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 & 5 others Solly Weiler, S. Kirk Wright, Jie Lin, Barb Brandhuber, Guy Vigers

Research output: Contribution to journalArticle

36 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)2206-2210
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number6
DOIs
StatePublished - Mar 15 2008

Fingerprint

Transketolase
Thiamine
Tumors
Neoplasms
Cells
Pharmacodynamics
Pentoses
Pentose Phosphate Pathway
Ribose
Glucosephosphate Dehydrogenase
Enzymes
Nude Mice
Chlorides
Oxidoreductases
Blood
Spleen
Phosphates
In Vitro Techniques

Keywords

  • Cancer
  • Metabolism
  • Pyrophosphate
  • Thiamine
  • Transketolase

ASJC Scopus subject areas

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

Cite this

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

In: Bioorganic and Medicinal Chemistry Letters, Vol. 18, No. 6, 15.03.2008, p. 2206-2210.

Research output: Contribution to journalArticle

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
Thomas, Allen A ; Le Huerou, Y. ; De Meese, J. ; Gunawardana, Indrani ; Kaplan, Tomas ; Romoff, Todd T. ; Gonzales, Stephen S. ; Condroski, Kevin ; Boyd, Steven A. ; Ballard, Josh ; Bernat, Bryan ; DeWolf, Walter ; Han, May ; Lee, Patrice ; Lemieux, Christine ; Pedersen, Robin ; Pheneger, Jed ; Poch, Greg ; Smith, Darin ; Sullivan, Francis ; Weiler, Solly ; Wright, S. Kirk ; Lin, Jie ; Brandhuber, Barb ; Vigers, Guy. / Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2008 ; Vol. 18, No. 6. pp. 2206-2210.
@article{b8672ba5c15a40cbba3bd4a4b623cb5a,
title = "Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors",
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.",
keywords = "Cancer, Metabolism, Pyrophosphate, Thiamine, Transketolase",
author = "Thomas, {Allen A} and {Le Huerou}, Y. and {De Meese}, J. and Indrani Gunawardana and Tomas Kaplan and Romoff, {Todd T.} and Gonzales, {Stephen S.} and Kevin Condroski and Boyd, {Steven A.} and Josh Ballard and Bryan Bernat and Walter DeWolf and May Han and Patrice Lee and Christine Lemieux and Robin Pedersen and Jed Pheneger and Greg Poch and Darin Smith and Francis Sullivan and Solly Weiler and Wright, {S. Kirk} and Jie Lin and Barb Brandhuber and Guy Vigers",
year = "2008",
month = "3",
day = "15",
doi = "10.1016/j.bmcl.2007.11.101",
language = "English (US)",
volume = "18",
pages = "2206--2210",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "6",

}

TY - JOUR

T1 - Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors

AU - Thomas, Allen A

AU - Le Huerou, Y.

AU - De Meese, J.

AU - Gunawardana, Indrani

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

PY - 2008/3/15

Y1 - 2008/3/15

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

UR - http://www.scopus.com/inward/record.url?scp=40749095542&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=40749095542&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2007.11.101

DO - 10.1016/j.bmcl.2007.11.101

M3 - Article

VL - 18

SP - 2206

EP - 2210

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 6

ER -