An adamantyl-substituted retinoid-derived molecule that inhibits cancer cell growth and angiogenesis by inducing apoptosis and binds to small heterodimer partner nuclear receptor: effects of modifying its carboxylate group on apoptosis, proliferation, and protein-tyrosine phosphatase activity

J Med Chem. 2007 May 31;50(11):2622-39. doi: 10.1021/jm0613323. Epub 2007 May 10.


Apoptotic and antiproliferative activities of small heterodimer partner (SHP) nuclear receptor ligand (E)-4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC), which was derived from 6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN), and several carboxyl isosteric or hydrogen bond-accepting analogues were examined. 3-Cl-AHPC continued to be the most effective apoptotic agent, whereas tetrazole, thiazolidine-2,4-dione, methyldinitrile, hydroxamic acid, boronic acid, 2-oxoaldehyde, and ethyl phosphonic acid hydrogen bond-acceptor analogues were inactive or less efficient inducers of KG-1 acute myeloid leukemia and MDA-MB-231 breast, H292 lung, and DU-145 prostate cancer cell apoptosis. Similarly, 3-Cl-AHPC was the most potent inhibitor of cell proliferation. 4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorophenyltetrazole, (2E)-5-{2-[3'-(1-adamantyl)-2-chloro-4'-hydroxy-4-biphenyl]ethenyl}-1H-tetrazole, 5-{4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorobenzylidene}thiazolidine-2,4-dione, and (3E)-4-[3'-(1-adamantyl)-2-chloro-4'-hydroxy-4-biphenyl]-2-oxobut-3-enal were very modest inhibitors of KG-1 proliferation. The other analogues were minimal inhibitors. Fragment-based QSAR analyses relating the polar termini with cancer cell growth inhibition revealed that length and van der Waals electrostatic surface potential were the most influential features on activity. 3-Cl-AHPC and the 3-chlorophenyltetrazole and 3-chlorobenzylidenethiazolidine-2,4-dione analogues were also able to inhibit SHP-2 protein-tyrosine phosphatase, which is elevated in some leukemias. 3-Cl-AHPC at 1.0 microM induced human microvascular endothelial cell apoptosis but did not inhibit cell migration or tube formation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / analogs & derivatives*
  • Adamantane / chemical synthesis
  • Adamantane / pharmacology
  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Apoptosis*
  • Cell Movement
  • Cell Proliferation / drug effects
  • Cinnamates / chemical synthesis*
  • Cinnamates / pharmacology
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / physiology
  • Humans
  • In Vitro Techniques
  • Microcirculation / cytology
  • Protein Tyrosine Phosphatases / antagonists & inhibitors
  • Protein Tyrosine Phosphatases / metabolism*
  • Quantitative Structure-Activity Relationship
  • Radioligand Assay
  • Receptors, Cytoplasmic and Nuclear / biosynthesis
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Retinoids / chemical synthesis*
  • Retinoids / pharmacology
  • Stereoisomerism


  • 4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid
  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Cinnamates
  • Receptors, Cytoplasmic and Nuclear
  • Retinoids
  • nuclear receptor subfamily 0, group B, member 2
  • Protein Tyrosine Phosphatases
  • Adamantane