Article (Scientific journals)
Discovery and Characterization of R/S-N-3-Cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea, a New Histone Deacetylase Class III Inhibitor Exerting Antiproliferative Activity against Cancer Cell Lines
Schnekenburger, M; Goffin, Eric; Lee, J-Y et al.
2017In Journal of Medicinal Chemistry, 60 (11), p. 4714-4733
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Abstract :
[en] A new series of N-aryl-N'-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)ureas bearing an alkoxycarbonylamino group at the 6-position were synthesized and examined as putative anticancer agents targeting sirtuins in glioma cells. On the basis of computational docking combined to in vitro sirtuin 1/2 inhibition assays, we selected compound 18 [R/S-N-3-cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea] which displays a potent antiproliferative activity on various glioma cell types, assessed by quantitative videomicroscopy, eventually triggering senescence. The impact on normal glial cells was lower with a selectivity index of >10. Furthermore, human U373 and Hs683 glioblastoma cell lines served to demonstrate the inhibitory activity of 18 against histone deacetylase (HDAC) class III sirtuins 1 and 2 (SIRT1/2) by quantifying acetylation levels of histone and non-histone proteins. The translational potential of 18 was validated by an NCI-60 cell line screen and validation of growth inhibition of drug resistant cancer cell models. Eventually, the anticancer potential of 18 was validated in 3D glioblastoma spheroids and in vivo by zebrafish xenografts. In summary, compound 18 is the first representative of a new class of SIRT inhibitors opening new perspectives in the medicinal chemistry of HDAC inhibitors.
Disciplines :
Neurosciences & behavior
Author, co-author :
Schnekenburger, M
Goffin, Eric ;  Université de Liège > GIGA-Research
Lee, J-Y
Jang, J.Y
Mazumder, A
Ji, S
Rogister, Bernard  ;  Université de Liège > Département des sciences biomédicales et précliniques > Biochimie et physiologie générales, et biochimie humaine
Bouider, N
Lefranc, F
Miklos, W
Mathieu, V
De Tullio, Pascal ;  Université de Liège > Département de pharmacie > Chimie pharmaceutique
Kim, K-W
Dicato, Mario
Berger, W
Han, BW
Kiss, R
Pirotte, Bernard ;  Université de Liège > Département de pharmacie > Chimie pharmaceutique
Diederich, M
More authors (9 more) Less
Language :
English
Title :
Discovery and Characterization of R/S-N-3-Cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea, a New Histone Deacetylase Class III Inhibitor Exerting Antiproliferative Activity against Cancer Cell Lines
Publication date :
08 June 2017
Journal title :
Journal of Medicinal Chemistry
ISSN :
0022-2623
eISSN :
1520-4804
Publisher :
American Chemical Society, Washington, United States - District of Columbia
Volume :
60
Issue :
11
Pages :
4714-4733
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 16 July 2017

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