title: Modulation of Retinoic Acid Receptor Subtypes by 5- and 8-Substituted (Naphthalen-2-yl)-based Arotinoids.
abstract: Retinoid receptors (RARs and RXRs) transduce the signals of their natural and synthetic ligands (retinoids and rexinoids) to cellular transcriptional machinery to induce gene programs that control diverse biological and physiological effects on organisms. All-trans-retinoic acid, the natural ligand for RARs, is used therapeutically for the treatment of acute promyelocytic leukemia (APL), whereas the synthetic rexinoid bexarotene (a representative member of the aromatic retinoids or arotinoids) is approved for the treatment of cutaneous T-cell lymphoma (CTCL). Other retinoids have found applications in the topical treatment of skin disorders. In continuation of previous work on the naphthalene-based arotinoid scaffold, we synthesized a new series of (3-halo)benzoic acids connected to C5- or C8-substituted naphthyl rings via (E)-ethenyl and amide and, for the C5 series, (E)-chalcone linkers. These compounds were evaluated as RAR modulators in comparison with previously described dihydronaphthalene arotinoids with the same substitution pattern. Transactivation studies in this series revealed an absence of synergy between small halogen atoms (F, Cl) at C3 and the groups at C5 or C8, as had been observed on some of the dihydronaphthalene analogues. Instead, non-halogenated 4-(2-naphthamido)benzoic acid derivatives transactivated toward the RARβ subtype in preference to the paralogues. The derivatives with bulkier substituents at C8 were characterized as dual RARβ/RARα antagonists, and (E)-4-[(8-(phenylethynyl)naphthalene-2-yl)ethenyl]benzoic acid (11 c), with an ethenyl connector, was shown to be a potent antagonist of RARα.
authors.affiliation: Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, CINBIO and IBI, As Lagoas-Marcosende, 36310 Vigo (Spain).
authors.forename: Susana
authors.initials: S
authors.lastname: Álvarez
authors.affiliation: Department of Cancer Biology, Institut de Génetique et de Biologie Moleculaire et Cellulaire (IGBMC)/CNRS/INSERM/ULP, BP 163, Ilkirch Cedex, C.U. de Strasbourg (France).
authors.forename: Michele
authors.initials: M
authors.lastname: Lieb
authors.affiliation: Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, CINBIO and IBI, As Lagoas-Marcosende, 36310 Vigo (Spain).
authors.forename: Claudio
authors.initials: C
authors.lastname: Martínez
authors.affiliation: Department of Cancer Biology, Institut de Génetique et de Biologie Moleculaire et Cellulaire (IGBMC)/CNRS/INSERM/ULP, BP 163, Ilkirch Cedex, C.U. de Strasbourg (France).
authors.forename: Harshal
authors.initials: H
authors.lastname: Khanwalkar
authors.affiliation: Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, CINBIO and IBI, As Lagoas-Marcosende, 36310 Vigo (Spain).
authors.forename: Fátima
authors.initials: F
authors.lastname: Rodríguez-Barrios
authors.affiliation: Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, CINBIO and IBI, As Lagoas-Marcosende, 36310 Vigo (Spain). qolera@uvigo.es.
authors.forename: Rosana
authors.initials: R
authors.lastname: Álvarez
authors.affiliation: Department of Cancer Biology, Institut de Génetique et de Biologie Moleculaire et Cellulaire (IGBMC)/CNRS/INSERM/ULP, BP 163, Ilkirch Cedex, C.U. de Strasbourg (France). hinrich.gronemeyer@igbmc.fr.
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
authors.affiliation: Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, CINBIO and IBI, As Lagoas-Marcosende, 36310 Vigo (Spain). rar@uvigo.es.
authors.forename: Angel R
authors.initials: AR
authors.lastname: de Lera
mesh_terms: D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D009281:Naphthalenes / Q000737:chemistry; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation
chemical_list: D001565:Benzoates; D008024:Ligands; D009281:Naphthalenes; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C082925:retinoic acid receptor beta; C031721:naphthalene
keywords: agonists; antagonists; arotinoids; naphthalenes; retinoid receptors; transactivation