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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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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. |
format | Online Article Text |
id | pubmed-10552512 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
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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