Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds

Gian Filippo Ruda, Pui Ee Wong, Vincent P. Alibu, Suzanne Norval, Kevin D. Read, Michael P. Barrett, Ian H. Gilbert

    Research output: Contribution to journalArticle

    34 Citations (Scopus)
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    Abstract

    RNAi and enzymatic studies have shown the importance of 6-phosphogluconate dehydrogenase (6-PGDH) in Trypanosoma brucei for the parasite survival and make it an attractive drug target for the development of new treatments against human African trypanosomiasis. 2,3-O-Isopropylidene-4-erythrono hydroxamate is a potent inhibitor of parasite Trypanosoma brucei 6-phosphogluconate dehydrogenase (6-PGDH), the third enzyme of the pentose phosphate pathway. However, this compound does not have trypanocidal activity due to its poor membrane permeability. Consequently, we have previously reported a prodrug approach to improve the antiparasitic activity of this inhibitor by converting the phosphate group into a less charged phosphate prodrug. The activity of prodrugs appeared to be dependent on their stability in phosphate buffer. Here we have successfully further extended the development of the aryl phosphoramidate prodrugs of 2,3-O-isopropylidene-4-erythrono hydroxamate by synthesizing a small library of phosphoramidates and evaluating their biological activity and stability in a variety of assays. Some of the compounds showed high trypanocidal activity and good correlation of activity with their stability in fresh mouse blood.
    Reprinted with permission from Ruda, GF, Wong, PE, Alibu, VP, Norval, S, Read, KD, Barrett, MP & Gilbert, IH 2010, 'Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds' Journal of Medicinal Chemistry, vol 53, no. 16, pp. 6071-6078.. Copyright 2010 American Chemical Society.

    Original languageEnglish
    Pages (from-to)6071-6078
    Number of pages8
    JournalJournal of Medicinal Chemistry
    Volume53
    Issue number16
    DOIs
    Publication statusPublished - 2010

    Keywords

    • 6-PHOSPHOGLUCONATE DEHYDROGENASE
    • PRODRUGS
    • D4T
    • NUCLEOTIDES
    • DERIVATIVES
    • INHIBITORS
    • DISCOVERY
    • DELIVERY
    • SERIES

    Cite this

    @article{a3f85e73228a42adbdf69d3e5d4bddc7,
    title = "Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds",
    abstract = "RNAi and enzymatic studies have shown the importance of 6-phosphogluconate dehydrogenase (6-PGDH) in Trypanosoma brucei for the parasite survival and make it an attractive drug target for the development of new treatments against human African trypanosomiasis. 2,3-O-Isopropylidene-4-erythrono hydroxamate is a potent inhibitor of parasite Trypanosoma brucei 6-phosphogluconate dehydrogenase (6-PGDH), the third enzyme of the pentose phosphate pathway. However, this compound does not have trypanocidal activity due to its poor membrane permeability. Consequently, we have previously reported a prodrug approach to improve the antiparasitic activity of this inhibitor by converting the phosphate group into a less charged phosphate prodrug. The activity of prodrugs appeared to be dependent on their stability in phosphate buffer. Here we have successfully further extended the development of the aryl phosphoramidate prodrugs of 2,3-O-isopropylidene-4-erythrono hydroxamate by synthesizing a small library of phosphoramidates and evaluating their biological activity and stability in a variety of assays. Some of the compounds showed high trypanocidal activity and good correlation of activity with their stability in fresh mouse blood. Reprinted with permission from Ruda, GF, Wong, PE, Alibu, VP, Norval, S, Read, KD, Barrett, MP & Gilbert, IH 2010, 'Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds' Journal of Medicinal Chemistry, vol 53, no. 16, pp. 6071-6078.. Copyright 2010 American Chemical Society.",
    keywords = "6-PHOSPHOGLUCONATE DEHYDROGENASE, PRODRUGS, D4T, NUCLEOTIDES, DERIVATIVES, INHIBITORS, DISCOVERY, DELIVERY, SERIES",
    author = "Ruda, {Gian Filippo} and Wong, {Pui Ee} and Alibu, {Vincent P.} and Suzanne Norval and Read, {Kevin D.} and Barrett, {Michael P.} and Gilbert, {Ian H.}",
    year = "2010",
    doi = "10.1021/jm1004754",
    language = "English",
    volume = "53",
    pages = "6071--6078",
    journal = "Journal of Medicinal Chemistry",
    issn = "0022-2623",
    publisher = "American Chemical Society",
    number = "16",

    }

    Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds. / Ruda, Gian Filippo; Wong, Pui Ee; Alibu, Vincent P.; Norval, Suzanne; Read, Kevin D.; Barrett, Michael P.; Gilbert, Ian H.

