3-Fluoroazetidinecarboxylic Acids and trans,trans-3,4-Difluoroproline as Peptide Scaffolds: Inhibition of Pancreatic Cancer Cell Growth by a Fluoroazetidine Iminosugar

J Org Chem. 2015 May 1;80(9):4244-58. doi: 10.1021/acs.joc.5b00463. Epub 2015 Apr 17.

Abstract

Reverse aldol opening renders amides of 3-hydroxyazetidinecarboxylic acids (3-OH-Aze) unstable above pH 8. Aze, found in sugar beet, is mis-incorporated for proline in peptides in humans and is associated with multiple sclerosis and teratogenesis. Aze-containing peptides may be oxygenated by prolyl hydroxylases resulting in potential damage of the protein by a reverse aldol of the hydroxyazetidine; this, rather than changes in conformation, may account for the deleterious effects of Aze. This paper describes the synthesis of 3-fluoro-Aze amino acids as hydroxy-Aze analogues which are not susceptible to aldol cleavage. 4-(Azidomethyl)-3-fluoro-Aze and 3,4-difluoroproline are new peptide building blocks. trans,trans-2,4-Dihydroxy-3-fluoroazetidine, an iminosugar, inhibits the growth of pancreatic cancer cells to a similar degree as gemcitabine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Azetidines / chemical synthesis
  • Azetidines / chemistry
  • Azetidines / pharmacology*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Imino Sugars / chemistry
  • Imino Sugars / pharmacology*
  • Molecular Conformation
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology
  • Peptides / chemistry*
  • Proline / analogs & derivatives*
  • Proline / chemistry
  • Proline / pharmacology
  • Structure-Activity Relationship

Substances

  • 2,4-dihydroxy-3-fluoroazetidine
  • Antineoplastic Agents
  • Azetidines
  • Imino Sugars
  • Peptides
  • Proline