{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T10:54:15Z","timestamp":1785840855482,"version":"3.56.0"},"reference-count":82,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T00:00:00Z","timestamp":1671408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"publisher","award":["1 R15 CA139364-01A2"],"award-info":[{"award-number":["1 R15 CA139364-01A2"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"publisher","award":["1R15CA249617-01"],"award-info":[{"award-number":["1R15CA249617-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL128447"],"award-info":[{"award-number":["R01 HL128447"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Siteman Investment Program","award":["1 R15 CA139364-01A2"],"award-info":[{"award-number":["1 R15 CA139364-01A2"]}]},{"name":"Siteman Investment Program","award":["1R15CA249617-01"],"award-info":[{"award-number":["1R15CA249617-01"]}]},{"name":"Siteman Investment Program","award":["R01 HL128447"],"award-info":[{"award-number":["R01 HL128447"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Bexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene analogs, as well as three unique CD3254 analogs and thirteen novel NEt-TMN analogs, were synthesized and characterized for their ability to induce RXR agonism in comparison to bexarotene (1). Several analogs in all three groups possessed an isochroman ring substitution for the bexarotene aliphatic group. Analogs were modeled for RXR binding affinity, and EC50 as well as IC50 values were established for all analogs in a KMT2A-MLLT3 leukemia cell line. All analogs were assessed for liver-X-receptor (LXR) activity in an LXRE system to gauge the potential for the compounds to provoke raised triglycerides by increasing LXR activity, as well as to drive LXRE-mediated transcription of brain ApoE expression as a marker for potential therapeutic use in neurodegenerative disorders. Preliminary results suggest these compounds display a broad spectrum of off-target activities. However, many of the novel compounds were observed to be more potent than 1. While some RXR agonists cross-signal the retinoic acid receptor (RAR), many of the rexinoids in this work displayed reduced RAR activity. The isochroman group did not appear to substantially reduce RXR activity on its own. The results of this study reveal that modifying potent, selective rexinoids like bexarotene, CD3254, and NEt-TMN can provide rexinoids with increased RXR selectivity, decreased potential for cross-signaling, and improved anti-proliferative characteristics in leukemia models compared to 1.<\/jats:p>","DOI":"10.3390\/ijms232416213","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T07:59:21Z","timestamp":1671436761000},"page":"16213","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4950-9161","authenticated-orcid":false,"given":"Peter W.","family":"Jurutka","sequence":"first","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"},{"name":"Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7620-0290","authenticated-orcid":false,"given":"Orsola","family":"di Martino","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Washington University, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabeeha","family":"Reshi","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanchita","family":"Mallick","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Sausedo","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2930-6444","authenticated-orcid":false,"given":"Grant A.","family":"Moen","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac J.","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic J.","family":"Ivan","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler D.","family":"Krall","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel J.","family":"Peoples","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"},{"name":"School of Molecular Sciences, Arizona State University, Tempe, AZ 85281, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Perez","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Tromba","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anh","family":"Le","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iraj","family":"Khadka","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Petros","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianna M.","family":"Savage","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleine","family":"Salama","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakline","family":"Salama","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph W.","family":"Ziller","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of California, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngbin","family":"Noh","sequence":"additional","affiliation":[{"name":"School of Molecular Sciences, Arizona State University, Tempe, AZ 85281, 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl E.","family":"Wagner","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.cell.2014.03.012","article-title":"Nuclear Receptors, RXR, and the Big Bang","volume":"157","author":"Evans","year":"2014","journal-title":"Cell"},{"key":"ref_2","unstructured":"Mangelsdorf, D.J., Umesono, K., and Evans, R.M. (1994). The Retinoids, Academic Press."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/0968-0004(92)90014-Z","article-title":"Multiplicity generates diversity in the retinoic acid signalling pathways","volume":"17","author":"Leid","year":"1992","journal-title":"Trends Biochem. