Chemical probes to study ADP-ribosylation : Synthesis and biochemical evaluation of inhibitors of the human ADP-ribosyltransferase ARTD3/PARP3
(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.
(Less)
- author
- publishing date
- 2013-12-12
- 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}}, }