title: C-H activation generates period-shortening molecules that target cryptochrome in the mammalian circadian clock.
abstract: The synthesis and functional analysis of KL001 derivatives, which are modulators of the mammalian circadian clock, are described. By using cutting-edge C-H activation chemistry, a focused library of KL001 derivatives was rapidly constructed, which enabled the identification of the critical sites on KL001 derivatives that induce a rhythm-changing activity along with the components that trigger opposite modes of action. The first period-shortening molecules that target the cryptochrome (CRY) were thus discovered. Detailed studies on the effects of these compounds on CRY stability implicate the existence of an as yet undiscovered regulatory mechanism.
authors.affiliation: Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya, 464-8601 (Japan).|Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa, Nagoya, 464-8602 (Japan).
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Oshima
authors.affiliation: Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya, 464-8601 (Japan).
authors.forename: Iori
authors.initials: I
authors.lastname: Yamanaka
authors.affiliation: Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya, 464-8601 (Japan).
authors.forename: Anupriya
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya, 464-8601 (Japan).|Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa, Nagoya, 464-8602 (Japan).
authors.forename: Junichiro
authors.initials: J
authors.lastname: Yamaguchi
authors.affiliation: Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya, 464-8601 (Japan).|Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya, 464-8601 (Japan).
authors.forename: Taeko
authors.initials: T
authors.lastname: Nishiwaki-Ohkawa
authors.affiliation: Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya, 464-8601 (Japan).|Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa, Nagoya, 464-8602 (Japan).
authors.forename: Kei
authors.initials: K
authors.lastname: Muto
authors.affiliation: Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya, 464-8601 (Japan).|Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya, 464-8601 (Japan).
authors.forename: Rika
authors.initials: R
authors.lastname: Kawamura
authors.affiliation: Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya, 464-8601 (Japan).|JST, PRESTO, Chikusa, Nagoya, 464-8602 (Japan).
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hirota
authors.affiliation: Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566 (Japan).
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yagita
authors.affiliation: Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya, 464-8601 (Japan). sirle@chem.nagoya-u.ac.jp.|Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa, Nagoya, 464-8602 (Japan). sirle@chem.nagoya-u.ac.jp.
authors.forename: Stephan
authors.initials: S
authors.lastname: Irle
authors.affiliation: Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya, 464-8601 (Japan).|Dornsife College of Letters, Arts and Sciences, University of Southern California, 3430 S. Vermont Avenue, Los Angeles, CA 90089-3301 (USA).
authors.forename: Steve A
authors.initials: SA
authors.lastname: Kay
authors.affiliation: Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya, 464-8601 (Japan). takashiy@agr.nagoya-u.ac.jp.|Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya, 464-8601 (Japan). takashiy@agr.nagoya-u.ac.jp.|National Institute for Basic Biology, Myodaiji-cho, Okazaki 444-8585 (Japan). takashiy@agr.nagoya-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshimura
authors.affiliation: Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya, 464-8601 (Japan). itami@chem.nagoya-u.ac.jp.|Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa, Nagoya, 464-8602 (Japan). itami@chem.nagoya-u.ac.jp.|JST, ERATO, Itami Molecular Nanocarbon Project, Chikusa, Nagoya, 464-8602 (Japan). itami@chem.nagoya-u.ac.jp.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Itami
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics; D001665:Binding Sites; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002244:Carbon / Q000737:chemistry; D002460:Cell Line; D002940:Circadian Rhythm / Q000187:drug effects; D056931:Cryptochromes / Q000737:chemistry* / Q000378:metabolism; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D006859:Hydrogen / Q000737:chemistry; D008163:Luminescent Measurements; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D056930:ARNTL Transcription Factors; D002227:Carbazoles; D056931:Cryptochromes; C574808:KL001; D013449:Sulfonamides; D002244:Carbon; D006859:Hydrogen
keywords: CH activation; circadian clock; cryptochrome; small-molecule modulators; structure-activity relationships