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"36863","DOI":"10.1074\/jbc.R100047200","article-title":"Nuclear Receptor Minireview Series","volume":"276","author":"Olefsky","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1101\/gad.7.7b.1411","article-title":"Determinants for selective RAR and TR recognition of direct repeat HREs","volume":"7","author":"Perlmann","year":"1993","journal-title":"Genes Dev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.mce.2009.11.010","article-title":"DNA recognition by thyroid hormone and retinoic acid receptors: 3,4,5 rule modified","volume":"319","author":"Phan","year":"2010","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1210\/mend-3-10-1610","article-title":"A Domain Containing Leucine-Zipper-Like Motifs Mediate Novel in Vivo Interactions between the Thyroid Hormone and Retinoic Acid Receptors","volume":"3","author":"Forman","year":"1989","journal-title":"Mol. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/0092-8674(95)90200-7","article-title":"The RXR heterodimers and orphan receptors","volume":"83","author":"Mangelsdorf","year":"1995","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/358587a0","article-title":"Homodimer formation of retinoid X receptor induced by 9-cis retinoic acid","volume":"358","author":"Zhang","year":"1992","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1677\/jme.0.0270211","article-title":"Distinct retinoid X receptor activation function-2 residues mediate transactivation in homodimeric and vitamin D receptor heterodimeric contexts","volume":"27","author":"Thompson","year":"2001","journal-title":"J. Mol. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4625","DOI":"10.1093\/emboj\/cdg456","article-title":"Crystal structure of the heterodimeric complex of LXR\u03b1 and RXR\u03b2 ligand-binding domains in a fully agonistic conformation","volume":"22","author":"Svensson","year":"2003","journal-title":"EMBO J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"17323","DOI":"10.1073\/pnas.0705356104","article-title":"Modulators of the structural dynamics of the retinoid X receptor to reveal receptor function","volume":"104","author":"Nahoum","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/0092-8674(95)90075-6","article-title":"Unique response pathways are established by allosteric interactions among nuclear hormone receptors","volume":"81","author":"Forman","year":"1995","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/383450a0","article-title":"Activation of specific RXR heterodimers by an antagonist of RXR homodimers","volume":"383","author":"Lala","year":"1996","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1128\/MCB.16.3.1006","article-title":"Selective effects of ligands on vitamin D3 receptor- and retinoid X receptor-mediated gene activation in vivo","volume":"16","author":"Lemon","year":"1996","journal-title":"Mol. Cell. Biol."},{"key":"ref_16","first-page":"5907","article-title":"Retinoid X receptors stimulate and 9-cis retinoic acid inhibits 1,25-dihydroxyvitamin D3-activated expression of the rat osteocalcin gene","volume":"13","author":"MacDonald","year":"1993","journal-title":"Mol. Cell. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8483","DOI":"10.1074\/jbc.273.14.8483","article-title":"Heterodimeric DNA Binding by the Vitamin D Receptor and Retinoid X Receptors Is Enhanced by 1,25-Dihydroxyvitamin D3 and Inhibited by 9-cis-Retinoic Acid: Evidence for Allosteric Receptor Interactions","volume":"273","author":"Thompson","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_18","first-page":"7698","article-title":"Formation of retinoid X receptor homodimers leads to repression of T3 response: Hormonal cross talk by ligand-induced squelching","volume":"13","author":"Lehmann","year":"1993","journal-title":"Mol. Cell. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10910","DOI":"10.1074\/jbc.271.18.10910","article-title":"Vitamin D receptors repress basal transcription and exert dominant negative activity on triiodothyronine-mediated transcriptional activity","volume":"271","author":"Yen","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1210\/mend.12.9.0165","article-title":"Thyroid hormone receptor does not heterodimerize with the vitamin D receptor but represses vitamin D receptor-mediated transactivation","volume":"12","author":"Freedman","year":"1998","journal-title":"Mol. Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1002\/(SICI)1097-4644(19991201)75:3<462::AID-JCB11>3.0.CO;2-D","article-title":"Vitamin D receptor displays DNA binding and transactivation as a heterodimer with the retinoid X receptor, but not with the thyroid hormone receptor","volume":"75","author":"Thompson","year":"1999","journal-title":"J. Cell. Biochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/nrd2397","article-title":"RAR and RXR modulation in cancer and metabolic disease","volume":"6","author":"Altucci","year":"2007","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1126\/science.1335166","article-title":"Retinoids selective for retinoid X receptor response pathways","volume":"258","author":"Lehmann","year":"1992","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2605","DOI":"10.1021\/jm00070a003","article-title":"Conformational effects on retinoid receptor selectivity. 