C-H activation generates period-shortening molecules that target cryptochrome in the mammalian circadian clock

Tsuyoshi Oshima, Iori Yamanaka, Anupriya Kumar, Junichiro Yamaguchi, Taeko Nishiwaki-Ohkawa, Kei Muto, Rika Kawamura, Tsuyoshi Hirota, Kazuhiro Yagita, Stephan Irle, Steve A. Kay, Takashi Yoshimura, Kenichiro Itami

Research output: Contribution to journalArticle

22 Citations (Scopus)

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. A change in rhythm: The first functional analysis of KL001 derivatives, which are mammalian circadian-clock modulators, was enabled by cutting-edge CH activation. The sites of the KL001 derivatives that are critical for their rhythm-changing activity were elucidated, which led to the discovery of the first period-shortening molecules that target the cryptochrome.

Original languageEnglish
Pages (from-to)7193-7197
Number of pages5
JournalAngewandte Chemie - International Edition
Volume54
Issue number24
DOIs
Publication statusPublished - 2015 Jun 1
Externally publishedYes

Fingerprint

Cryptochromes
Clocks
Chemical activation
Derivatives
Molecules
Functional analysis
Modulators
KL001

Keywords

  • circadian clock
  • cryptochrome
  • CH activation
  • small-molecule modulators
  • structure-activity relationships

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis

Cite this

C-H activation generates period-shortening molecules that target cryptochrome in the mammalian circadian clock. / Oshima, Tsuyoshi; Yamanaka, Iori; Kumar, Anupriya; Yamaguchi, Junichiro; Nishiwaki-Ohkawa, Taeko; Muto, Kei; Kawamura, Rika; Hirota, Tsuyoshi; Yagita, Kazuhiro; Irle, Stephan; Kay, Steve A.; Yoshimura, Takashi; Itami, Kenichiro.

In: Angewandte Chemie - International Edition, Vol. 54, No. 24, 01.06.2015, p. 7193-7197.

Research output: Contribution to journalArticle

Oshima, T, Yamanaka, I, Kumar, A, Yamaguchi, J, Nishiwaki-Ohkawa, T, Muto, K, Kawamura, R, Hirota, T, Yagita, K, Irle, S, Kay, SA, Yoshimura, T & Itami, K 2015, 'C-H activation generates period-shortening molecules that target cryptochrome in the mammalian circadian clock', Angewandte Chemie - International Edition, vol. 54, no. 24, pp. 7193-7197. https://doi.org/10.1002/anie.201502942
Oshima, Tsuyoshi ; Yamanaka, Iori ; Kumar, Anupriya ; Yamaguchi, Junichiro ; Nishiwaki-Ohkawa, Taeko ; Muto, Kei ; Kawamura, Rika ; Hirota, Tsuyoshi ; Yagita, Kazuhiro ; Irle, Stephan ; Kay, Steve A. ; Yoshimura, Takashi ; Itami, Kenichiro. / C-H activation generates period-shortening molecules that target cryptochrome in the mammalian circadian clock. In: Angewandte Chemie - International Edition. 2015 ; Vol. 54, No. 24. pp. 7193-7197.
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