The first total synthesis of (±)-cyclophostin and (±)-cyclipostin P: inhibitors of the serine hydrolases acetyl cholinesterase and hormone sensitive lipase

Org Lett. 2011 Jun 17;13(12):3094-7. doi: 10.1021/ol200991x. Epub 2011 May 17.

Abstract

Cyclophostin, a structurally unique and potent naturally occurring acetyl cholinesterase (AChE) inhibitor, and its unnatural diastereomer were prepared in 6 steps and 15% overall yield from hydroxymethyl butyrolactone. The unnatural diastereomer of cyclophostin was converted into cyclipostin P, a potent naturally occurring hormone sensitive lipase (HSL) inhibitor, using a one pot dealkylation-alkylation process. The inhibition [IC(50)] of human AChE by cyclophostin and its diastereomer are reported, as well as constituent binding (K(I)) and reactivity (k(2)) constants.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacokinetics
  • Cholinesterase Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Lipase / antagonists & inhibitors*
  • Molecular Structure
  • Organophosphorus Compounds / chemical synthesis*
  • Organophosphorus Compounds / chemistry
  • Organophosphorus Compounds / pharmacokinetics
  • Organophosphorus Compounds / pharmacology*
  • Stereoisomerism

Substances

  • Cholinesterase Inhibitors
  • Organophosphorus Compounds
  • cyclipostin P
  • cyclophostin
  • Lipase