1. Effect of 9-double bond geometry on retinoid X receptor activity","volume":"36","author":"Jong","year":"1993","journal-title":"J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3368","DOI":"10.1021\/jm00017a021","article-title":"Conformational Effects on Retinoid Receptor Selectivity. 2. Effects of Retinoid Bridging Group on Retinoid X Receptor Activity and Selectivity","volume":"38","author":"Dawson","year":"1995","journal-title":"J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2930","DOI":"10.1021\/jm00044a014","article-title":"Synthesis and Structure-Activity Relationships of Novel Retinoid X Receptor-Selective Retinoids","volume":"37","author":"Boehm","year":"1994","journal-title":"J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3192","DOI":"10.1021\/om040143k","article-title":"Synthesis, Crystal Structure Analysis, and Pharmacological Characterization of Disila-bexarotene, a Disila-Analogue of the RXR-Selective Retinoid Agonist Bexarotene","volume":"24","author":"Daiss","year":"2005","journal-title":"Organometallics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1158\/1940-6207.CAPR-18-0317","article-title":"Testing Novel Pyrimidinyl Rexinoids: A New Paradigm for Evaluating Rexinoids for Cancer Prevention","volume":"12","author":"Zhang","year":"2019","journal-title":"Cancer Prev. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s10549-004-1426-5","article-title":"Synergistic effect of a retinoid X receptor-selective ligand bexarotene (LGD1069, Targretin) and paclitaxel (Taxol) in mammary carcinoma","volume":"88","author":"Yen","year":"2004","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.canlet.2005.09.010","article-title":"Differentiation and growth inhibition mediated via the RXR:PPAR\u03b3 heterodimer in colon cancer","volume":"240","author":"Cesario","year":"2006","journal-title":"Cancer Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8656","DOI":"10.1158\/1078-0432.CCR-04-0979","article-title":"A Selective Retinoid X Receptor Agonist Bexarotene (Targretin) Prevents and Overcomes Acquired Paclitaxel (Taxol) Resistance in Human Non\u2013Small Cell Lung Cancer","volume":"10","author":"Yen","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1158\/1078-0432.CCR-06-1836","article-title":"A Proof-of-Principle Clinical Trial of Bexarotene in Patients with Non\u2013Small Cell Lung Cancer","volume":"13","author":"Dragnev","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/386407a0","article-title":"Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists","volume":"386","author":"Mukherjee","year":"1997","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1056\/NEJM199904083401404","article-title":"Central Hypothyroidism Associated with Retinoid X Receptor\u2013Selective Ligands","volume":"340","author":"Sherman","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5782","DOI":"10.1128\/MCB.22.16.5782-5792.2002","article-title":"Functional Evidence for Retinoid X Receptor (RXR) as a Nonsilent Partner in the Thyroid Hormone Receptor\/RXR Heterodimer","volume":"22","author":"Li","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1194\/jlr.M300473-JLR200","article-title":"LXR\/RXR ligand activation enhances basolateral efflux of beta-sitosterol in CaCo-2 cells","volume":"45","author":"Field","year":"2004","journal-title":"J. Lipid Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1194\/jlr.M100358-JLR200","article-title":"LXR\/RXR activation enhances basolateral efflux of cholesterol in CaCo-2 cells","volume":"43","author":"Murthy","year":"2002","journal-title":"J. Lipid Res."},{"key":"ref_38","first-page":"528","article-title":"Receptor Specificity of Retinoid-Induced Epidermal Hyperplasia: Effect of RXR-Selective Agonists and Correlation with Topical Irritation","volume":"282","author":"Thacher","year":"1997","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1126\/science.1217697","article-title":"ApoE-Directed Therapeutics Rapidly Clear \u03b2-Amyloid and Reverse Deficits in AD Mouse Models","volume":"335","author":"Cramer","year":"2012","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1021\/cn400100f","article-title":"Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson\u2019s Disease","volume":"4","author":"McFarland","year":"2013","journal-title":"ACS Chem. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s13195-016-0173-2","article-title":"Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer\u2019s disease","volume":"8","author":"Cummings","year":"2016","journal-title":"Alzheimers Res. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5073","DOI":"10.1200\/jco.2014.32.15_suppl.5073","article-title":"An open-label phase II clinical trial of the RXR agonist IRX4204 in taxane-resistant, castration-resistant metastatic prostate cancer (CRPC)","volume":"32","author":"Kabbinavar","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.1021\/jm0100584","article-title":"Enantioselective syntheses of potent retinoid X receptor ligands: Differential biological activities of individual antipodes","volume":"44","author":"Vuligonda","year":"2001","journal-title":"J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1021\/jm970635h","article-title":"Conformationally Defined Retinoic Acid Analogues. 4. Potential New Agents for Acute Promyelocytic and Juvenile Myelomonocytic Leukemias","volume":"41","author":"Muccio","year":"1998","journal-title":"J. