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Design and Synthesis of l-1′-Homologated Adenosine Derivatives as Potential Anti-inflammatory Agents

[Image: see text] Inflammatory responses are fundamental protective warning mechanisms. However, in certain instances, they contribute significantly to the development of several chronic diseases such as cancer. Based on previous studies of truncated 1′-homologated adenosine derivatives, l-nucleosid...

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Autores principales: Nguyen, Mai, Aslam, Muhammad Arif, Nguyen, Yen, Javaid, Hafiz Muhammad Ahmad, Pham, Linh, Huh, Joo Young, Kim, Gyudong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10552512/
https://www.ncbi.nlm.nih.gov/pubmed/37810713
http://dx.doi.org/10.1021/acsomega.3c05029
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author Nguyen, Mai
Aslam, Muhammad Arif
Nguyen, Yen
Javaid, Hafiz Muhammad Ahmad
Pham, Linh
Huh, Joo Young
Kim, Gyudong
author_facet Nguyen, Mai
Aslam, Muhammad Arif
Nguyen, Yen
Javaid, Hafiz Muhammad Ahmad
Pham, Linh
Huh, Joo Young
Kim, Gyudong
author_sort Nguyen, Mai
collection PubMed
description [Image: see text] Inflammatory responses are fundamental protective warning mechanisms. However, in certain instances, they contribute significantly to the development of several chronic diseases such as cancer. Based on previous studies of truncated 1′-homologated adenosine derivatives, l-nucleosides and their nucleobase-modified quinolone analogues were designed, synthesized, and evaluated for anti-inflammatory activities. The target molecules were synthesized via the key intramolecular cyclization of monotosylate and Mitsunobu condensation from the natural product, d-ribose. All compounds tested and showed potent anti-inflammatory activities, as indicated by their inhibition of LPS-induced IL-1β secretion from the RAW 264.7 macrophages. Gene expressions of pro-inflammatory cytokines showed that all compounds, except 3a and 3b, significantly reduced LPS-induced IL-1β and IL-6 mRNA expressions. The half-maximal inhibitory concentrations (IC(50)) of 2g and 2h against IL-1β were 1.08 and 2.28 μM, respectively. In contrast, only 2d, 2g, and 3d effectively reversed LPS-induced TNFα mRNA expression. Our mechanistic study revealed that LPS-induced phosphorylation of NF-κB was significantly downregulated by all compounds tested, providing evidence that the NF-κB signaling pathway is involved in their anti-inflammatory activities. Among the compounds tested, 2g and 2h had the most potent anti-inflammatory effects, as shown by the extent of decrease in pro-inflammatory gene expression, protein secretion, and NF-κB phosphorylation. These findings suggest that the l-truncated 1′-homologated adenosine skeleton and its nucleobase-modified analogues have therapeutic potential as treatments for various human diseases by mediating inflammatory processes.
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spelling pubmed-105525122023-10-06 Design and Synthesis of l-1′-Homologated Adenosine Derivatives as Potential Anti-inflammatory Agents Nguyen, Mai Aslam, Muhammad Arif Nguyen, Yen Javaid, Hafiz Muhammad Ahmad Pham, Linh Huh, Joo Young Kim, Gyudong ACS Omega [Image: see text] Inflammatory responses are fundamental protective warning mechanisms. However, in certain instances, they contribute significantly to the development of several chronic diseases such as cancer. Based on previous studies of truncated 1′-homologated adenosine derivatives, l-nucleosides and their nucleobase-modified quinolone analogues were designed, synthesized, and evaluated for anti-inflammatory activities. The target molecules were synthesized via the key intramolecular cyclization of monotosylate and Mitsunobu condensation from the natural product, d-ribose. All compounds tested and showed potent anti-inflammatory activities, as indicated by their inhibition of LPS-induced IL-1β secretion from the RAW 264.7 macrophages. Gene expressions of pro-inflammatory cytokines showed that all compounds, except 3a and 3b, significantly reduced LPS-induced IL-1β and IL-6 mRNA expressions. The half-maximal inhibitory concentrations (IC(50)) of 2g and 2h against IL-1β were 1.08 and 2.28 μM, respectively. In contrast, only 2d, 2g, and 3d effectively reversed LPS-induced TNFα mRNA expression. Our mechanistic study revealed that LPS-induced phosphorylation of NF-κB was significantly downregulated by all compounds tested, providing evidence that the NF-κB signaling pathway is involved in their anti-inflammatory activities. Among the compounds tested, 2g and 2h had the most potent anti-inflammatory effects, as shown by the extent of decrease in pro-inflammatory gene expression, protein secretion, and NF-κB phosphorylation. These findings suggest that the l-truncated 1′-homologated adenosine skeleton and its nucleobase-modified analogues have therapeutic potential as treatments for various human diseases by mediating inflammatory processes. American Chemical Society 2023-09-19 /pmc/articles/PMC10552512/ /pubmed/37810713 http://dx.doi.org/10.1021/acsomega.3c05029 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Nguyen, Mai
Aslam, Muhammad Arif
Nguyen, Yen
Javaid, Hafiz Muhammad Ahmad
Pham, Linh
Huh, Joo Young
Kim, Gyudong
Design and Synthesis of l-1′-Homologated Adenosine Derivatives as Potential Anti-inflammatory Agents
title Design and Synthesis of l-1′-Homologated Adenosine Derivatives as Potential Anti-inflammatory Agents
title_full Design and Synthesis of l-1′-Homologated Adenosine Derivatives as Potential Anti-inflammatory Agents
title_fullStr Design and Synthesis of l-1′-Homologated Adenosine Derivatives as Potential Anti-inflammatory Agents
title_full_unstemmed Design and Synthesis of l-1′-Homologated Adenosine Derivatives as Potential Anti-inflammatory Agents
title_short Design and Synthesis of l-1′-Homologated Adenosine Derivatives as Potential Anti-inflammatory Agents
title_sort design and synthesis of l-1′-homologated adenosine derivatives as potential anti-inflammatory agents
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10552512/
https://www.ncbi.nlm.nih.gov/pubmed/37810713
http://dx.doi.org/10.1021/acsomega.3c05029
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