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Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement
Circadian dysfunction is closely associated with an increased risk of various diseases. Considering that molecular clock machinery serves as an intrinsic time-keeping system underlying the circadian rhythm of biological processes, the modulation of the molecular clock machinery is an attractive ther...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225008/ https://www.ncbi.nlm.nih.gov/pubmed/34073760 http://dx.doi.org/10.3390/ph14060496 |
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author | Jeong, Yong Uk Jin, Hyo-Eon Lim, Hye Young Choi, Goyeong Joo, Hansol Kang, Bohun Lee, Ga-Hyun Liu, Kwang-Hyeon Maeng, Han-Joo Chung, Sooyoung Son, Gi Hoon Jung, Jong-Wha |
author_facet | Jeong, Yong Uk Jin, Hyo-Eon Lim, Hye Young Choi, Goyeong Joo, Hansol Kang, Bohun Lee, Ga-Hyun Liu, Kwang-Hyeon Maeng, Han-Joo Chung, Sooyoung Son, Gi Hoon Jung, Jong-Wha |
author_sort | Jeong, Yong Uk |
collection | PubMed |
description | Circadian dysfunction is closely associated with an increased risk of various diseases. Considering that molecular clock machinery serves as an intrinsic time-keeping system underlying the circadian rhythm of biological processes, the modulation of the molecular clock machinery is an attractive therapeutic target with novel mechanisms of action. Based on the previous structure–activity relationship study of small molecule cryptochrome (CRY) inhibitors possessing an ethoxypropanoic acid moiety, non-ethoxypropanoic acid-type inhibitors have been developed by bioisosteric replacement. They were evaluated as potent and effective enhancers of E-box-mediated transcription, and, in particular, ester 5d and its hydrolysis product 2d exhibited desirable metabolic and pharmacokinetic profiles as promising drug candidates. Compound 2d directly bound to both CRY1 and 2 in surface plasmon resonance analyses, suggesting that the molecular target is CRY. Effects of compound 5d and 2d on suppressive action of CRY1 on CLOCK:BMAL1-activated E-box-LUC reporter activity revealed that both compounds inhibited the negative feedback actions of CRY on CLOCK:BMAL1. Most importantly, compounds 5d and 2d exhibited significant effects on molecular circadian rhythmicity to be considered circadian clock-enhancers, distinct from the previously developed CRY inhibitors possessing an ethoxypropanoic acid moiety. |
format | Online Article Text |
id | pubmed-8225008 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-82250082021-06-25 Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement Jeong, Yong Uk Jin, Hyo-Eon Lim, Hye Young Choi, Goyeong Joo, Hansol Kang, Bohun Lee, Ga-Hyun Liu, Kwang-Hyeon Maeng, Han-Joo Chung, Sooyoung Son, Gi Hoon Jung, Jong-Wha Pharmaceuticals (Basel) Article Circadian dysfunction is closely associated with an increased risk of various diseases. Considering that molecular clock machinery serves as an intrinsic time-keeping system underlying the circadian rhythm of biological processes, the modulation of the molecular clock machinery is an attractive therapeutic target with novel mechanisms of action. Based on the previous structure–activity relationship study of small molecule cryptochrome (CRY) inhibitors possessing an ethoxypropanoic acid moiety, non-ethoxypropanoic acid-type inhibitors have been developed by bioisosteric replacement. They were evaluated as potent and effective enhancers of E-box-mediated transcription, and, in particular, ester 5d and its hydrolysis product 2d exhibited desirable metabolic and pharmacokinetic profiles as promising drug candidates. Compound 2d directly bound to both CRY1 and 2 in surface plasmon resonance analyses, suggesting that the molecular target is CRY. Effects of compound 5d and 2d on suppressive action of CRY1 on CLOCK:BMAL1-activated E-box-LUC reporter activity revealed that both compounds inhibited the negative feedback actions of CRY on CLOCK:BMAL1. Most importantly, compounds 5d and 2d exhibited significant effects on molecular circadian rhythmicity to be considered circadian clock-enhancers, distinct from the previously developed CRY inhibitors possessing an ethoxypropanoic acid moiety. MDPI 2021-05-24 /pmc/articles/PMC8225008/ /pubmed/34073760 http://dx.doi.org/10.3390/ph14060496 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Jeong, Yong Uk Jin, Hyo-Eon Lim, Hye Young Choi, Goyeong Joo, Hansol Kang, Bohun Lee, Ga-Hyun Liu, Kwang-Hyeon Maeng, Han-Joo Chung, Sooyoung Son, Gi Hoon Jung, Jong-Wha Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement |
title | Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement |
title_full | Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement |
title_fullStr | Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement |
title_full_unstemmed | Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement |
title_short | Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement |
title_sort | development of non-ethoxypropanoic acid type cryptochrome inhibitors with circadian molecular clock-enhancing activity by bioisosteric replacement |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225008/ https://www.ncbi.nlm.nih.gov/pubmed/34073760 http://dx.doi.org/10.3390/ph14060496 |
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