Design, synthesis, and anti-HIV activity of 2',3'-didehydro-2',3'-dideoxyuridine (d4U), 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives

Youcef Mehellou; Christopher McGuigan; Andrea Brancale; Jan Balzarini

doi:10.1016/j.bmcl.2007.04.043

Design, synthesis, and anti-HIV activity of 2',3'-didehydro-2',3'-dideoxyuridine (d4U), 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives

Youcef Mehellou
, Christopher McGuigan
, Andrea Brancale
, Jan Balzarini

Birmingham Medical School

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

28 Citations (Scopus)

Abstract

We report the synthesis of 2',3'-didehydro-2',3'-dideoxyuridine (d4U) and 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives and their evaluation against HIV-1 and HIV-2. In addition, we conducted molecular modeling studies on both d4U and ddU monophosphates to investigate their second phosphorylation process. The findings from the modeling studies provide compelling evidence for the lack of anti-HIV activity of d4U phosphoramidates, in contrast with the corresponding ddU phosphoramidates.

Original language	English
Pages (from-to)	3666-9
Number of pages	4
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	17
Issue number	13
DOIs	https://doi.org/10.1016/j.bmcl.2007.04.043
Publication status	Published - 1 Jul 2007

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Amides
Anti-HIV Agents
Chemistry, Pharmaceutical
Dideoxynucleosides
Drug Design
HIV-1
HIV-2
Models, Chemical
Models, Molecular
Nucleoside-Phosphate Kinase
Nucleosides
Phosphates
Phosphoric Acids
Phosphorylation
Thymidine Monophosphate

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10.1016/j.bmcl.2007.04.043

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title = "Design, synthesis, and anti-HIV activity of 2',3'-didehydro-2',3'-dideoxyuridine (d4U), 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives",

abstract = "We report the synthesis of 2',3'-didehydro-2',3'-dideoxyuridine (d4U) and 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives and their evaluation against HIV-1 and HIV-2. In addition, we conducted molecular modeling studies on both d4U and ddU monophosphates to investigate their second phosphorylation process. The findings from the modeling studies provide compelling evidence for the lack of anti-HIV activity of d4U phosphoramidates, in contrast with the corresponding ddU phosphoramidates.",

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author = "Youcef Mehellou and Christopher McGuigan and Andrea Brancale and Jan Balzarini",

year = "2007",

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doi = "10.1016/j.bmcl.2007.04.043",

language = "English",

volume = "17",

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journal = "Bioorganic \& Medicinal Chemistry Letters",

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Design, synthesis, and anti-HIV activity of 2',3'-didehydro-2',3'-dideoxyuridine (d4U), 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives. / Mehellou, Youcef; McGuigan, Christopher; Brancale, Andrea et al.
In: Bioorganic & Medicinal Chemistry Letters, Vol. 17, No. 13, 01.07.2007, p. 3666-9.

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

TY - JOUR

T1 - Design, synthesis, and anti-HIV activity of 2',3'-didehydro-2',3'-dideoxyuridine (d4U), 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives

AU - Mehellou, Youcef

AU - McGuigan, Christopher

AU - Brancale, Andrea

AU - Balzarini, Jan

PY - 2007/7/1

Y1 - 2007/7/1

N2 - We report the synthesis of 2',3'-didehydro-2',3'-dideoxyuridine (d4U) and 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives and their evaluation against HIV-1 and HIV-2. In addition, we conducted molecular modeling studies on both d4U and ddU monophosphates to investigate their second phosphorylation process. The findings from the modeling studies provide compelling evidence for the lack of anti-HIV activity of d4U phosphoramidates, in contrast with the corresponding ddU phosphoramidates.

AB - We report the synthesis of 2',3'-didehydro-2',3'-dideoxyuridine (d4U) and 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives and their evaluation against HIV-1 and HIV-2. In addition, we conducted molecular modeling studies on both d4U and ddU monophosphates to investigate their second phosphorylation process. The findings from the modeling studies provide compelling evidence for the lack of anti-HIV activity of d4U phosphoramidates, in contrast with the corresponding ddU phosphoramidates.

KW - Amides

KW - Anti-HIV Agents

KW - Chemistry, Pharmaceutical

KW - Dideoxynucleosides

KW - Drug Design

KW - HIV-1

KW - HIV-2

KW - Models, Chemical

KW - Models, Molecular

KW - Nucleoside-Phosphate Kinase

KW - Nucleosides

KW - Phosphates

KW - Phosphoric Acids

KW - Phosphorylation

KW - Thymidine Monophosphate

U2 - 10.1016/j.bmcl.2007.04.043

DO - 10.1016/j.bmcl.2007.04.043

M3 - Article

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SN - 0960-894X

VL - 17

SP - 3666

EP - 3669

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 13

ER -

Design, synthesis, and anti-HIV activity of 2',3'-didehydro-2',3'-dideoxyuridine (d4U), 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives

Abstract

UN SDGs

Keywords

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