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Chemical probes to study ADP-ribosylation : Synthesis and biochemical evaluation of inhibitors of the human ADP-ribosyltransferase ARTD3/PARP3

Lindgren, Anders E G ; Karlberg, Tobias LU ; Ekblad, Torun ; Spjut, Sara ; Thorsell, Ann-Gerd ; Andersson, C David ; Nhan, Ton Tong ; Hellsten, Victor ; Weigelt, Johan and Linusson, Anna , et al. (2013) In Journal of Medicinal Chemistry 56(23). p.68-9556
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
keywords
ADP Ribose Transferases/antagonists & inhibitors, Enzyme Inhibitors/chemical synthesis, GPI-Linked Proteins/antagonists & inhibitors, Humans, Models, Molecular, Quinazolinones/chemical synthesis, Solubility, Stereoisomerism, Structure-Activity Relationship
in
Journal of Medicinal Chemistry
volume
56
issue
23
pages
13 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:84890514665
  • pmid:24188023
ISSN
1520-4804
DOI
10.1021/jm401394u
language
English
LU publication?
no
id
2cc5e7bb-54c4-42c4-9304-a6c381cc1be5
date added to LUP
2024-11-21 17:55:46
date last changed
2025-04-11 21:51:53
@article{2cc5e7bb-54c4-42c4-9304-a6c381cc1be5,
  abstract     = {{<p>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.</p>}},
  author       = {{Lindgren, Anders E G and Karlberg, Tobias and Ekblad, Torun and Spjut, Sara and Thorsell, Ann-Gerd and Andersson, C David and Nhan, Ton Tong and Hellsten, Victor and Weigelt, Johan and Linusson, Anna and Schüler, Herwig and Elofsson, Mikael}},
  issn         = {{1520-4804}},
  keywords     = {{ADP Ribose Transferases/antagonists & inhibitors; Enzyme Inhibitors/chemical synthesis; GPI-Linked Proteins/antagonists & inhibitors; Humans; Models, Molecular; Quinazolinones/chemical synthesis; Solubility; Stereoisomerism; Structure-Activity Relationship}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{23}},
  pages        = {{68--9556}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Medicinal Chemistry}},
  title        = {{Chemical probes to study ADP-ribosylation : Synthesis and biochemical evaluation of inhibitors of the human ADP-ribosyltransferase ARTD3/PARP3}},
  url          = {{http://dx.doi.org/10.1021/jm401394u}},
  doi          = {{10.1021/jm401394u}},
  volume       = {{56}},
  year         = {{2013}},
}