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3766","DOI":"10.1021\/jm030095q","article-title":"Conformationally Defined Retinoic Acid Analogues. 5. Large-Scale Synthesis and Mammary Cancer Chemopreventive Activity for (2E,4E,6Z,8E)-8-(3\u2018,4\u2018-Dihydro-1\u2018(2\u2018H)-naphthalen-1\u2018-ylidene)-3,7-dimethyl-2,4,6-octatrienoic Acid (9cUAB30)","volume":"46","author":"Atigadda","year":"2003","journal-title":"J. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1158\/1940-6207.CAPR-10-0149","article-title":"A Pilot, First-in-Human, Pharmacokinetic Study of 9cUAB30 in Healthy Volunteers","volume":"3","author":"Kolesar","year":"2010","journal-title":"Cancer Prev. Res."},{"key":"ref_47","first-page":"641","article-title":"The low-toxicity 9-cis UAB30 novel retinoid down-regulates the DNA methyltransferases and has anti-telomerase activity in human breast cancer cells","volume":"30","author":"Hansen","year":"2007","journal-title":"Int. J. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5370","DOI":"10.1021\/jm5004792","article-title":"Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity","volume":"57","author":"Atigadda","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.bmc.2013.11.039","article-title":"Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention","volume":"22","author":"Desphande","year":"2014","journal-title":"Bioorganic Med. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2683","DOI":"10.1021\/jm020340q","article-title":"Novel (2E,4E,6Z)-7-(2-alkoxy-3,5-dialkylbenzene)-3-methylocta-2,4,6-trienoic acid retinoid X receptor modulators are active in models of type 2 diabetes","volume":"46","author":"Michellys","year":"2003","journal-title":"J. Med. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4087","DOI":"10.1021\/jm020401k","article-title":"Design, synthesis, and structure-activity relationship studies of novel 6,7-locked-[7-(2-alkoxy-3,5-dialkylbenzene)-3-methylocta]-2,4,6-trienoic acids","volume":"46","author":"Michellys","year":"2003","journal-title":"J. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1016\/j.bmcl.2003.12.089","article-title":"Design, synthesis and structure-activity relationship of novel RXR-selective modulators","volume":"14","author":"Michellys","year":"2004","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5950","DOI":"10.1021\/jm900496b","article-title":"Modeling, Synthesis and Biological Evaluation of Potential Retinoid X Receptor (RXR) Selective Agonists: Novel Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene)","volume":"52","author":"Wagner","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1002\/cmdc.201200319","article-title":"Modeling, Synthesis and Biological Evaluation of Potential Retinoid\u2005X Receptor-Selective Agonists: Novel Halogenated Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene)","volume":"7","author":"Furmick","year":"2012","journal-title":"ChemMedChem"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3146","DOI":"10.1021\/jm00016a018","article-title":"Design and Synthesis of Potent Retinoid X Receptor Selective Ligands That Induce Apoptosis in Leukemia Cells","volume":"38","author":"Boehm","year":"1995","journal-title":"J. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"8432","DOI":"10.1021\/jm4008517","article-title":"Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR) Selective Agonists: Novel Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic Acid (CD3254)","volume":"56","author":"Jurutka","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"5902","DOI":"10.1158\/1078-0432.CCR-06-1119","article-title":"The Combination of the Rexinoid, LG100268, and a Selective Estrogen Receptor Modulator, Either Arzoxifene or Acolbifene, Synergizes in the Prevention and Treatment of Mammary Tumors in an Estrogen Receptor\u2013Negative Model of Breast Cancer","volume":"12","author":"Liby","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1002\/jlcr.2580360712","article-title":"Syntheses of isotopically labeled 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzoic acid (LGD1069), a potent retinoid x receptor-selective ligand","volume":"36","author":"Zhang","year":"1995","journal-title":"J. Label. Comp. Radiopharm."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"5772","DOI":"10.1021\/jo0103064","article-title":"Synthesis of Novel Retinoid X Receptor-Selective Retinoids","volume":"66","author":"Faul","year":"2001","journal-title":"J. Org. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e00122","DOI":"10.1002\/prp2.122","article-title":"Analysis of differential secondary effects of novel rexinoids: Select rexinoid X receptor ligands demonstrate differentiated side effect profiles","volume":"3","author":"Marshall","year":"2015","journal-title":"Pharm. Res. Perspect."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3150","DOI":"10.1021\/jm900096q","article-title":"Modulating Retinoid X Receptor with a Series of (E)-3-[4-Hydroxy-3-(3-alkoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]acrylic Acids and Their 4-Alkoxy Isomers","volume":"52","author":"Germain","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/sj.cdd.4400673","article-title":"Retinoid-dependent growth inhibition, differentiation and apoptosis in acute promyelocytic leukemia cells. Expression and activation of caspases","volume":"7","author":"Gianni","year":"2000","journal-title":"Cell Death Differ."