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

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-Cell Immune Responses

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 › Research › peer-review

29 Citations (Scopus)

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
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	61
Issue number	5
DOIs	https://doi.org/10.1021/acs.jmedchem.7b01824
Publication status	Published - 8 Mar 2018
Externally published	Yes

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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-Cell Immune Responses. 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-Cell Immune Responses",

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 = mar,

day = "8",

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

language = "English",

volume = "61",

pages = "2111--2117",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "5",

}

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-Cell Immune Responses', 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-Cell Immune Responses. / Davey, Martin S.; Malde, Roshni; Mykura, Rory C. et al.
In: Journal of Medicinal Chemistry, Vol. 61, No. 5, 08.03.2018, p. 2111-2117.

Research output: Contribution to journal › Article › Research › 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-Cell Immune Responses

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 - 2018/3/8

Y1 - 2018/3/8

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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.

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JO - Journal of Medicinal Chemistry

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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-Cell Immune Responses

Abstract

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