Convergent synthesis of alpha-ketoamide inhibitors of Pin1

Org Lett. 2010 Feb 19;12(4):696-9. doi: 10.1021/ol9027013.

Abstract

A convergent synthesis of alpha-ketoamide inhibitors of Pin1 is described. An alpha-hydroxyorthothioester derivative of Ser was reacted directly with an amine synthon. The reaction was catalyzed by HgO and HgCl(2) to form alpha-hydroxyamide. Thus, hydrolysis and coupling were combined in one step with 80% yield. Two diastereomers of a phospho-Ser-Pro alpha-ketoamide analogue were synthesized. The IC(50) values of 100 and 200 microM were surprisingly weak for Pin1 peptidyl prolyl isomerase.

Publication types

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

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amides / pharmacology
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Inhibitory Concentration 50
  • Ketones / chemical synthesis*
  • Ketones / chemistry
  • Ketones / pharmacology*
  • Molecular Structure
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Peptidylprolyl Isomerase / antagonists & inhibitors*
  • Stereoisomerism

Substances

  • Amides
  • Enzyme Inhibitors
  • Ketones
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Peptidylprolyl Isomerase