Rational design of antitumor prostaglandins with high biological stability

J Med Chem. 1998 Jul 30;41(16):3084-90. doi: 10.1021/jm9801657.


microolecular design can overcome the metabolic instability of Delta7-PGA1, while maintaining its antitumor potency. Saturation of the C(13)-C(14) double bond enhances the biological stability but decreases the antiproliferative activity. Configurational inversion of the isomerase-sensitive C(12) stereocenter from the natural S to the unnatural R geometry not only enhances biological stability but also significantly suppresses the growth of the tumor cells. The 12R derivatives markedly increase the induction of p21, a Cdk inhibitor, leading to sharp cell cycle arrest at the G1 phase at a dose level so low that at this dose Delta7-PGA1 methyl ester scarcely exerts an effect. These conspicuous biological properties lead to long-term suppression of tumor cell growth. The structure-stability relationship demonstrates that the stability of prostaglandins (PGs) is crucially controlled by the C(12) configuration and is unaffected by the geometry of the hydroxy-bearing C(15). The successful design of antitumor PGs resistant to enzymatic metabolism provides a new strategy applicable to creating a useful PG for cancer chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Division / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / biosynthesis
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Drug Stability
  • G1 Phase / drug effects
  • Humans
  • Prostaglandins / blood
  • Prostaglandins / chemical synthesis*
  • Prostaglandins / chemistry
  • Prostaglandins / pharmacology*
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • CDKN1A protein, human
  • Cdkn1a protein, rat
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Prostaglandins