title: ΔF508-CFTR correctors: synthesis and evaluation of thiazole-tethered imidazolones, oxazoles, oxadiazoles, and thiadiazoles.
abstract: The most common mutation causing cystic fibrosis (CF) is deletion of phenylalanine residue 508 in the cystic fibrosis transmembrane regulator conductance (CFTR) protein. Small molecules that are able to correct the misfolding of defective ΔF508-CFTR have considerable promise for therapy. Reported here are the design, preparation, and evaluation of five more hydrophilic bisazole analogs of previously identified bithiazole CF corrector 1. Interestingly, bisazole ΔF508-CFTR corrector activity was not increased by incorporation of more H-bond acceptors (O or N), but correlated best with the overall bisazole molecular geometry. The structure activity data, together with molecular modeling, suggested that active bisazole correctors adopt a U-shaped conformation, and that corrector activity depends on the molecule's ability to access this molecular geometry.
authors.affiliation: Department of Chemistry, College of Chemical Engineering and Technology, Wuhan University of Science and Technology, Wuhan, Hubei 430081, PR China. Electronic address: yelong@wust.edu.cn.
authors.forename: Long
authors.initials: L
authors.lastname: Ye
authors.affiliation: Department of Chemistry, College of Chemical Engineering and Technology, Wuhan University of Science and Technology, Wuhan, Hubei 430081, PR China.
authors.forename: Bao
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Chemistry, University of California, One Shields Ave, Davis, CA 95616, United States.
authors.forename: Faris
authors.initials: F
authors.lastname: El-Badri
authors.affiliation: Department of Chemistry, University of California, One Shields Ave, Davis, CA 95616, United States.
authors.forename: Brandi M
authors.initials: BM
authors.lastname: Hudson
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94143-0521, United States; Department Physiology, University of California, San Francisco, CA 94143-0521, United States.
authors.forename: Puay-Wah
authors.initials: PW
authors.lastname: Phuan
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94143-0521, United States; Department Physiology, University of California, San Francisco, CA 94143-0521, United States.
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
authors.affiliation: Department of Chemistry, University of California, One Shields Ave, Davis, CA 95616, United States.
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Tantillo
authors.affiliation: Department of Chemistry, University of California, One Shields Ave, Davis, CA 95616, United States. Electronic address: mjkurth@ucdavis.edu.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kurth
mesh_terms: D003550:Cystic Fibrosis / Q000378:metabolism / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008968:Molecular Conformation; D010069:Oxadiazoles / Q000737:chemistry* / Q000378:metabolism; D010080:Oxazoles / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013830:Thiadiazoles / Q000737:chemistry* / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D007093:Imidazoles; D010069:Oxadiazoles; D010080:Oxazoles; D013830:Thiadiazoles; D013844:Thiazoles; C093349:cystic fibrosis transmembrane conductance regulator delta F508; C117197:imidazolone; D014867:Water; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: C,C-linked bisazoles; Correctors; Cystic fibrosis; Transmembrane regulator