Non-charged thiamine analogs as inhibitors of enzyme transketolase

Allen A. Thomas; J. De Meese; Y. Le Huerou; Steven A. Boyd; Todd T. Romoff; Steven S. Gonzales; Indrani Gunawardana; Tomas Kaplan; Francis Sullivan; Kevin Condroski; Joseph P. Lyssikatos; Thomas D. Aicher; Josh Ballard; Bryan Bernat; Walter DeWolf; May Han; Christine Lemieux; Darin Smith; Solly Weiler; S. Kirk Wright; Guy Vigers; Barb Brandhuber

doi:10.1016/j.bmcl.2007.11.098

Non-charged thiamine analogs as inhibitors of enzyme transketolase

Allen A. Thomas, J. De Meese, Y. Le Huerou, Steven A. Boyd, Todd T. Romoff, Steven S. Gonzales, Indrani Gunawardana, Tomas Kaplan, Francis Sullivan, Kevin Condroski, Joseph P. Lyssikatos, Thomas D. Aicher, Josh Ballard, Bryan Bernat, Walter DeWolf, May Han, Christine Lemieux, Darin Smith, Solly Weiler, S. Kirk WrightGuy Vigers, Barb Brandhuber

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

35 Scopus citations

Abstract

Inhibition of the thiamine-utilizing enzyme transketolase (TK) has been linked with diminished tumor cell proliferation. Most thiamine antagonists have a permanent positive charge on the B-ring, and it has been suggested that this charge is required for diphosphorylation by thiamine pyrophosphokinase (TPPK) and binding to TK. We sought to make neutral thiazolium replacements that would be substrates for TPPK, while not necessarily needing thiamine transporters (ThTr1 and ThTr2) for cell penetration. The synthesis, SAR, and structure-based rationale for highly potent non-thiazolium TK antagonists are presented.

Original language	English (US)
Pages (from-to)	509-512
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	2
DOIs	https://doi.org/10.1016/j.bmcl.2007.11.098
State	Published - Jan 15 2008
Externally published	Yes

Keywords

Deazathiamine
Pyrazolothiamine
Pyrophosphate
Pyrophosphokinase
Thiamine
Thiazolone
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.2007.11.098

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Thomas, A. A., De Meese, J., Le Huerou, Y., Boyd, S. A., Romoff, T. T., Gonzales, S. S., Gunawardana, I., Kaplan, T., Sullivan, F., Condroski, K., Lyssikatos, J. P., Aicher, T. D., Ballard, J., Bernat, B., DeWolf, W., Han, M., Lemieux, C., Smith, D., Weiler, S., ... Brandhuber, B. (2008). Non-charged thiamine analogs as inhibitors of enzyme transketolase. Bioorganic and Medicinal Chemistry Letters, 18(2), 509-512. https://doi.org/10.1016/j.bmcl.2007.11.098

Thomas, AA, De Meese, J, Le Huerou, Y, Boyd, SA, Romoff, TT, Gonzales, SS, Gunawardana, I, Kaplan, T, Sullivan, F, Condroski, K, Lyssikatos, JP, Aicher, TD, Ballard, J, Bernat, B, DeWolf, W, Han, M, Lemieux, C, Smith, D, Weiler, S, Wright, SK, Vigers, G & Brandhuber, B 2008, 'Non-charged thiamine analogs as inhibitors of enzyme transketolase', Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 2, pp. 509-512. https://doi.org/10.1016/j.bmcl.2007.11.098

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abstract = "Inhibition of the thiamine-utilizing enzyme transketolase (TK) has been linked with diminished tumor cell proliferation. Most thiamine antagonists have a permanent positive charge on the B-ring, and it has been suggested that this charge is required for diphosphorylation by thiamine pyrophosphokinase (TPPK) and binding to TK. We sought to make neutral thiazolium replacements that would be substrates for TPPK, while not necessarily needing thiamine transporters (ThTr1 and ThTr2) for cell penetration. The synthesis, SAR, and structure-based rationale for highly potent non-thiazolium TK antagonists are presented.",

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AU - Thomas, Allen A.

AU - De Meese, J.

AU - Le Huerou, Y.

AU - Boyd, Steven A.

AU - Romoff, Todd T.

AU - Gonzales, Steven S.

AU - Gunawardana, Indrani

AU - Kaplan, Tomas

AU - Sullivan, Francis

AU - Condroski, Kevin

AU - Lyssikatos, Joseph P.

AU - Aicher, Thomas D.

AU - Ballard, Josh

AU - Bernat, Bryan

AU - DeWolf, Walter

AU - Han, May

AU - Lemieux, Christine

AU - Smith, Darin

AU - Weiler, Solly

AU - Wright, S. Kirk

AU - Vigers, Guy

AU - Brandhuber, Barb

PY - 2008/1/15

Y1 - 2008/1/15

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AB - Inhibition of the thiamine-utilizing enzyme transketolase (TK) has been linked with diminished tumor cell proliferation. Most thiamine antagonists have a permanent positive charge on the B-ring, and it has been suggested that this charge is required for diphosphorylation by thiamine pyrophosphokinase (TPPK) and binding to TK. We sought to make neutral thiazolium replacements that would be substrates for TPPK, while not necessarily needing thiamine transporters (ThTr1 and ThTr2) for cell penetration. The synthesis, SAR, and structure-based rationale for highly potent non-thiazolium TK antagonists are presented.

KW - Deazathiamine

KW - Pyrazolothiamine

KW - Pyrophosphate

KW - Pyrophosphokinase

KW - Thiamine

KW - Thiazolone

KW - Transketolase

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Non-charged thiamine analogs as inhibitors of enzyme transketolase

Abstract

Keywords

ASJC Scopus subject areas

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