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

Abstract

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.

Adamantyl-Substituted Retinoid-Related Molecules Bind Small Heterodimer Partner and Modulate the Sin3A Repressor

“…4D), also inhibited 3-Cl-AHPC-enhanced SHP association with the Sin3A complex (Fig. 5B) and blocked 3-Cl-AHPC-mediated apoptosis as we have previously shown (22). We speculated that if 3-Cl-AHPC binding to SHP plays an important role in 3-Cl-AHPC-mediated apoptosis, loss of SHP (Fig.…”

“…3-Cl-AHPC, (E)-4-[3 ¶-(1-adamantyl)-4 ¶-hydroxyphenyl]-3-(3 ¶-acetamidopropyloxy)cinnamic acid (3-A-AHPC) and [5,5 ¶-3 H 2 ] AHPN, were synthesized as described previously (14,22,23). [11, H 2 ]tRA was purchased from Perkin-Elmer Life Sciences (Boston, MA).…”

SHP and Sin3A expression are essential for adamantyl-substituted retinoid-related molecule–mediated nuclear factor-κB activation, c-Fos/c-Jun expression, and cellular apoptosis

“…Previous studies suggested that ARR-mediated growth inhibition and apoptosis seem to involve separate pathways (32,33). We found that exposure of cells to ARRs resulted in the enhanced association of SHP with the Sin3A complex and modification of the Sin3A complex with the enhanced binding of N-CoR, HDAC-4, and HSP90 and increased Sin3A-associated HDAC activity (27).…”

Apoptosis-based therapies for hematologic malignancies

“…The prototype compound, 3Cl-AHPC, lacks activity against retinoid receptors, though having evolved from attempts to synthesize highly selective retinoid ligands. 44 3Cl-AHPC has demonstrated activity against cultured leukemia cells and in preclinical animal models of AML, 45,46 retaining activity even against retinoid refractory leukemia cell lines. 3Cl-AHPC appears to induce phosphorylation of TR3, possibly via a Jun N-terminal kinase (JNK) pathway, correlating with its exodus from the nucleus.…”