Detailed Information

Cited 0 time in webofscience Cited 0 time in scopus
Metadata Downloads

Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement

Authors
Jeong, Yong UkJin, Hyo-EonLim, Hye YoungChoi, GoyeongJoo, HansolKang, BohunLee, Ga-HyunLiu, Kwang-HyeonMaeng, Han-JooChung, SooyoungSon, Gi HoonJung, Jong-Wha
Issue Date
6월-2021
Publisher
MDPI
Keywords
bioisosteric replacement; circadian clock; circadian rhythm; cryptochrome inhibitor
Citation
PHARMACEUTICALS, v.14, no.6
Indexed
SCIE
SCOPUS
Journal Title
PHARMACEUTICALS
Volume
14
Number
6
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/137354
DOI
10.3390/ph14060496
ISSN
1424-8247
Abstract
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.
Files in This Item
There are no files associated with this item.
Appears in
Collections
Graduate School > Department of Biomedical Sciences > 1. Journal Articles

qrcode

Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.

Related Researcher

Researcher Son, Gi Hoon photo

Son, Gi Hoon
의과학과
Read more

Altmetrics

Total Views & Downloads

BROWSE