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Chemical probes to study ADP-ribosylation: synthesis and biochemical evaluation of inhibitors of the human ADP-ribosyltransferase ARTD3/PARP3
- Source :
- Journal of medicinal chemistry. 56(23)
- Publication Year :
- 2013
-
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.
- Subjects :
- ADP Ribose Transferases
Models, Molecular
Stereochemistry
Stereoisomerism
GPI-Linked Proteins
Propanamide
chemistry.chemical_compound
Structure-Activity Relationship
chemistry
Solubility
ADP-ribosylation
Amide
Drug Discovery
Molecular Medicine
Structure–activity relationship
Humans
Enzyme Inhibitors
Selectivity
Linker
Quinazolinone
Quinazolinones
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 56
- Issue :
- 23
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....f79356d99b7fd9ab888a1f4ea089eb61