2 research outputs found
Chemical Probes to Study ADP-Ribosylation: Synthesis and Biochemical Evaluation of Inhibitors of the Human ADP-Ribosyltransferase ARTD3/PARP3
The
racemic 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-<i>N</i>-[1-(pyridin-2-yl)ethyl]propanamide, <b>1</b>, has previously
been identified as a potent but unselective inhibitor of diphtheria
toxin-like ADP-ribosyltransferase 3 (ARTD3). Herein we describe synthesis
and evaluation of 55 compounds in this class. It was found that the
stereochemistry is of great importance for both selectivity and potency
and that substituents on the phenyl ring resulted in poor solubility.
Certain variations at the meso position were tolerated and caused
a large shift in the binding pose. Changes to the ethylene linker
that connects the quinazolinone to the amide were also investigated
but proved detrimental to binding. By combination of synthetic organic
chemistry and structure-based design, two selective inhibitors of
ARTD3 were discovered