    In: Journal of Medicinal Chemistry, Vol. 53, No. 16, 2010, p. 6071-6078.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds

    AU - Ruda, Gian Filippo

    AU - Wong, Pui Ee

    AU - Alibu, Vincent P.

    AU - Norval, Suzanne

    AU - Read, Kevin D.

    AU - Barrett, Michael P.

    AU - Gilbert, Ian H.

    PY - 2010

    Y1 - 2010

    N2 - RNAi and enzymatic studies have shown the importance of 6-phosphogluconate dehydrogenase (6-PGDH) in Trypanosoma brucei for the parasite survival and make it an attractive drug target for the development of new treatments against human African trypanosomiasis. 2,3-O-Isopropylidene-4-erythrono hydroxamate is a potent inhibitor of parasite Trypanosoma brucei 6-phosphogluconate dehydrogenase (6-PGDH), the third enzyme of the pentose phosphate pathway. However, this compound does not have trypanocidal activity due to its poor membrane permeability. Consequently, we have previously reported a prodrug approach to improve the antiparasitic activity of this inhibitor by converting the phosphate group into a less charged phosphate prodrug. The activity of prodrugs appeared to be dependent on their stability in phosphate buffer. Here we have successfully further extended the development of the aryl phosphoramidate prodrugs of 2,3-O-isopropylidene-4-erythrono hydroxamate by synthesizing a small library of phosphoramidates and evaluating their biological activity and stability in a variety of assays. Some of the compounds showed high trypanocidal activity and good correlation of activity with their stability in fresh mouse blood. Reprinted with permission from Ruda, GF, Wong, PE, Alibu, VP, Norval, S, Read, KD, Barrett, MP & Gilbert, IH 2010, 'Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds' Journal of Medicinal Chemistry, vol 53, no. 16, pp. 6071-6078.. Copyright 2010 American Chemical Society.

    AB - RNAi and enzymatic studies have shown the importance of 6-phosphogluconate dehydrogenase (6-PGDH) in Trypanosoma brucei for the parasite survival and make it an attractive drug target for the development of new treatments against human African trypanosomiasis. 2,3-O-Isopropylidene-4-erythrono hydroxamate is a potent inhibitor of parasite Trypanosoma brucei 6-phosphogluconate dehydrogenase (6-PGDH), the third enzyme of the pentose phosphate pathway. However, this compound does not have trypanocidal activity due to its poor membrane permeability. Consequently, we have previously reported a prodrug approach to improve the antiparasitic activity of this inhibitor by converting the phosphate group into a less charged phosphate prodrug. The activity of prodrugs appeared to be dependent on their stability in phosphate buffer. Here we have successfully further extended the development of the aryl phosphoramidate prodrugs of 2,3-O-isopropylidene-4-erythrono hydroxamate by synthesizing a small library of phosphoramidates and evaluating their biological activity and stability in a variety of assays. Some of the compounds showed high trypanocidal activity and good correlation of activity with their stability in fresh mouse blood. Reprinted with permission from Ruda, GF, Wong, PE, Alibu, VP, Norval, S, Read, KD, Barrett, MP & Gilbert, IH 2010, 'Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds' Journal of Medicinal Chemistry, vol 53, no. 16, pp. 6071-6078.. Copyright 2010 American Chemical Society.

    KW - 6-PHOSPHOGLUCONATE DEHYDROGENASE

    KW - PRODRUGS

    KW - D4T

    KW - NUCLEOTIDES

    KW - DERIVATIVES

    KW - INHIBITORS

    KW - DISCOVERY

    KW - DELIVERY

    KW - SERIES

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    DO - 10.1021/jm1004754

    M3 - Article

    VL - 53

    SP - 6071

    EP - 6078

    JO - Journal of Medicinal Chemistry

    JF - Journal of Medicinal Chemistry

    SN - 0022-2623

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    ER -