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"5139","DOI":"10.1016\/j.bmcl.2010.07.012","article-title":"Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation","volume":"20","author":"Fujii","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1021\/ml100184k","article-title":"Modification at the Lipophilic Domain of RXR Agonists Differentially Influences Activation of RXR Heterodimers","volume":"1","author":"Ohsawa","year":"2010","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1021\/ml300055n","article-title":"RXR Partial Agonist CBt-PMN Exerts Therapeutic Effects on Type 2 Diabetes without the Side Effects of RXR Full Agonists","volume":"3","author":"Kakuta","year":"2012","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1021\/jm400033f","article-title":"Mechanism of Retinoid X Receptor Partial Agonistic Action of 1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic Acid and Structural Development To Increase Potency","volume":"56","author":"Ohsawa","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_67","unstructured":"Kagechika, H., Koichi, S., Sugioka, T., Sotome, T., Nakayama, Y., and Doi, K. (1998). Retinoid Activity Regulators. (WO9845242A1), European Patent."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1248\/bpb.21.544","article-title":"Potent Retinoid Synergists with a Diphenylamine Skeleton","volume":"21","author":"Ohta","year":"1998","journal-title":"Biol. Pharm. Bull."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.1016\/j.bmc.2011.03.026","article-title":"Diphenylamine-based retinoid antagonists: Regulation of RAR and RXR function depending on the N-substituent","volume":"19","author":"Ohta","year":"2011","journal-title":"Bioorg. Med. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"8924","DOI":"10.1021\/acs.jmedchem.6b00812","article-title":"Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists: Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN)","volume":"59","author":"Heck","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1248\/cpb.48.1504","article-title":"Retinoidal pyrimidinecarboxylic acids. Unexpected diaza-substituent effects in retinobenzoic acids","volume":"48","author":"Ohta","year":"2000","journal-title":"Chem. Pharm. Bull."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1021\/ml100164p","article-title":"Drawing the PDB: Protein\u2212Ligand Complexes in Two Dimensions","volume":"1","author":"Stierand","year":"2010","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1002\/cmdc.200700010","article-title":"From Modeling to Medicinal Chemistry: Automatic Generation of Two-Dimensional Complex Diagrams","volume":"2","author":"Stierand","year":"2007","journal-title":"ChemMedChem"},{"key":"ref_75","unstructured":"Tachdjian, C., Guo, J., Boudjelal, M., Al-Shamma, H.A., Giachino, A.F., Jakubowicz-Jaillardon, K., Chen, Q., Zapf, J.W., and Pfahl, M. (2004). Preparation of Substituted Isochroman Compounds for the Treatment of Metabolic Disorders, Cancer and Other Diseases. (CN1774246A), Patent."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Jurutka, P.W., di Martino, O., Reshi, S., Mallick, S., Sabir, Z.L., Staniszewski, L.J.P., Warda, A., Maiorella, E.L., Minasian, A., and Davidson, J. (2021). Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB). Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212371"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2592","DOI":"10.1093\/emboj\/19.11.2592","article-title":"Crystal structure of the human RXRalpha ligand-binding domain bound to its natural ligand: 9-cis retinoic acid","volume":"19","author":"Egea","year":"2000","journal-title":"EMBO J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1002\/prot.21645","article-title":"Automated prediction of ligand-binding sites in proteins","volume":"70","author":"Harris","year":"2008","journal-title":"Proteins Struct. Funct. Bioinf."},{"key":"ref_79","first-page":"1008","article-title":"Endogenous and combination retinoids are active in myelomonocytic leukemias","volume":"106","author":"Niu","year":"2021","journal-title":"Haematologica"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"417","DOI":"10.3324\/haematol.2021.278603","article-title":"RXRA DT448\/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells","volume":"107","author":"Ferris","year":"2021","journal-title":"Haematologica"},{"key":"ref_81","unstructured":"Wilson, A.J.C., Hahn, T., Wilson, A.J.C., Shmueli, U., and Crystallography, I.U.O. (1992). International Tables for Crystallography, Volume C: Mathematical, Physical and Chemical Tables, Springer."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1107\/S2052519213010014","article-title":"Use of intensity quotients and differences in absolute structure refinement","volume":"69","author":"Parsons","year":"2013","journal-title":"Acta Crystallogr. Sect. B Struct. Sci. Cryst. Eng. Mater."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/16213\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:44:12Z","timestamp":1760147052000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/16213"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,19]]},"references-count":82,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ijms232416213"],"URL":"https:\/\/doi.org\/10.3390\/ijms232416213","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,19]]}}}