Synthesis and Biological Evaluation of (E)-4-Hydroxy-3-Methylbut-2-enyl Phosphate (HMBP) Aryloxy Triester Phosphoramidate Prodrugs as Activators of Vγ9/Vδ2 T-Cells Immune Response

Martin S. Davey; Roshni Malde; Rory C Mykura; Alfie T Baker; Taher E Taher; Cécile S. Le Duff; Benjamin E. Willcox; Youcef Mehellou

doi:10.1021/acs.jmedchem.7b01824

Synthesis and Biological Evaluation of (E)-4-Hydroxy-3-Methylbut-2-enyl Phosphate (HMBP) Aryloxy Triester Phosphoramidate Prodrugs as Activators of Vγ9/Vδ2 T-Cells Immune Response

Martin S. Davey, Roshni Malde, Rory C Mykura, Alfie T Baker, Taher E Taher, Cécile S. Le Duff, Benjamin E. Willcox, Youcef Mehellou

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

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Abstract

The aryloxy triester phosphoramidate prodrug approach has been used with success in drug discovery. Herein, we describe the first application of this prodrug technology to the monophosphate derivative of the phosphoantigen HMBPP and one of its analogues. Some of these prodrugs exhibited specific and potent activation of Vγ9/Vδ2 T-cells, which were then able to lyse bladder cancer cells in vitro. This work highlights the promise of this prodrug technology in the discovery of novel immunotherapeutics.

Original language	English
Pages (from-to)	2111-2117
Journal	Journal of Medicinal Chemistry
Volume	61
Issue number	5
DOIs	https://doi.org/10.1021/acs.jmedchem.7b01824
Publication status	Published - 19 Feb 2018

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10.1021/acs.jmedchem.7b01824

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Checked for eligibility: 21/03/2018 This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b01824
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Davey, M. S., Malde, R., Mykura, R. C., Baker, A. T., Taher, T. E., Le Duff, C. S., Willcox, B. E., & Mehellou, Y. (2018). Synthesis and Biological Evaluation of (E)-4-Hydroxy-3-Methylbut-2-enyl Phosphate (HMBP) Aryloxy Triester Phosphoramidate Prodrugs as Activators of Vγ9/Vδ2 T-Cells Immune Response. Journal of Medicinal Chemistry, 61(5), 2111-2117. https://doi.org/10.1021/acs.jmedchem.7b01824

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title = "Synthesis and Biological Evaluation of (E)-4-Hydroxy-3-Methylbut-2-enyl Phosphate (HMBP) Aryloxy Triester Phosphoramidate Prodrugs as Activators of Vγ9/Vδ2 T-Cells Immune Response",

abstract = "The aryloxy triester phosphoramidate prodrug approach has been used with success in drug discovery. Herein, we describe the first application of this prodrug technology to the monophosphate derivative of the phosphoantigen HMBPP and one of its analogues. Some of these prodrugs exhibited specific and potent activation of Vγ9/Vδ2 T-cells, which were then able to lyse bladder cancer cells in vitro. This work highlights the promise of this prodrug technology in the discovery of novel immunotherapeutics.",

author = "Davey, {Martin S.} and Roshni Malde and Mykura, {Rory C} and Baker, {Alfie T} and Taher, {Taher E} and {Le Duff}, {C{\'e}cile S.} and Willcox, {Benjamin E.} and Youcef Mehellou",

year = "2018",

month = feb,

day = "19",

doi = "10.1021/acs.jmedchem.7b01824",

language = "English",

volume = "61",

pages = "2111--2117",

journal = "Journal of Medicinal Chemistry",

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publisher = "American Chemical Society",

number = "5",

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Davey, MS, Malde, R, Mykura, RC, Baker, AT, Taher, TE, Le Duff, CS, Willcox, BE & Mehellou, Y 2018, 'Synthesis and Biological Evaluation of (E)-4-Hydroxy-3-Methylbut-2-enyl Phosphate (HMBP) Aryloxy Triester Phosphoramidate Prodrugs as Activators of Vγ9/Vδ2 T-Cells Immune Response', Journal of Medicinal Chemistry, vol. 61, no. 5, pp. 2111-2117. https://doi.org/10.1021/acs.jmedchem.7b01824

Synthesis and Biological Evaluation of (E)-4-Hydroxy-3-Methylbut-2-enyl Phosphate (HMBP) Aryloxy Triester Phosphoramidate Prodrugs as Activators of Vγ9/Vδ2 T-Cells Immune Response. / Davey, Martin S.; Malde, Roshni; Mykura, Rory C et al.
In: Journal of Medicinal Chemistry, Vol. 61, No. 5, 19.02.2018, p. 2111-2117.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Synthesis and Biological Evaluation of (E)-4-Hydroxy-3-Methylbut-2-enyl Phosphate (HMBP) Aryloxy Triester Phosphoramidate Prodrugs as Activators of Vγ9/Vδ2 T-Cells Immune Response

AU - Davey, Martin S.

AU - Malde, Roshni

AU - Mykura, Rory C

AU - Baker, Alfie T

AU - Taher, Taher E

AU - Le Duff, Cécile S.

AU - Willcox, Benjamin E.

AU - Mehellou, Youcef

PY - 2018/2/19

Y1 - 2018/2/19

N2 - The aryloxy triester phosphoramidate prodrug approach has been used with success in drug discovery. Herein, we describe the first application of this prodrug technology to the monophosphate derivative of the phosphoantigen HMBPP and one of its analogues. Some of these prodrugs exhibited specific and potent activation of Vγ9/Vδ2 T-cells, which were then able to lyse bladder cancer cells in vitro. This work highlights the promise of this prodrug technology in the discovery of novel immunotherapeutics.

AB - The aryloxy triester phosphoramidate prodrug approach has been used with success in drug discovery. Herein, we describe the first application of this prodrug technology to the monophosphate derivative of the phosphoantigen HMBPP and one of its analogues. Some of these prodrugs exhibited specific and potent activation of Vγ9/Vδ2 T-cells, which were then able to lyse bladder cancer cells in vitro. This work highlights the promise of this prodrug technology in the discovery of novel immunotherapeutics.

U2 - 10.1021/acs.jmedchem.7b01824

DO - 10.1021/acs.jmedchem.7b01824

M3 - Article

SN - 0022-2623

VL - 61

SP - 2111

EP - 2117

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 5

ER -

Synthesis and Biological Evaluation of (E)-4-Hydroxy-3-Methylbut-2-enyl Phosphate (HMBP) Aryloxy Triester Phosphoramidate Prodrugs as Activators of Vγ9/Vδ2 T-Cells Immune Response

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