Inhibition of galactosyltransferases by a novel class of donor analogues

Journal of Medicinal Chemistry
Karine DescroixGerd K Wagner

Abstract

Galactosyltransferases (GalT) are important molecular targets in a range of therapeutic areas, including infection, inflammation, and cancer. GalT inhibitors are therefore sought after as potential lead compounds for drug discovery. We have recently discovered a new class of GalT inhibitors with a novel mode of action. In this publication, we describe a series of analogues which provide insights, for the first time, into SAR for this new mode of GalT inhibition. We also report that a new C-glycoside, designed as a chemically stable analogue of the most potent inhibitor in this series, retains inhibitory activity against a panel of GalTs. Initial results from cellular studies suggest that despite their polarity, these sugar-nucleotides are taken up by HL-60 cells. Results from molecular modeling studies with a representative bacterial GalT provide a rationale for the differences in bioactivity observed in this series. These findings may provide a blueprint for the rational development of new GalT inhibitors with improved potency.

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Citations

Feb 5, 2013·Bioorganic & Medicinal Chemistry·Yin GaoInka Brockhausen
Jul 10, 2013·The Journal of Biological Chemistry·René JørgensenGerd K Wagner
Sep 23, 2014·The Journal of Pharmacy and Pharmacology·Jon Cuccui, Brendan Wren
Apr 14, 2015·Biotechnology Progress·David BrühlmannHervé Broly
Jul 24, 2012·Current Opinion in Structural Biology·Christelle BretonMonica M Palcic
Feb 18, 2016·Chemical Communications : Chem Comm·Jingqian JiangGerd K Wagner
Jul 10, 2017·Innovative Surgical Sciences·Peter M VogtRamin Ipaktchi
Jun 25, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Igor TvaroškaJaroslav Koča
Nov 6, 2012·Chemical Communications : Chem Comm·Andrew EvittGerd K Wagner

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