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Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators.

Journal of medicinal chemistry (2011-07-06)
Eduard Dolusić, Pierre Larrieu, Laurence Moineaux, Vincent Stroobant, Luc Pilotte, Didier Colau, Lionel Pochet, Benoît Van den Eynde, Bernard Masereel, Johan Wouters, Raphaël Frédérick
ABSTRACT

Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an active area of research in drug development. Recently, our group has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. Herein, we report a structure-activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure-activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His(55) and Thr(254) residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (K(i) = 5.5 μM), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Melatonin, powder, ≥98% (TLC)
Sigma-Aldrich
L-Tryptophan, reagent grade, ≥98% (HPLC)
Sigma-Aldrich
L-Tryptophan, from non-animal source, meets EP, JP, USP testing specifications, suitable for cell culture, 99.0-101.0%
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L-Tryptophan, BioUltra, ≥99.5% (NT)
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Indole-3-carboxaldehyde, 97%
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Isatin, 97%
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Atenolol, ≥98% (TLC), powder
Supelco
L-Tryptophan, certified reference material, TraceCERT®
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Harmine, 98%
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2-Methylindole, 98%
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5-Fluoroindole, 98%
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3-Indoleacetonitrile, 98%
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5-Nitroindole, 98%
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2-Phenylindole, technical grade, 95%
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3-Indoleacrylic acid, BioReagent, ≥98% (HPLC)
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trans-3-Indoleacrylic acid, 98%
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Indole-5-carboxylic acid, 99%
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4-Cyanoindole, 97%
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6-Hydroxyindole, ≥99.0% (GC)
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1H-Benzo[g]indole, 97%
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6-Fluoroindole, 98%
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3-Indoleacrylic acid, powder
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5-Methylindole, 99%
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6-Methoxyindole, 98%
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7-Methylindole, 97%
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4-Fluoroindole, 97%
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3-Formyl-1H-indole-5-carbonitrile, 97%
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5-Methoxyindole-3-carboxaldehyde, ≥99%
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2-Methylindole-3-carboxaldehyde, 97%
Sigma-Aldrich
7-Azaindole-3-carboxaldehyde, 97%

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