Discovery and Characterization of R/S-N-3-Cyanophenyl-N %26apos;-(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

作者：Schnekenburger Michael; Goffin Eric; Lee Jin Young; Jang Young; Mazurnder Aloran; Ji Seungwon; Rogister Bernard; Bouider Nafila; Lefranc Florence; Miklos Walter; Mathieu Veronique; de Tullio Pascal; Kirn Kyu Won; Dicato Mario; Berger Walter; Han Byung Woo; Kiss Robert; Pirotte Bernard; Diederich Marc

来源：Journal of Medicinal Chemistry, 2017, 60(11): 4714-4733.

DOI：10.1021/acs.jmedchem.7b00533

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 anti.proliferative 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.

• 出版日期2017-6-8