Indol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors

Eduard Dolušić, Pierre Larrieu, Sébastien Blanc, Frédéric Sapunaric, Bernadette Norberg, Laurence Moineaux, Delphine Colette, Vincent Stroobant, Luc Pilotte, Didier Colau, Thierry Ferain, Graeme Fraser, Moreno Galeni, Jean Marie Frre, Bernard Masereel, Benoît Van Den Eynde, Johan Wouters, Raphaël Frédérick

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Abstract

Indoleamine 2,3-dioxygenase (IDO) is a heme dioxygenase which has been shown to be involved in the pathological immune escape of diseases such as cancer. The synthesis and structure-activity relationships (SAR) of a novel series of IDO inhibitors based on the indol-2-yl ethanone scaffold is described. In vitro and in vivo biological activities have been evaluated, leading to compounds with IC 50 values in the micromolar range in both tests. Introduction of small substituents in the 5- and 6-positions of the indole ring, indole N-methylation and variations of the aromatic side chain are all well tolerated. An iron coordinating group on the linker is a prerequisite for biological activity, thus corroborating the virtual screening results. © 2011 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)1550-1561
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number4
DOIs
Publication statusPublished - 15 Feb 2011
EventJFB 2011. - Liege, Belgium
Duration: 19 May 2011 → …

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Bioactivity
Dioxygenases
Methylation
Immune System Diseases
Structure-Activity Relationship
Heme
Scaffolds
Screening
Iron
Neoplasms
indole
In Vitro Techniques

Keywords

  • Anticancer
  • IDO
  • Immunotherapy
  • Indoleamine 2,3-dioxygenase

Cite this

Dolušić, Eduard ; Larrieu, Pierre ; Blanc, Sébastien ; Sapunaric, Frédéric ; Norberg, Bernadette ; Moineaux, Laurence ; Colette, Delphine ; Stroobant, Vincent ; Pilotte, Luc ; Colau, Didier ; Ferain, Thierry ; Fraser, Graeme ; Galeni, Moreno ; Frre, Jean Marie ; Masereel, Bernard ; Van Den Eynde, Benoît ; Wouters, Johan ; Frédérick, Raphaël. / Indol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors. In: Bioorganic and Medicinal Chemistry. 2011 ; Vol. 19, No. 4. pp. 1550-1561.
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abstract = "Indoleamine 2,3-dioxygenase (IDO) is a heme dioxygenase which has been shown to be involved in the pathological immune escape of diseases such as cancer. The synthesis and structure-activity relationships (SAR) of a novel series of IDO inhibitors based on the indol-2-yl ethanone scaffold is described. In vitro and in vivo biological activities have been evaluated, leading to compounds with IC 50 values in the micromolar range in both tests. Introduction of small substituents in the 5- and 6-positions of the indole ring, indole N-methylation and variations of the aromatic side chain are all well tolerated. An iron coordinating group on the linker is a prerequisite for biological activity, thus corroborating the virtual screening results. {\circledC} 2011 Elsevier Ltd. All rights reserved.",
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Dolušić, E, Larrieu, P, Blanc, S, Sapunaric, F, Norberg, B, Moineaux, L, Colette, D, Stroobant, V, Pilotte, L, Colau, D, Ferain, T, Fraser, G, Galeni, M, Frre, JM, Masereel, B, Van Den Eynde, B, Wouters, J & Frédérick, R 2011, 'Indol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors', Bioorganic and Medicinal Chemistry, vol. 19, no. 4, pp. 1550-1561. https://doi.org/10.1016/j.bmc.2010.12.032

Indol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors. / Dolušić, Eduard; Larrieu, Pierre; Blanc, Sébastien; Sapunaric, Frédéric; Norberg, Bernadette; Moineaux, Laurence; Colette, Delphine; Stroobant, Vincent; Pilotte, Luc; Colau, Didier; Ferain, Thierry; Fraser, Graeme; Galeni, Moreno; Frre, Jean Marie; Masereel, Bernard; Van Den Eynde, Benoît; Wouters, Johan; Frédérick, Raphaël.

In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 4, 15.02.2011, p. 1550-1561.

Research output: Contribution to journalArticle

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AU - Dolušić, Eduard

AU - Larrieu, Pierre

AU - Blanc, Sébastien

AU - Sapunaric, Frédéric

AU - Norberg, Bernadette

AU - Moineaux, Laurence

AU - Colette, Delphine

AU - Stroobant, Vincent

AU - Pilotte, Luc

AU - Colau, Didier

AU - Ferain, Thierry

AU - Fraser, Graeme

AU - Galeni, Moreno

AU - Frre, Jean Marie

AU - Masereel, Bernard

AU - Van Den Eynde, Benoît

AU - Wouters, Johan

AU - Frédérick, Raphaël

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N2 - Indoleamine 2,3-dioxygenase (IDO) is a heme dioxygenase which has been shown to be involved in the pathological immune escape of diseases such as cancer. The synthesis and structure-activity relationships (SAR) of a novel series of IDO inhibitors based on the indol-2-yl ethanone scaffold is described. In vitro and in vivo biological activities have been evaluated, leading to compounds with IC 50 values in the micromolar range in both tests. Introduction of small substituents in the 5- and 6-positions of the indole ring, indole N-methylation and variations of the aromatic side chain are all well tolerated. An iron coordinating group on the linker is a prerequisite for biological activity, thus corroborating the virtual screening results. © 2011 Elsevier Ltd. All rights reserved.

AB - Indoleamine 2,3-dioxygenase (IDO) is a heme dioxygenase which has been shown to be involved in the pathological immune escape of diseases such as cancer. The synthesis and structure-activity relationships (SAR) of a novel series of IDO inhibitors based on the indol-2-yl ethanone scaffold is described. In vitro and in vivo biological activities have been evaluated, leading to compounds with IC 50 values in the micromolar range in both tests. Introduction of small substituents in the 5- and 6-positions of the indole ring, indole N-methylation and variations of the aromatic side chain are all well tolerated. An iron coordinating group on the linker is a prerequisite for biological activity, thus corroborating the virtual screening results. © 2011 Elsevier Ltd. All rights reserved.

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KW - IDO

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DO - 10.1016/j.bmc.2010.12.032

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