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

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.

• Authors: Zilei Liu, Sarah F Jenkinson, Tom Vermaas, Isao Adachi, Mark R Wormald, Yukako Hata, Yukiko Kurashima, Akira Kaji, Chu-Yi Yu, Atsushi Kato, George W J Fleet
• Journal: The Journal of organic chemistry (J Org Chem) Vol. 80 Issue 9 Pg. 4244-58 (May 01 2015) ISSN: 1520-6904 [Electronic] United States
• PMID: 25859886 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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