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Bioorg Med Chem. 2010 Mar 15;18(6):2265-2274. doi: 10.1016/j.bmc.2010.01.063. Epub 2010 Feb 4.

Synthesis and kinetic analysis of some phosphonate analogs of cyclophostin as inhibitors of human acetylcholinesterase.

Author information

1
Center for Nanoscience, University of Missouri St. Louis, St. Louis, MO 63121, United States.
2
Department of Chemistry & Biochemistry, University of Missouri St. Louis, St. Louis, MO 63121, United States.

Abstract

Two new monocyclic analogs of the natural AChE inhibitor cyclophostin and two exocyclic enol phosphates were synthesized. The potencies and mechanisms of inhibition of the bicyclic and monocyclic enol phosphonates and the exocyclic enol phosphates toward human AChE are examined. One diastereoisomer of the bicyclic phosphonate exhibits an IC(50) of 3 microM. Potency is only preserved when the cyclic enol phosphonate is intact and conjugated to an ester. Kinetic analysis indicates both a binding and a slow inactivation step for all active compounds. Mass spectrometric analysis indicates that the active site Ser is indeed phosphorylated by the bicyclic phosphonate.

PMID:
20189400
PMCID:
PMC2841358
DOI:
10.1016/j.bmc.2010.01.063
[Indexed for MEDLINE]
Free PMC Article

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