title: Synthesis of isosteric selenium analog of the PPARbeta/delta agonist GW501516 and comparison of biological activity.
abstract: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear hormone receptor superfamily. Herein, we describe an efficient synthesis of a novel isosteric selenium analog of the highly specific PPARbeta/delta ligand 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (GW501516; 1). The study examined the efficiency of the novel selenium analog 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-selenazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (2) to activate PPARbeta/delta and the effect of ligand activation of PPARbeta/delta on cell proliferation and target gene expression in human HaCaT keratinocytes. The results showed that similar to GW501516, the Se-analog 2 increased expression of the known PPARbeta/delta target gene angiopoietin-like protein 4 (ANGPTL4); the compound 2 was comparable in efficacy as compared to GW501516. Consistent with a large body of evidence, the Se-analog inhibited cell proliferation in HaCaT keratinocytes similar to that observed with GW501516. In summary, the novel Se-analog 2 has been developed as a potent PPARbeta/delta ligand that may possess additional anti-cancer properties of selenium.
authors.affiliation: Department of Pharmacology, Chemical Carcinogenesis and Chemoprevention Program of Penn State Hershey Cancer Institute, Penn State College of Medicine, CH72, 500 University Drive, Hershey, PA 17033, USA. aks14@psu.edu
authors.forename: Arun K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Ugir Hossain
authors.initials: UH
authors.lastname: Sk
authors.forename: Pengfei
authors.initials: P
authors.lastname: He
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists*; D048068:PPAR-beta / Q000819:agonists*; D012643:Selenium / Q000737:chemistry*; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C425931:GW 501516; D047494:PPAR delta; D048068:PPAR-beta; D013844:Thiazoles; D012643:Selenium