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Synthesis and biological evaluation of flavonoid-based IP6K2 inhibitors

Inositol polyphosphates (IPs) are a group of inositol metabolites that act as secondary messengers for external signalling cues. They play various physiological roles such as insulin release, telomere length maintenance, cell metabolism, and aging. Inositol hexakisphosphate kinase 2 (IP6K2) is a key...

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Autores principales: Ahn, Myunghwan, Park, Seung Eun, Choi, Jiyeon, Choi, Jiahn, Choi, Doyoung, An, Dongju, Jeon, Hayoung, Oh, Soowhan, Lee, Kiho, Kim, Jaehoon, Jang, Jaebong, Kim, Seyun, Byun, Youngjoo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10075506/
https://www.ncbi.nlm.nih.gov/pubmed/37013838
http://dx.doi.org/10.1080/14756366.2023.2193866
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author Ahn, Myunghwan
Park, Seung Eun
Choi, Jiyeon
Choi, Jiahn
Choi, Doyoung
An, Dongju
Jeon, Hayoung
Oh, Soowhan
Lee, Kiho
Kim, Jaehoon
Jang, Jaebong
Kim, Seyun
Byun, Youngjoo
author_facet Ahn, Myunghwan
Park, Seung Eun
Choi, Jiyeon
Choi, Jiahn
Choi, Doyoung
An, Dongju
Jeon, Hayoung
Oh, Soowhan
Lee, Kiho
Kim, Jaehoon
Jang, Jaebong
Kim, Seyun
Byun, Youngjoo
author_sort Ahn, Myunghwan
collection PubMed
description Inositol polyphosphates (IPs) are a group of inositol metabolites that act as secondary messengers for external signalling cues. They play various physiological roles such as insulin release, telomere length maintenance, cell metabolism, and aging. Inositol hexakisphosphate kinase 2 (IP6K2) is a key enzyme that produces 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-IP7), which influences the early stages of glucose-induced exocytosis. Therefore, regulation of IP6Ks may serve as a promising strategy for treating diseases such as diabetes and obesity. In this study, we designed, synthesised, and evaluated flavonoid-based compounds as new inhibitors of IP6K2. Structure-activity relationship studies identified compound 20s as the most potent IP6K2 inhibitor with an IC(50) value of 0.55 μM, making it 5-fold more potent than quercetin, the reported flavonoid-based IP6K2 inhibitor. Compound 20s showed higher inhibitory potency against IP6K2 than IP6K1 and IP6K3. Compound 20s can be utilised as a hit compound for further structural modifications of IP6K2 inhibitors.
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spelling pubmed-100755062023-04-06 Synthesis and biological evaluation of flavonoid-based IP6K2 inhibitors Ahn, Myunghwan Park, Seung Eun Choi, Jiyeon Choi, Jiahn Choi, Doyoung An, Dongju Jeon, Hayoung Oh, Soowhan Lee, Kiho Kim, Jaehoon Jang, Jaebong Kim, Seyun Byun, Youngjoo J Enzyme Inhib Med Chem Research Paper Inositol polyphosphates (IPs) are a group of inositol metabolites that act as secondary messengers for external signalling cues. They play various physiological roles such as insulin release, telomere length maintenance, cell metabolism, and aging. Inositol hexakisphosphate kinase 2 (IP6K2) is a key enzyme that produces 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-IP7), which influences the early stages of glucose-induced exocytosis. Therefore, regulation of IP6Ks may serve as a promising strategy for treating diseases such as diabetes and obesity. In this study, we designed, synthesised, and evaluated flavonoid-based compounds as new inhibitors of IP6K2. Structure-activity relationship studies identified compound 20s as the most potent IP6K2 inhibitor with an IC(50) value of 0.55 μM, making it 5-fold more potent than quercetin, the reported flavonoid-based IP6K2 inhibitor. Compound 20s showed higher inhibitory potency against IP6K2 than IP6K1 and IP6K3. Compound 20s can be utilised as a hit compound for further structural modifications of IP6K2 inhibitors. Taylor & Francis 2023-04-04 /pmc/articles/PMC10075506/ /pubmed/37013838 http://dx.doi.org/10.1080/14756366.2023.2193866 Text en © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
spellingShingle Research Paper
Ahn, Myunghwan
Park, Seung Eun
Choi, Jiyeon
Choi, Jiahn
Choi, Doyoung
An, Dongju
Jeon, Hayoung
Oh, Soowhan
Lee, Kiho
Kim, Jaehoon
Jang, Jaebong
Kim, Seyun
Byun, Youngjoo
Synthesis and biological evaluation of flavonoid-based IP6K2 inhibitors
title Synthesis and biological evaluation of flavonoid-based IP6K2 inhibitors
title_full Synthesis and biological evaluation of flavonoid-based IP6K2 inhibitors
title_fullStr Synthesis and biological evaluation of flavonoid-based IP6K2 inhibitors
title_full_unstemmed Synthesis and biological evaluation of flavonoid-based IP6K2 inhibitors
title_short Synthesis and biological evaluation of flavonoid-based IP6K2 inhibitors
title_sort synthesis and biological evaluation of flavonoid-based ip6k2 inhibitors
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10075506/
https://www.ncbi.nlm.nih.gov/pubmed/37013838
http://dx.doi.org/10.1080/14756366.2023.2193866
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