A Multistage Halogen Bond Catalyzed Strain-Release Glycosylation Unravels New Hedgehog Signaling Inhibitors.
J Am Chem Soc
; 141(13): 5381-5391, 2019 04 03.
Article
em En
| MEDLINE
| ID: mdl-30848592
ABSTRACT
Halogen bonding (XB) has recently emerged as a promising noncovalent activation mode that can be employed in catalysis. However, methodologies utilizing XB remain rare, and the hydrogen-bonding (HB) catalysis congeners are more widespread in comparison. Herein, we demonstrate a remarkable case whereby employment of XB catalysis in strain-release glycosylation generates O, N-glycosides in excellent anomeric selectivity exceeding HB activation. Deeper investigation unraveled XB catalyst dependencies on multiple stages of the mechanism and a hitherto unknown XB-glycosyl acceptor activation. We present a proof of concept to interrogate sp3-rich glycosidic chemical space for novel biological activity, by integrating XB-catalyzed construction of a glycosidic compound collection, and evaluating these analogues via cell-based phenotypic screens. We show that XB-catalyzed strain-release glycosylation defines a new class of glycosides that inhibit the hedgehog signaling pathway through a nonsmoothened mode of action, opening new opportunities to combat acquired cancer resistance.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Hedgehog
/
Glicosídeos
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article