title: Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity.
abstract: (2E,4E,6Z,8E)-8-(3',4'-Dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring. The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRα. We demonstrate that each homologue of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.
authors.affiliation: Departments of †Chemistry, ‡Biochemistry and Molecular Genetics, §Medicine, and ∥Vision Sciences, University of Alabama at Birmingham , Birmingham, Alabama 35294, United States.
authors.forename: Venkatram R
authors.initials: VR
authors.lastname: Atigadda
authors.forename: Gang
authors.initials: G
authors.lastname: Xia
authors.forename: Anil
authors.initials: A
authors.lastname: Desphande
authors.forename: LeeAnn J
authors.initials: LJ
authors.lastname: Boerma
authors.forename: Susan
authors.initials: S
authors.lastname: Lobo-Ruppert
authors.forename: Clinton J
authors.initials: CJ
authors.lastname: Grubbs
authors.forename: Craig D
authors.initials: CD
authors.lastname: Smith
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Brouillette
authors.forename: Donald D
authors.initials: DD
authors.lastname: Muccio
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D000077610:Bexarotene; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D018360:Crystallography, X-Ray; D005231:Fatty Acids, Unsaturated / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D006801:Humans; D006949:Hyperlipidemias / Q000139:chemically induced*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D047490:Retinoid X Receptor alpha / Q000819:agonists* / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000494:pharmacology / Q000633:toxicity; D015533:Transcriptional Activation
chemical_list: D016588:Anticarcinogenic Agents; D005231:Fatty Acids, Unsaturated; D009281:Naphthalenes; D047490:Retinoid X Receptor alpha; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene; C112106:UAB 30