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CH Activation Generates Period‐Shortening Molecules That Target Cryptochrome in the Mammalian Circadian Clock |
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| Authors: | Tsuyoshi Oshima Dr Iori Yamanaka Dr Anupriya Kumar Dr Junichiro Yamaguchi Dr Taeko Nishiwaki‐Ohkawa Kei Muto Rika Kawamura Dr Tsuyoshi Hirota Prof Dr Kazuhiro Yagita Prof Dr Stephan Irle Prof Dr Steve A Kay Prof Dr Takashi Yoshimura Prof Dr Kenichiro Itami |
| Institution: | 1. Institute of Transformative Bio‐Molecules (WPI‐ITbM), Nagoya University, Chikusa, Nagoya, 464‐8601 (Japan);2. Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa, Nagoya, 464‐8602 (Japan);3. Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya, 464‐8601 (Japan);4. JST, PRESTO, Chikusa, Nagoya, 464‐8602 (Japan);5. Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602‐8566 (Japan);6. Dornsife College of Letters, Arts and Sciences, University of Southern California, 3430 S. Vermont Avenue, Los Angeles, CA 90089‐3301 (USA);7. National Institute for Basic Biology, Myodaiji‐cho, Okazaki 444‐8585 (Japan);8. JST, ERATO, Itami Molecular Nanocarbon Project, Chikusa, Nagoya, 464‐8602 (Japan) |
| 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. |
| Keywords: | C H activation circadian clock cryptochrome small‐molecule modulators structure– activity relationships |