Synthesis and kinetic analysis of some phosphonate analogs of cyclophostin as inhibitors of human acetylcholinesterase.
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.
Dutta
Supratik
S
Center for Nanoscience, University of Missouri St. Louis, St. Louis, MO 63121, United States.
Malla
Raj K
RK
Department of Chemistry & Biochemistry, University of Missouri St. Louis, St. Louis, MO 63121, United States.
Bandyopadhyay
Saibal
S
Department of Chemistry & Biochemistry, University of Missouri St. Louis, St. Louis, MO 63121, United States.
Spilling
Christopher D
CD
Department of Chemistry & Biochemistry, University of Missouri St. Louis, St. Louis, MO 63121, United States.
Dupureur
Cynthia M
CM
Center for Nanoscience, University of Missouri St. Louis, St. Louis, MO 63121, United States.
D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D013058:Mass Spectrometry; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C083659:cyclophostin; D000110:Acetylcholinesterase