Enantioselective approach for expanding the three‐dimensional space of tetrahydroquinoline to develop bet bromodomain inhibitors
Marie‐ange Lespinasse
(1)
,
Kaiyao Wei
(2, 3)
,
Justine Perrin
,
Matthias Winkler
,
Sieme Hamaidia
(2, 4)
,
Alexis Leroy
(2)
,
Zuzana Macek Jilkova
(2, 4)
,
Christian Philouze
(5)
,
Patrice Marche
(2)
,
Carlo Petosa
(3)
,
Jérôme Govin
(2)
,
Anouk Emadali
(2, 4)
,
Yung‐sing Wong
(1)
Marie‐ange Lespinasse
- Fonction : Auteur
- PersonId : 1172423
- ORCID : 0000-0002-0784-6450
Justine Perrin
- Fonction : Auteur
Matthias Winkler
- Fonction : Auteur
Sieme Hamaidia
- Fonction : Auteur
- PersonId : 1172424
- ORCID : 0000-0002-9958-1399
Zuzana Macek Jilkova
- Fonction : Auteur
- PersonId : 803101
- ORCID : 0000-0002-2553-5971
Patrice Marche
- Fonction : Auteur
- PersonId : 170615
- IdHAL : patrice-marche
- ORCID : 0000-0002-8930-9340
- IdRef : 067388965
Carlo Petosa
- Fonction : Auteur
- PersonId : 742156
- IdHAL : carlo-petosa
- ORCID : 0000-0002-9975-1167
- IdRef : 158806298
Jérôme Govin
- Fonction : Auteur
- PersonId : 1172406
- ORCID : 0000-0001-5511-6965
Anouk Emadali
- Fonction : Auteur
- PersonId : 1172425
- ORCID : 0000-0002-1976-2668
Yung‐sing Wong
- Fonction : Auteur
- PersonId : 180036
- IdHAL : yung-sing-wong
- ORCID : 0000-0003-1038-9681
- IdRef : 12279544X
Résumé
The pharmaceutical industry has a pervasive need for chiral specific molecules with optimal affinity for their biological targets. However, the mass production of such compounds is currently limited by conventional chemical routes, that are costly and have an environmental impact. Here, we propose an easy access to obtain new tetrahydroquinolines, a motif found in many bioactive compounds, that is rapid and cost effective. Starting from simple raw materials, the procedure uses a proline-catalyzed Mannich reaction followed by the addition of BF3.OEt2, which generates a highly electrophilic aza-ortho-quinone methide intermediate capable of reacting with different nucleophiles to form the diversely functionalized tetrahydroquinoline. Moreover, this enantioselective one-pot process provides access for the first time to tetrahydroquinolines with a cis-2,3 and trans-3,4 configuration. As proof of concept, we demonstrate that a three-step reaction sequence, from simple and inexpensive starting compounds and catalysts, can generate a BD2-selective BET bromodomain inhibitor with anti-inflammatory effect.
Format du dépôt | Fichier |
---|---|
Type de dépôt | Article dans une revue |
Titre |
en
Enantioselective approach for expanding the three‐dimensional space of tetrahydroquinoline to develop bet bromodomain inhibitors
|
Résumé |
en
The pharmaceutical industry has a pervasive need for chiral specific molecules with optimal affinity for their biological targets. However, the mass production of such compounds is currently limited by conventional chemical routes, that are costly and have an environmental impact. Here, we propose an easy access to obtain new tetrahydroquinolines, a motif found in many bioactive compounds, that is rapid and cost effective. Starting from simple raw materials, the procedure uses a proline-catalyzed Mannich reaction followed by the addition of BF3.OEt2, which generates a highly electrophilic aza-ortho-quinone methide intermediate capable of reacting with different nucleophiles to form the diversely functionalized tetrahydroquinoline. Moreover, this enantioselective one-pot process provides access for the first time to tetrahydroquinolines with a cis-2,3 and trans-3,4 configuration. As proof of concept, we demonstrate that a three-step reaction sequence, from simple and inexpensive starting compounds and catalysts, can generate a BD2-selective BET bromodomain inhibitor with anti-inflammatory effect.
|
Auteur(s) |
Marie‐ange Lespinasse
1
, Kaiyao Wei
2, 3
, Justine Perrin
, Matthias Winkler
, Sieme Hamaidia
2, 4
, Alexis Leroy
2
, Zuzana Macek Jilkova
2, 4
, Christian Philouze
5
, Patrice Marche
2
, Carlo Petosa
3
, Jérôme Govin
2
, Anouk Emadali
2, 4
, Yung‐sing Wong
1
1
DPM -
Département de pharmacochimie moléculaire
( 1043041 )
- Batiment E André Rassat 470 rue de la chimie - BP 53 38041 GRENOBLE Cedex 9
- France
2
IAB -
Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
( 1043222 )
- Institut pour l'Avancée des Biosciences
Centre de Recherche UGA / Inserm U 1209 / CNRS UMR 5309
Site Santé - Allée des Alpes
38700 La Tronche
- France
3
IBS - UMR 5075 -
Institut de biologie structurale
( 1043235 )
- Institut de Biologie Structurale, 71 avenue des martyrs, CS 10090, 38044 Grenoble Cedex 9
- France
4
CHUGA -
Centre Hospitalier Universitaire [CHU Grenoble]
( 257328 )
- CS 10217
38043 Grenoble cedex 9
- France
5
DCM -
Département de Chimie Moléculaire
( 1043098 )
- 301, rue de la Chimie 38041 GRENOBLE CEDEX 9
570, rue de la Chimie 38041 GRENOBLE CEDEX 9
- France
|
Langue du document |
Anglais
|
Nom de la revue |
|
Vulgarisation |
Non
|
Comité de lecture |
Oui
|
Audience |
Internationale
|
Volume |
2022
|
Page/Identifiant |
e202202293
|
Date de publication |
2022
|
Collaboration/Projet |
|
Domaine(s) |
|
Projet(s) ANR |
|
Mots-clés |
en
anti-inflammatory agent, za-ortho-quinone methide, BET bromodomain inhibitor, organocatalysis, tetrahydroquinoline
|
DOI | 10.1002/chem.202202293 |
Origine :
Fichiers produits par l'(les) auteur(s)
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