Synthesis, Structure-Affinity Relationships, and Biological Activities of Ligands Binding to Retinoic Acid Receptor Subtypes

Abstract

The retinoic acid receptors (RARs) transduce retinoid dependant gene regulation, and many biological effects of retinoids are mediated through binding and activation of three closely related receptor subtypes (RAR alpha, RAR beta, and RAR gamma). In order to investigate the role of receptor subtypes, we have carried out a chemical synthesis program to seek selective retinoids for these receptors. We measured receptor binding affinity using recombinant RAR alpha, -beta, and -gamma proteins and assessed cellular differentiating activity in F9 murine teratocarcinoma cells (F9 cells). This research has identified the 4-substituted-3-(1-adamantyl)phenyl moiety as a new pharmacophore which can replace the beta-cyclogeranylidene ring of the naturally occurring all-trans-retinoic acid. Two chemical series derived from the general structures 6-(3-tertioalkylphenyl)-2-naphthoic acid (series I) and 4-[(E)-2-(3-tertioalkylphenyl)propenyl]benzoic acid (series II) were developed. In particular, we have obtained the RAR gamma selective derivatives 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoic acid (7) [Ki(RAR alpha) = 6500 nM, Ki(RAR beta) = 2480 nM, Ki(RAR gamma) = 77 nM] and 4-[(E)-2-[3-(1-adamantyl)-4-hydroxyphenyl]propenyl]benzoic acid (19) [Ki(RAR alpha) = 1,144 nM, Ki(RAR beta) = 1245 nM, Ki(RAR gamma) = 53 nM]. In series I, the presence of a phenol group, irrespective of the nature of tertioalkyl group, imparted at least partial RAR gamma selectivity, whereas in series II, the presence of both adamantyl and phenol groups is needed to confer RAR gamma selectivity. The RAR gamma selective ligands induce differentiation in F9 cells (7, AC50 = 33 nM; 19, AC50 = 66 nM). From series I, a mixed RAR beta-gamma agonist with potent cellular differentiating activity was selected for development as a topical antiacne agent, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid (5, CD 271) [Ki(RAR alpha) = 1100 nM, Ki-(RAR beta) = 34 nM, Ki(RAR gamma) = 130 nM, AC50(F9) = 37 nM]. Finally, from series II, we have obtained a weak antagonist in the F9 cellular differentiation assay, 4-[(E)-2-(3-tert-butyl-4-hydroxyphenyl)propenyl]benzoic acid (15, IC50 = 700 nM).

Identification and Characterization of a Cell Cycle and Apoptosis Regulatory Protein-1 as a Novel Mediator of Apoptosis Signaling by Retinoid CD437

“…DISCUSSION CD437 is a novel, RAR␥-selective adamantyl retinoid that causes cell cycle arrest and apoptosis in a number of cell types. CD437 displays poor binding and trans-activation of RAR␤ and RAR␣, and no binding to RXRs (25). CD437 also causes apoptosis of human leukemia cell line HL-60R that does not express any functional RARs (7), indicating that CD437 functions independently of direct interactions with retinoid receptors.…”

Apoptosis signaling by the novel compound 3-Cl-AHPC involves increased EGFR proteolysis and accompanying decreased phosphatidylinositol 3-kinase and AKT kinase activities

“…In addition, ecoptic overexpression in breast carcinoma cells of the tumor suppressor gene PTEN, which inhibits the phosphorylation of the activating residues of AKT, results in apoptosis induction (Ghosh et al, 1999). We and others have previously demonstrated that the retinoid nuclear receptor (RAR) g selective retinoid 6- [3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437) induces apoptosis in prostate and breast carcinoma cells (Charpenter et al, 1995;Shao et al, 1995;Liang et al, 1999). In this study, we demonstrate that the novel compound 4- [3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC), which does not transactivate the RARs, inhibits AKT activation followed by the induction of apoptosis in breast and prostate carcinoma cells.…”

A Novel Molecular Target for Breast Cancer Prevention and Treatment

“…A report of the RARy selectivity of AHPN (12) led to the hypothesis of an apoptotic role for RARy in breast cancer, melanoma, and neuroblastoma cells (17,23,24). To support this, RARy transcriptionally active AHPN derivatives and analogues were also reported to inhibit growth and induce apoptosis (28,48,49). Other reports present data strongly suggesting an RAR-independent pathway, such as growth inhibition and apoptosis of retinoid-resistant cancer cells (13,14,21,27,42,44,50).…”

“…AHPN [1] was prepared by modifying a reported procedure (28). AHPN (MM11453) [2] was synthesized as follows.…”