE realkylation test. The relative activity of 2-PAM control was 1.2%, implying the near completeness of aging. Aged AChE samples treated with tested QMPs were not obviously more active than the negative control (Neg Ctrl).
See this image and copyright information in PMC

References

    1. Barr D. B.; Allen R.; Olsson A. O.; Bravo R.; Caltabiano L. M.; Montesano A.; Nguyen J.; Udunka S.; Walden D.; Walker R. D.; Weerasekera G.; Whitehead R. D. Jr.; Schober S. E.; Needham L. L. Concentrations of Selective Metabolites of Organophosphorus Pesticides in the United States Population. Environ. Res. 2005, 99, 314–326. 10.1016/j.envres.2005.03.012. - DOI - PubMed
    1. Bronstein A. C.; Spyker D. A.; Cantilena L. R.; Green J. L.; Rumack B. H.; Giffin S. L. 2008 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 26th Annual Report. Clin. Toxicol. 2009, 47, 911–1084. 10.3109/15563650903438566. - DOI - PubMed
    1. Delfino R. T.; Ribeiro T. S.; Figueroa-Villar J. D. Organophosphorus Compounds as Chemical Warfare Agents: a Review. J. Braz. Chem. Soc. 2009, 20, 407–428. 10.1590/S0103-50532009000300003. - DOI
    1. Dolgin E. Syrian Gas Attack Reinforces Need for Better Anti-sarin Drugs. Nat. Med. 2013, 19, 1194–1195. 10.1038/nm1013-1194. - DOI - PubMed
    1. Quinn D. M. Acetylcholinesterase: Enzyme Structure, Reaction Dynamics, and Virtual Transition States. Chem. Rev. 1987, 87, 955–979. 10.1021/cr00081a005. - DOI