{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:51:43Z","timestamp":1760316703784,"version":"build-2065373602"},"reference-count":62,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2015,5,26]],"date-time":"2015-05-26T00:00:00Z","timestamp":1432598400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2015,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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\u2010<jats:italic>trans<\/jats:italic>\u2010retinoic 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\u2010cell lymphoma (CTCL). Other retinoids have found applications in the topical treatment of skin disorders. In continuation of previous work on the naphthalene\u2010based arotinoid scaffold, we synthesized a new series of (3\u2010halo)benzoic acids connected to C5\u2010 or C8\u2010substituted naphthyl rings via (<jats:italic>E<\/jats:italic>)\u2010ethenyl and amide and, for the C5 series, (<jats:italic>E<\/jats:italic>)\u2010chalcone 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\u2010halogenated 4\u2010(2\u2010naphthamido)benzoic acid derivatives transactivated toward the RAR\u03b2 subtype in preference to the paralogues. The derivatives with bulkier substituents at C8 were characterized as dual RAR\u03b2\/RAR\u03b1 antagonists, and (<jats:italic>E<\/jats:italic>)\u20104\u2010[(8\u2010(phenylethynyl)naphthalene\u20102\u2010yl)ethenyl]benzoic acid (<jats:bold>11\u2009c<\/jats:bold>), with an ethenyl connector, was shown to be a potent antagonist of RAR\u03b1.<\/jats:p>","DOI":"10.1002\/cmdc.201500150","type":"journal-article","created":{"date-parts":[[2015,5,27]],"date-time":"2015-05-27T11:59:50Z","timestamp":1432727990000},"page":"1378-1391","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Modulation of Retinoic Acid Receptor Subtypes by 5\u2010 and 8\u2010Substituted (Naphthalen\u20102\u2010yl)\u2010based Arotinoids"],"prefix":"10.1002","volume":"10","author":[{"given":"Susana","family":"\u00c1lvarez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele","family":"Lieb","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harshal","family":"Khanwalkar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F\u00e1tima","family":"Rodr\u00edguez\u2010Barrios","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosana","family":"\u00c1lvarez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hinrich","family":"Gronemeyer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angel R.","family":"de\u2005Lera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,5,26]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.03.012"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.58.4.4"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.58.4.7"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.3390\/nu3040385"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.065938"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12037"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2397"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr400126u"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/35106036"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1040-8428(01)00144-5"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.46.120604.141156"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-011110-130303"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr400161b"},{"volume-title":"The Nuclear Receptor Facts Book","year":"2002","author":"Laudet V.","key":"e_1_2_6_14_2"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1551"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1043-2760(01)00527-6"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00064-7"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2003-0023"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015119"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2009.03.008"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1855"},{"key":"e_1_2_6_22_2","first-page":"485","volume-title":"Methods in Enzymology","author":"Agonists \u201cInverse","year":"2010"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2011.04.003"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.2174\/156802612799436687"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/415187a"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(04)00119-9"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.200900214"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2009.05.035"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1995.tb07102.x"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1359-6446(02)02526-6"},{"key":"e_1_2_6_31_2","first-page":"9","volume":"15","author":"Loeliger P.","year":"1980","journal-title":"Eur. 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