Antagonist analogue of 6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN) family of apoptosis inducers that effectively blocks AHPN-induced apoptosis but not cell-cycle arrest

J Med Chem. 2004 Jul 1;47(14):3518-36. doi: 10.1021/jm030524k.


The retinoid 6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN) and its active analogues induce cell-cycle arrest and programmed cell death (apoptosis) in cancer cells independently of retinoic acid receptor (RAR) interaction. Its analogue, (E)-4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-(3'-acetamidopropyloxy)cinnamic acid (3-A-AHPC) selectively antagonized cell apoptotic events (TR3/nur77/NGFI-B expression and nuclear-to-mitochondrial translocation) but not the proliferative events (cell-cycle arrest and p21(WAF1/CIP1) expression) induced by proapoptotic AHPN and its analogues. The syntheses of 3-A-AHPC and proapoptotic (E)-6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-5-chloronaphthalenecarboxylic acid (5-Cl-AHPN) are described. Computational studies on AHPN, AHPC, and three substituted analogues (5-Cl-AHPN, 3-Cl-AHPC, and 3-A-AHPC) suggested reasons for their diametric effects on RAR activation. Density functional theory studies indicated that the 1-adamantyl (1-Ad) groups of the AHPN and AHPC configurations assumed positions that were nearly planar with the aromatic rings of their polar termini. In contrast, in the configurations of the substituted analogues having chloro and 3-acetamidopropyloxy groups, rather than a hydrogen, ortho to the diaryl bonds, the diaryl bond torsion angles increased so that the 1-Ad groups were oriented out of this plane. Docking and molecular dynamics of AHPN, AHPC, and these substituted analogues in the RARgamma ligand-binding domain illustrated how specific substituents on the AHPN and AHPC scaffolds modulated the positions and dynamics of the 1-Ad groups. As a result, the position of RARgamma helix H12 in forming the coactivator-binding site was impacted in a manner consistent with the experimental effect of each analogue on RARgamma transcriptional activation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adamantane / analogs & derivatives
  • Adamantane / chemical synthesis*
  • Adamantane / chemistry
  • Adamantane / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Binding, Competitive
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cinnamates / chemical synthesis*
  • Cinnamates / chemistry
  • Cinnamates / pharmacology
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / biosynthesis
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology
  • Quantitative Structure-Activity Relationship
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Retinoic Acid / metabolism
  • Retinoid X Receptors
  • Transcription Factors / metabolism
  • Transcriptional Activation


  • 4-(3'-(1-adamantyl)-4'-hydroxyphenyl)-3-(3'-acetamidopropyloxy)cinnamic acid
  • 6-(3'-(1-adamantyl)-4'-hydroxyphenyl)-5-chloronaphthalenecarboxylic acid
  • Antineoplastic Agents
  • CDKN1A protein, human
  • Cinnamates
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Ligands
  • Naphthalenes
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Transcription Factors
  • Adamantane