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

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Dutta S, Malla RK, Bandyopadhyay S, Spilling CD, Dupureur CM

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

Bioorg Med Chem. 2010 Mar 15;18(6):2265-74. doi: 10.1016/j.bmc.2010.01.063. Epub 2010 Feb 4.

PubMed ID

20189400 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Isoflurophate	Acetylcholinesterase	IC 50 (nM)	120	N/A	N/A	Details
Isoflurophate	Acetylcholinesterase	Ki (nM)	6000	N/A	N/A	Details