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Synthesis of enantiomerically pure d- and l-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation
Based upon the fact that l-nucleosides have been generally known to be less cytotoxic than d-counterparts, l-bicyclo[3.1.0]hexenyl carbanucleoside derivatives with a fixed north conformation were designed and synthesized by employing a novel synthetic strategy starting from (R)-epichlorohydrin in or...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier Ltd.
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7126181/ https://www.ncbi.nlm.nih.gov/pubmed/21658957 http://dx.doi.org/10.1016/j.bmc.2011.05.026 |
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author | Park, Ah-Young Kim, Won Hee Kang, Jin-Ah Lee, Hye Jin Lee, Chong-Kyo Moon, Hyung Ryong |
author_facet | Park, Ah-Young Kim, Won Hee Kang, Jin-Ah Lee, Hye Jin Lee, Chong-Kyo Moon, Hyung Ryong |
author_sort | Park, Ah-Young |
collection | PubMed |
description | Based upon the fact that l-nucleosides have been generally known to be less cytotoxic than d-counterparts, l-bicyclo[3.1.0]hexenyl carbanucleoside derivatives with a fixed north conformation were designed and synthesized by employing a novel synthetic strategy starting from (R)-epichlorohydrin in order to search for new anti-HIV agents with high potency and less cytotoxicity. A tandem alkylation, γ-lactonization, a chemoselective reduction of ester in the presence of γ-lactone functional group, a RCM reaction, and a Mitsunobu coupling reaction were used as key reactions. d-Counterpart nucleosides were also prepared according to the same synthetic method. Among the synthesized carbanucleosides, d-thymine nucleoside, d-2 and l-thymine nucleoside, l-2 exhibited excellent anti-HIV-1 and -2 activities, in MT-4 cells, which were higher than those of ddI, an anti-AIDS drug. Whereas d-2 exhibited high cytotoxicity in MT-4 cell lines, l-2 did not show any discernible cytotoxicity in all cell lines tested, reflecting that l-2 may be a good candidate for an anti-AIDS drug. l-2 also showed weak anti-HSV-2 activity without cytotoxicity. However, none of the synthesized nucleosides exhibited antiviral activities against RNA viruses including coxsakie, influenza, corona and polio viruses, maybe due to their 2′,3′-dideoxy structure. Potent antiviral effects of d-2 and l-2 indicate that nucleosides belonging to a class of D4Ns can be an excellent candidate for anti-DNA virus agents. This research strongly supports l-nucleosides of a class of D4Ns to be a very promising candidate for antiviral agents due to its low cytotoxicity and a good antiviral activity. |
format | Online Article Text |
id | pubmed-7126181 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Elsevier Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-71261812020-04-08 Synthesis of enantiomerically pure d- and l-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation Park, Ah-Young Kim, Won Hee Kang, Jin-Ah Lee, Hye Jin Lee, Chong-Kyo Moon, Hyung Ryong Bioorg Med Chem Article Based upon the fact that l-nucleosides have been generally known to be less cytotoxic than d-counterparts, l-bicyclo[3.1.0]hexenyl carbanucleoside derivatives with a fixed north conformation were designed and synthesized by employing a novel synthetic strategy starting from (R)-epichlorohydrin in order to search for new anti-HIV agents with high potency and less cytotoxicity. A tandem alkylation, γ-lactonization, a chemoselective reduction of ester in the presence of γ-lactone functional group, a RCM reaction, and a Mitsunobu coupling reaction were used as key reactions. d-Counterpart nucleosides were also prepared according to the same synthetic method. Among the synthesized carbanucleosides, d-thymine nucleoside, d-2 and l-thymine nucleoside, l-2 exhibited excellent anti-HIV-1 and -2 activities, in MT-4 cells, which were higher than those of ddI, an anti-AIDS drug. Whereas d-2 exhibited high cytotoxicity in MT-4 cell lines, l-2 did not show any discernible cytotoxicity in all cell lines tested, reflecting that l-2 may be a good candidate for an anti-AIDS drug. l-2 also showed weak anti-HSV-2 activity without cytotoxicity. However, none of the synthesized nucleosides exhibited antiviral activities against RNA viruses including coxsakie, influenza, corona and polio viruses, maybe due to their 2′,3′-dideoxy structure. Potent antiviral effects of d-2 and l-2 indicate that nucleosides belonging to a class of D4Ns can be an excellent candidate for anti-DNA virus agents. This research strongly supports l-nucleosides of a class of D4Ns to be a very promising candidate for antiviral agents due to its low cytotoxicity and a good antiviral activity. Elsevier Ltd. 2011-07-01 2011-05-23 /pmc/articles/PMC7126181/ /pubmed/21658957 http://dx.doi.org/10.1016/j.bmc.2011.05.026 Text en Copyright © 2011 Elsevier Ltd. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Article Park, Ah-Young Kim, Won Hee Kang, Jin-Ah Lee, Hye Jin Lee, Chong-Kyo Moon, Hyung Ryong Synthesis of enantiomerically pure d- and l-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation |
title | Synthesis of enantiomerically pure d- and l-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation |
title_full | Synthesis of enantiomerically pure d- and l-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation |
title_fullStr | Synthesis of enantiomerically pure d- and l-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation |
title_full_unstemmed | Synthesis of enantiomerically pure d- and l-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation |
title_short | Synthesis of enantiomerically pure d- and l-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation |
title_sort | synthesis of enantiomerically pure d- and l-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7126181/ https://www.ncbi.nlm.nih.gov/pubmed/21658957 http://dx.doi.org/10.1016/j.bmc.2011.05.026 |
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