title: Chemical probes to study ADP-ribosylation: synthesis and biochemical evaluation of inhibitors of the human ADP-ribosyltransferase ARTD3/PARP3.
abstract: The racemic 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[1-(pyridin-2-yl)ethyl]propanamide, 1, 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.
authors.affiliation: Department of Chemistry, Umeå University , SE-90187 Umeå, Sweden.
authors.forename: Anders E G
authors.initials: AE
authors.lastname: Lindgren
authors.forename: Tobias
authors.initials: T
authors.lastname: Karlberg
authors.forename: Torun
authors.initials: T
authors.lastname: Ekblad
authors.forename: Sara
authors.initials: S
authors.lastname: Spjut
authors.forename: Ann-Gerd
authors.initials: AG
authors.lastname: Thorsell
authors.forename: C David
authors.initials: CD
authors.lastname: Andersson
authors.forename: Ton Tong
authors.initials: TT
authors.lastname: Nhan
authors.forename: Victor
authors.initials: V
authors.lastname: Hellsten
authors.forename: Johan
authors.initials: J
authors.lastname: Weigelt
authors.forename: Anna
authors.initials: A
authors.lastname: Linusson
authors.forename: Herwig
authors.initials: H
authors.lastname: Schüler
authors.forename: Mikael
authors.initials: M
authors.lastname: Elofsson
mesh_terms: D036002:ADP Ribose Transferases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D008958:Models, Molecular; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000494:pharmacology; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D052999:Quinazolinones; D036002:ADP Ribose Transferases; C105233:ART3 protein, human