Volume 10, Issue 8 p. 1378-1391
Full Paper

Modulation of Retinoic Acid Receptor Subtypes by 5- and 8-Substituted (Naphthalen-2-yl)-based Arotinoids

Dr. Susana Álvarez

Dr. Susana Álvarez

Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, CINBIO and IBI, As Lagoas-Marcosende, 36310 Vigo (Spain)

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Michele Lieb

Michele Lieb

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)

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Dr. Claudio Martínez

Dr. Claudio Martínez

Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, CINBIO and IBI, As Lagoas-Marcosende, 36310 Vigo (Spain)

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Dr. Harshal Khanwalkar

Dr. Harshal Khanwalkar

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)

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Dr. Fátima Rodríguez-Barrios

Dr. Fátima Rodríguez-Barrios

Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, CINBIO and IBI, As Lagoas-Marcosende, 36310 Vigo (Spain)

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Prof. Dr. Rosana Álvarez

Corresponding Author

Prof. Dr. Rosana Álvarez

Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, CINBIO and IBI, As Lagoas-Marcosende, 36310 Vigo (Spain)

Rosana Álvarez, Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, CINBIO and IBI, As Lagoas-Marcosende, 36310 Vigo (Spain)

Hinrich Gronemeyer, 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)

Angel R. de Lera, Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, CINBIO and IBI, As Lagoas-Marcosende, 36310 Vigo (Spain)

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Dr. Hinrich Gronemeyer

Corresponding Author

Dr. Hinrich Gronemeyer

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)

Rosana Álvarez, Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, CINBIO and IBI, As Lagoas-Marcosende, 36310 Vigo (Spain)

Hinrich Gronemeyer, 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)

Angel R. de Lera, Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, CINBIO and IBI, As Lagoas-Marcosende, 36310 Vigo (Spain)

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Prof. Dr. Angel R. de Lera

Corresponding Author

Prof. Dr. Angel R. de Lera

Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, CINBIO and IBI, As Lagoas-Marcosende, 36310 Vigo (Spain)

Rosana Álvarez, Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, CINBIO and IBI, As Lagoas-Marcosende, 36310 Vigo (Spain)

Hinrich Gronemeyer, 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)

Angel R. de Lera, Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, CINBIO and IBI, As Lagoas-Marcosende, 36310 Vigo (Spain)

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First published: 26 May 2015
Citations: 3

Graphical Abstract

Aromatic retinoids! Arotinoids with hydrophobic naphthalene rings and bulky substituents at C8 were characterized as dual retinoic acid receptor (RAR) β/α antagonists. The analogue with an ethenyl connector, compound 11 c (stick format, in green), was found to be a particularly potent antagonist of RARα.

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.