Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Park, Ah-Young, Kim, Won Hee, Kang, Jin-Ah, Lee, Hye Jin, Lee, Chong-Kyo, Moon, Hyung Ryong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Ltd. 2011
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
_version_ 1783516093817552896
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
work_keys_str_mv AT parkahyoung synthesisofenantiomericallypuredandlbicyclo310hexenylcarbanucleosidesandtheirantiviralevaluation
AT kimwonhee synthesisofenantiomericallypuredandlbicyclo310hexenylcarbanucleosidesandtheirantiviralevaluation
AT kangjinah synthesisofenantiomericallypuredandlbicyclo310hexenylcarbanucleosidesandtheirantiviralevaluation
AT leehyejin synthesisofenantiomericallypuredandlbicyclo310hexenylcarbanucleosidesandtheirantiviralevaluation
AT leechongkyo synthesisofenantiomericallypuredandlbicyclo310hexenylcarbanucleosidesandtheirantiviralevaluation
AT moonhyungryong synthesisofenantiomericallypuredandlbicyclo310hexenylcarbanucleosidesandtheirantiviralevaluation