title: Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention.
abstract: (2E,4E,6Z,8Z)-8-(3',4'-Dihydro-1'(2H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid, 9cUAB30, is a selective rexinoid for the retinoid X nuclear receptors (RXR). 9cUAB30 displays substantial chemopreventive capacity with little toxicity and is being translated to the clinic as a novel cancer prevention agent. To improve on the potency of 9cUAB30, we synthesized 4-methyl analogs of 9cUAB30, which introduced chirality at the 4-position of the tetralone ring. The syntheses and biological evaluations of the racemic homolog and enantiomers are reported. We demonstrate that the S-enantiomer is the most potent and least toxic even though these enantiomers bind in a similar conformation in the ligand binding domain of RXR.
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Desphande
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Xia
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: LeeAnn J
authors.initials: LJ
authors.lastname: Boerma
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Vines
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Venkatram R
authors.initials: VR
authors.lastname: Atigadda
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Lobo-Ruppert
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Clinton J
authors.initials: CJ
authors.lastname: Grubbs
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Fariba L
authors.initials: FL
authors.lastname: Moeinpour
authors.affiliation: Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Craig D
authors.initials: CD
authors.lastname: Smith
authors.affiliation: Department of Surgical Oncology, University of Illinois, Chicago, IL 60612, USA.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Christov
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: wbrou@uab.edu.
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Brouillette
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: muccio@uab.edu.
authors.forename: Donald D
authors.initials: DD
authors.lastname: Muccio
mesh_terms: D006801:Humans; D000090062:Kruppel-Like Factor 4; D008024:Ligands; D008968:Molecular Conformation; D009369:Neoplasms / Q000517:prevention & control* / Q000628:therapy*; D047488:Retinoid X Receptors / Q000378:metabolism*; D012176:Retinoids / Q000737:chemistry* / Q000378:metabolism
chemical_list: C000715467:KLF4 protein, human; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D008024:Ligands; D047488:Retinoid X Receptors; D012176:Retinoids
keywords: 2-iodoxybenzoic acid; Cancer prevention; Conformationally constrained retinoids; DMEM; Dulbecco’s modified Eagle medium; ER; GRIP-1; HMPA; IBX; KLF4; Kruppel-like factor 4; LBD; LBP; LXRs; Ligand–protein crystal structures; NR; PDB; RA; RAR; RKE; RMSD; RXR; Rexinoids; SCC; TG; THF; TLC; estrogen receptor; glucocorticoid receptor interacting protein-1; hexamethylphosphoramide; ligand binding domain; ligand binding pocket; liver X receptors; nuclear receptor; protein data bank; rat kidney epithelial; retinoic acid; retinoic acid receptor; retinoid X receptor; root mean square deviation; squamous cell carcinoma; tetrahydrofuran; thin layer chromatography; triglycerides