Selective inhibition of Trypanosoma brucei 6-phosphogluconate dehydrogenase by high-energy intermediate and transition-state analogues

Christophe Dardonville; Eliana Rinaldi; Michael P.  Barrett; Reto  Brun; Ian H.  Gilbert; Stefania  Hanau

doi:10.1021/jm031066i

Selective inhibition of Trypanosoma brucei 6-phosphogluconate dehydrogenase by high-energy intermediate and transition-state analogues

Christophe Dardonville
, Eliana Rinaldi
, Michael P. Barrett
, Reto Brun
, Ian H. Gilbert
, Stefania Hanau

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

38 Citations (Scopus)

Abstract

Two series of compounds were designed to mimic the transition state and high-energy intermediates (HEI) of the enzymatic reaction of 6-phosphogluconate dehydrogenase (6PGDH). Sulfoxide analogues (7-11) were designed to mimic the transition state during the oxidation of the substrate to 3-keto-6-phosphogluconate, an enzyme-bound intermediate of the enzyme. Hydroxamate and amide derivatives Of D-erythronic acid were designed to mimic the 1,2-cis-enediol HEI of the 6PGDH reaction. These two series of compounds were assayed as competitive inhibitors of the Trypanosoma brucei and sheep liver enzymes, and their selectivity value (ratio sheep/parasite) was calculated. The sulfoxide transition-state analogues showed weak and selective inhibition of the T. brucei enzyme. The hydroxamic derivatives showed potent and selective inhibition of the T brucei 6PGDH with a K-i in the nanomolar range.

Original language	English
Pages (from-to)	3427-3437
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	47
Issue number	13
DOIs	https://doi.org/10.1021/jm031066i
Publication status	Published - 17 Jun 2004

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title = "Selective inhibition of Trypanosoma brucei 6-phosphogluconate dehydrogenase by high-energy intermediate and transition-state analogues",

abstract = "Two series of compounds were designed to mimic the transition state and high-energy intermediates (HEI) of the enzymatic reaction of 6-phosphogluconate dehydrogenase (6PGDH). Sulfoxide analogues (7-11) were designed to mimic the transition state during the oxidation of the substrate to 3-keto-6-phosphogluconate, an enzyme-bound intermediate of the enzyme. Hydroxamate and amide derivatives Of D-erythronic acid were designed to mimic the 1,2-cis-enediol HEI of the 6PGDH reaction. These two series of compounds were assayed as competitive inhibitors of the Trypanosoma brucei and sheep liver enzymes, and their selectivity value (ratio sheep/parasite) was calculated. The sulfoxide transition-state analogues showed weak and selective inhibition of the T. brucei enzyme. The hydroxamic derivatives showed potent and selective inhibition of the T brucei 6PGDH with a K-i in the nanomolar range.",

author = "Christophe Dardonville and Eliana Rinaldi and Barrett, \{Michael P.\} and Reto Brun and Gilbert, \{Ian H.\} and Stefania Hanau",

year = "2004",

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doi = "10.1021/jm031066i",

language = "English",

volume = "47",

pages = "3427--3437",

journal = "Journal of Medicinal Chemistry",

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publisher = "American Chemical Society",

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TY - JOUR

T1 - Selective inhibition of Trypanosoma brucei 6-phosphogluconate dehydrogenase by high-energy intermediate and transition-state analogues

AU - Dardonville, Christophe

AU - Rinaldi, Eliana

AU - Barrett, Michael P.

AU - Brun, Reto

AU - Gilbert, Ian H.

AU - Hanau, Stefania

PY - 2004/6/17

Y1 - 2004/6/17

N2 - Two series of compounds were designed to mimic the transition state and high-energy intermediates (HEI) of the enzymatic reaction of 6-phosphogluconate dehydrogenase (6PGDH). Sulfoxide analogues (7-11) were designed to mimic the transition state during the oxidation of the substrate to 3-keto-6-phosphogluconate, an enzyme-bound intermediate of the enzyme. Hydroxamate and amide derivatives Of D-erythronic acid were designed to mimic the 1,2-cis-enediol HEI of the 6PGDH reaction. These two series of compounds were assayed as competitive inhibitors of the Trypanosoma brucei and sheep liver enzymes, and their selectivity value (ratio sheep/parasite) was calculated. The sulfoxide transition-state analogues showed weak and selective inhibition of the T. brucei enzyme. The hydroxamic derivatives showed potent and selective inhibition of the T brucei 6PGDH with a K-i in the nanomolar range.

AB - Two series of compounds were designed to mimic the transition state and high-energy intermediates (HEI) of the enzymatic reaction of 6-phosphogluconate dehydrogenase (6PGDH). Sulfoxide analogues (7-11) were designed to mimic the transition state during the oxidation of the substrate to 3-keto-6-phosphogluconate, an enzyme-bound intermediate of the enzyme. Hydroxamate and amide derivatives Of D-erythronic acid were designed to mimic the 1,2-cis-enediol HEI of the 6PGDH reaction. These two series of compounds were assayed as competitive inhibitors of the Trypanosoma brucei and sheep liver enzymes, and their selectivity value (ratio sheep/parasite) was calculated. The sulfoxide transition-state analogues showed weak and selective inhibition of the T. brucei enzyme. The hydroxamic derivatives showed potent and selective inhibition of the T brucei 6PGDH with a K-i in the nanomolar range.

U2 - 10.1021/jm031066i

DO - 10.1021/jm031066i

M3 - Article

C2 - 15189039

SN - 0022-2623

VL - 47

SP - 3427

EP - 3437

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 13

ER -

Selective inhibition of Trypanosoma brucei 6-phosphogluconate dehydrogenase by high-energy intermediate and transition-state analogues

Abstract

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