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

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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

Harvard

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.

APA

Ruda, G. F., Wong, P. E., Alibu, V. P., Norval, S., Read, K. D., Barrett, M. P., & Gilbert, I. H. (2010). Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds. Journal of Medicinal Chemistry, 53(16), 6071-6078doi: 10.1021/jm1004754

Vancouver

Ruda GF, Wong PE, Alibu VP, Norval S, Read KD, Barrett MP et al. Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds. Journal of Medicinal Chemistry. 2010;53(16):6071-6078.

Author

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

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

Research output: Contribution to journalArticle

Bibtex - Download

@article{a3f85e73228a42adbdf69d3e5d4bddc7,
title = "Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds",
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",
volume = "53",
number = "16",
pages = "6071--6078",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

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

A1 - Ruda,Gian Filippo

A1 - Wong,Pui Ee

A1 - Alibu,Vincent P.

A1 - Norval,Suzanne

A1 - Read,Kevin D.

A1 - Barrett,Michael P.

A1 - Gilbert,Ian H.

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 - <p>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.<br/> <strong>Reprinted with permission from Ruda, GF, Wong, PE, Alibu, VP, Norval, S, Read, KD, Barrett, MP &amp; 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.</strong></p>

AB - <p>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.<br/> <strong>Reprinted with permission from Ruda, GF, Wong, PE, Alibu, VP, Norval, S, Read, KD, Barrett, MP &amp; 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.</strong></p>

KW - 6-PHOSPHOGLUCONATE DEHYDROGENASE

KW - PRODRUGS

KW - D4T

KW - NUCLEOTIDES

KW - DERIVATIVES

KW - INHIBITORS

KW - DISCOVERY

KW - DELIVERY

KW - SERIES

UR - http://ukpmc.ac.uk/articles/PMC2923871

U2 - 10.1021/jm1004754

DO - 10.1021/jm1004754

M1 - Article

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 16

VL - 53

SP - 6071

EP - 6078

ER -

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