Prodrug thiamine analogs as inhibitors of the enzyme transketolase

Yvan Le Huerou; Indrani Gunawardana; Allen A. Thomas; Steven A. Boyd; Jason de Meese; Walter deWolf; Steven S. Gonzales; May Han; Laura Hayter; Tomas Kaplan; Christine Lemieux; Patrice Lee; Jed Pheneger; Gregory Poch; Todd T. Romoff; Francis Sullivan; Solly Weiler; S. Kirk Wright; Jie Lin

doi:10.1016/j.bmcl.2007.11.100

Prodrug thiamine analogs as inhibitors of the enzyme transketolase

Yvan Le Huerou, Indrani Gunawardana, Allen A. Thomas, Steven A. Boyd, Jason de Meese, Walter deWolf, Steven S. Gonzales, May Han, Laura Hayter, Tomas Kaplan, Christine Lemieux, Patrice Lee, Jed Pheneger, Gregory Poch, Todd T. Romoff, Francis Sullivan, Solly Weiler, S. Kirk Wright, Jie Lin

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

21 Scopus citations

Abstract

Transketolase, a key enzyme in the pentose phosphate pathway, has been suggested as a target for inhibition in the treatment of cancer. Compound 5a ('N3′-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of the transketolase cofactor thiamine, is a potent transketolase inhibitor but suffers from poor pharmacokinetics due to high clearance and C_max linked toxicity. An efficient way of improving the pharmacokinetic profile of 5a is to prepare oxidized prodrugs which are slowly reduced in vivo yielding longer, sustained blood levels of the drug. The synthesis of such prodrugs and their evaluation in rodent models is reported.

Original language	English (US)
Pages (from-to)	505-508
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	2
DOIs	https://doi.org/10.1016/j.bmcl.2007.11.100
State	Published - Jan 15 2008
Externally published	Yes

Keywords

Disulfides
Pharmacokinetic
Prodrug
Thiamine
Thiocarbonate
Transketolase

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2007.11.100

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Le Huerou, Y., Gunawardana, I., Thomas, A. A., Boyd, S. A., de Meese, J., deWolf, W., Gonzales, S. S., Han, M., Hayter, L., Kaplan, T., Lemieux, C., Lee, P., Pheneger, J., Poch, G., Romoff, T. T., Sullivan, F., Weiler, S., Wright, S. K., & Lin, J. (2008). Prodrug thiamine analogs as inhibitors of the enzyme transketolase. Bioorganic and Medicinal Chemistry Letters, 18(2), 505-508. https://doi.org/10.1016/j.bmcl.2007.11.100

Le Huerou, Y, Gunawardana, I, Thomas, AA, Boyd, SA, de Meese, J, deWolf, W, Gonzales, SS, Han, M, Hayter, L, Kaplan, T, Lemieux, C, Lee, P, Pheneger, J, Poch, G, Romoff, TT, Sullivan, F, Weiler, S, Wright, SK & Lin, J 2008, 'Prodrug thiamine analogs as inhibitors of the enzyme transketolase', Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 2, pp. 505-508. https://doi.org/10.1016/j.bmcl.2007.11.100

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abstract = "Transketolase, a key enzyme in the pentose phosphate pathway, has been suggested as a target for inhibition in the treatment of cancer. Compound 5a ('N3′-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of the transketolase cofactor thiamine, is a potent transketolase inhibitor but suffers from poor pharmacokinetics due to high clearance and Cmax linked toxicity. An efficient way of improving the pharmacokinetic profile of 5a is to prepare oxidized prodrugs which are slowly reduced in vivo yielding longer, sustained blood levels of the drug. The synthesis of such prodrugs and their evaluation in rodent models is reported.",

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author = "{Le Huerou}, Yvan and Indrani Gunawardana and Thomas, {Allen A.} and Boyd, {Steven A.} and {de Meese}, Jason and Walter deWolf and Gonzales, {Steven S.} and May Han and Laura Hayter and Tomas Kaplan and Christine Lemieux and Patrice Lee and Jed Pheneger and Gregory Poch and Romoff, {Todd T.} and Francis Sullivan and Solly Weiler and Wright, {S. Kirk} and Jie Lin",

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doi = "10.1016/j.bmcl.2007.11.100",

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AU - Le Huerou, Yvan

AU - Gunawardana, Indrani

AU - Thomas, Allen A.

AU - Boyd, Steven A.

AU - de Meese, Jason

AU - deWolf, Walter

AU - Gonzales, Steven S.

AU - Han, May

AU - Hayter, Laura

AU - Kaplan, Tomas

AU - Lemieux, Christine

AU - Lee, Patrice

AU - Pheneger, Jed

AU - Poch, Gregory

AU - Romoff, Todd T.

AU - Sullivan, Francis

AU - Weiler, Solly

AU - Wright, S. Kirk

AU - Lin, Jie

PY - 2008/1/15

Y1 - 2008/1/15

N2 - Transketolase, a key enzyme in the pentose phosphate pathway, has been suggested as a target for inhibition in the treatment of cancer. Compound 5a ('N3′-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of the transketolase cofactor thiamine, is a potent transketolase inhibitor but suffers from poor pharmacokinetics due to high clearance and Cmax linked toxicity. An efficient way of improving the pharmacokinetic profile of 5a is to prepare oxidized prodrugs which are slowly reduced in vivo yielding longer, sustained blood levels of the drug. The synthesis of such prodrugs and their evaluation in rodent models is reported.

AB - Transketolase, a key enzyme in the pentose phosphate pathway, has been suggested as a target for inhibition in the treatment of cancer. Compound 5a ('N3′-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of the transketolase cofactor thiamine, is a potent transketolase inhibitor but suffers from poor pharmacokinetics due to high clearance and Cmax linked toxicity. An efficient way of improving the pharmacokinetic profile of 5a is to prepare oxidized prodrugs which are slowly reduced in vivo yielding longer, sustained blood levels of the drug. The synthesis of such prodrugs and their evaluation in rodent models is reported.

KW - Disulfides

KW - Pharmacokinetic

KW - Prodrug

KW - Thiamine

KW - Thiocarbonate

KW - Transketolase

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AN - SCOPUS:38149006234

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JO - Bioorganic and Medicinal Chemistry Letters

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ER -

Prodrug thiamine analogs as inhibitors of the enzyme transketolase

Abstract

Keywords

ASJC Scopus subject areas

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