posted on 2012-03-08, 00:00authored byKarine Descroix, Thomas Pesnot, Yayoi Yoshimura, Sebastian
S. Gehrke, Warren Wakarchuk, Monica M. Palcic, Gerd K. Wagner
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.