Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors

Allen A. Thomas; Y. Le Huerou; J. De Meese; Indrani Gunawardana; Tomas Kaplan; Todd T. Romoff; Stephen S. Gonzales; Kevin Condroski; Steven A. Boyd; Josh Ballard; Bryan Bernat; Walter DeWolf; May Han; Patrice Lee; Christine Lemieux; Robin Pedersen; Jed Pheneger; Greg Poch; Darin Smith; Francis Sullivan; Solly Weiler; S. Kirk Wright; Jie Lin; Barb Brandhuber; Guy Vigers

doi:10.1016/j.bmcl.2007.11.101

Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors

Allen A. Thomas, Y. Le Huerou, J. De Meese, Indrani Gunawardana, Tomas Kaplan, Todd T. Romoff, Stephen S. Gonzales, Kevin Condroski, Steven A. Boyd, Josh Ballard, Bryan Bernat, Walter DeWolf, May Han, Patrice Lee, Christine Lemieux, Robin Pedersen, Jed Pheneger, Greg Poch, Darin Smith, Francis SullivanSolly Weiler, S. Kirk Wright, Jie Lin, Barb Brandhuber, Guy Vigers

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

46 Scopus citations

Abstract

Tumor cells extensively utilize the pentose phosphate pathway for the synthesis of ribose. Transketolase is a key enzyme in this pathway and has been suggested as a target for inhibition in the treatment of cancer. In a pharmacodynamic study, nude mice with xenografted HCT-116 tumors were dosed with 1 ('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 thiamine, the co-factor of transketolase. Transketolase activity was almost completely suppressed in blood, spleen, and tumor cells, but there was little effect on the activity of the other thiamine-utilizing enzymes α-ketoglutarate dehydrogenase or glucose-6-phosphate dehydrogenase. Synthesis and SAR of transketolase inhibitors is described.

Original language	English (US)
Pages (from-to)	2206-2210
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	6
DOIs	https://doi.org/10.1016/j.bmcl.2007.11.101
State	Published - Mar 15 2008
Externally published	Yes

Keywords

Cancer
Metabolism
Pyrophosphate
Thiamine
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.2007.11.101

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Thomas, A. A., Le Huerou, Y., De Meese, J., Gunawardana, I., Kaplan, T., Romoff, T. T., Gonzales, S. S., Condroski, K., Boyd, S. A., Ballard, J., Bernat, B., DeWolf, W., Han, M., Lee, P., Lemieux, C., Pedersen, R., Pheneger, J., Poch, G., Smith, D., ... Vigers, G. (2008). Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors. Bioorganic and Medicinal Chemistry Letters, 18(6), 2206-2210. https://doi.org/10.1016/j.bmcl.2007.11.101

Thomas, AA, Le Huerou, Y, De Meese, J, Gunawardana, I, Kaplan, T, Romoff, TT, Gonzales, SS, Condroski, K, Boyd, SA, Ballard, J, Bernat, B, DeWolf, W, Han, M, Lee, P, Lemieux, C, Pedersen, R, Pheneger, J, Poch, G, Smith, D, Sullivan, F, Weiler, S, Wright, SK, Lin, J, Brandhuber, B & Vigers, G 2008, 'Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 6, pp. 2206-2210. https://doi.org/10.1016/j.bmcl.2007.11.101

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abstract = "Tumor cells extensively utilize the pentose phosphate pathway for the synthesis of ribose. Transketolase is a key enzyme in this pathway and has been suggested as a target for inhibition in the treatment of cancer. In a pharmacodynamic study, nude mice with xenografted HCT-116 tumors were dosed with 1 ('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 thiamine, the co-factor of transketolase. Transketolase activity was almost completely suppressed in blood, spleen, and tumor cells, but there was little effect on the activity of the other thiamine-utilizing enzymes α-ketoglutarate dehydrogenase or glucose-6-phosphate dehydrogenase. Synthesis and SAR of transketolase inhibitors is described.",

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AU - De Meese, J.

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AU - Kaplan, Tomas

AU - Romoff, Todd T.

AU - Gonzales, Stephen S.

AU - Condroski, Kevin

AU - Boyd, Steven A.

AU - Ballard, Josh

AU - Bernat, Bryan

AU - DeWolf, Walter

AU - Han, May

AU - Lee, Patrice

AU - Lemieux, Christine

AU - Pedersen, Robin

AU - Pheneger, Jed

AU - Poch, Greg

AU - Smith, Darin

AU - Sullivan, Francis

AU - Weiler, Solly

AU - Wright, S. Kirk

AU - Lin, Jie

AU - Brandhuber, Barb

AU - Vigers, Guy

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N2 - Tumor cells extensively utilize the pentose phosphate pathway for the synthesis of ribose. Transketolase is a key enzyme in this pathway and has been suggested as a target for inhibition in the treatment of cancer. In a pharmacodynamic study, nude mice with xenografted HCT-116 tumors were dosed with 1 ('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 thiamine, the co-factor of transketolase. Transketolase activity was almost completely suppressed in blood, spleen, and tumor cells, but there was little effect on the activity of the other thiamine-utilizing enzymes α-ketoglutarate dehydrogenase or glucose-6-phosphate dehydrogenase. Synthesis and SAR of transketolase inhibitors is described.

AB - Tumor cells extensively utilize the pentose phosphate pathway for the synthesis of ribose. Transketolase is a key enzyme in this pathway and has been suggested as a target for inhibition in the treatment of cancer. In a pharmacodynamic study, nude mice with xenografted HCT-116 tumors were dosed with 1 ('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 thiamine, the co-factor of transketolase. Transketolase activity was almost completely suppressed in blood, spleen, and tumor cells, but there was little effect on the activity of the other thiamine-utilizing enzymes α-ketoglutarate dehydrogenase or glucose-6-phosphate dehydrogenase. Synthesis and SAR of transketolase inhibitors is described.

KW - Cancer

KW - Metabolism

KW - Pyrophosphate

KW - Thiamine

KW - Transketolase

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Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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