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Generation of Stable Isopentenyl Monophosphate Aryloxy Triester Phosphoramidates as Activators of Vγ9Vδ2 T Cells

Aryloxy triester phosphoramidate prodrugs of the monophosphate derivatives of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) were synthesized as lipophilic derivatives that can improve cell uptake. Despite the structural similarity of IPP and DMAPP, it was noted that their p...

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Autores principales: Xu, Qin, Taher, Taher E., Ashby, Elizabeth, Sharif, Maria, Willcox, Benjamin E., Mehellou, Youcef
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453817/
https://www.ncbi.nlm.nih.gov/pubmed/33899332
http://dx.doi.org/10.1002/cmdc.202100198
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author Xu, Qin
Taher, Taher E.
Ashby, Elizabeth
Sharif, Maria
Willcox, Benjamin E.
Mehellou, Youcef
author_facet Xu, Qin
Taher, Taher E.
Ashby, Elizabeth
Sharif, Maria
Willcox, Benjamin E.
Mehellou, Youcef
author_sort Xu, Qin
collection PubMed
description Aryloxy triester phosphoramidate prodrugs of the monophosphate derivatives of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) were synthesized as lipophilic derivatives that can improve cell uptake. Despite the structural similarity of IPP and DMAPP, it was noted that their phosphoramidate prodrugs exhibited distinct stability profiles in aqueous environments, which we show is due to the position of the allyl bond in the backbones of the IPP and DMAPP monophosphates. As the IPP monophosphate aryloxy triester phosphoramidates showed favorable stability, they were subsequently investigated for their ability to activate Vγ9/Vδ2 T cells and they showed promising activation of this subset of T cells. Together, these findings represent the first report of IPP and DMAPP monophosphate prodrugs and the ability of IPP aryloxy triester phosphoramidate prodrugs to activate Vγ9/Vδ2 T cells highlighting their potential as possible immunotherapeutics.
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spelling pubmed-84538172021-09-27 Generation of Stable Isopentenyl Monophosphate Aryloxy Triester Phosphoramidates as Activators of Vγ9Vδ2 T Cells Xu, Qin Taher, Taher E. Ashby, Elizabeth Sharif, Maria Willcox, Benjamin E. Mehellou, Youcef ChemMedChem Full Papers Aryloxy triester phosphoramidate prodrugs of the monophosphate derivatives of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) were synthesized as lipophilic derivatives that can improve cell uptake. Despite the structural similarity of IPP and DMAPP, it was noted that their phosphoramidate prodrugs exhibited distinct stability profiles in aqueous environments, which we show is due to the position of the allyl bond in the backbones of the IPP and DMAPP monophosphates. As the IPP monophosphate aryloxy triester phosphoramidates showed favorable stability, they were subsequently investigated for their ability to activate Vγ9/Vδ2 T cells and they showed promising activation of this subset of T cells. Together, these findings represent the first report of IPP and DMAPP monophosphate prodrugs and the ability of IPP aryloxy triester phosphoramidate prodrugs to activate Vγ9/Vδ2 T cells highlighting their potential as possible immunotherapeutics. John Wiley and Sons Inc. 2021-05-19 2021-08-05 /pmc/articles/PMC8453817/ /pubmed/33899332 http://dx.doi.org/10.1002/cmdc.202100198 Text en © 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Full Papers
Xu, Qin
Taher, Taher E.
Ashby, Elizabeth
Sharif, Maria
Willcox, Benjamin E.
Mehellou, Youcef
Generation of Stable Isopentenyl Monophosphate Aryloxy Triester Phosphoramidates as Activators of Vγ9Vδ2 T Cells
title Generation of Stable Isopentenyl Monophosphate Aryloxy Triester Phosphoramidates as Activators of Vγ9Vδ2 T Cells
title_full Generation of Stable Isopentenyl Monophosphate Aryloxy Triester Phosphoramidates as Activators of Vγ9Vδ2 T Cells
title_fullStr Generation of Stable Isopentenyl Monophosphate Aryloxy Triester Phosphoramidates as Activators of Vγ9Vδ2 T Cells
title_full_unstemmed Generation of Stable Isopentenyl Monophosphate Aryloxy Triester Phosphoramidates as Activators of Vγ9Vδ2 T Cells
title_short Generation of Stable Isopentenyl Monophosphate Aryloxy Triester Phosphoramidates as Activators of Vγ9Vδ2 T Cells
title_sort generation of stable isopentenyl monophosphate aryloxy triester phosphoramidates as activators of vγ9vδ2 t cells
topic Full Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453817/
https://www.ncbi.nlm.nih.gov/pubmed/33899332
http://dx.doi.org/10.1002/cmdc.202100198
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