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.

Abstract

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.

• Authors: Michael Schnekenburger, Eric Goffin, Jin-Young Lee, Jun Young Jang, Aloran Mazumder, Seungwon Ji, Bernard Rogister, Nafila Bouider, Florence Lefranc, Walter Miklos, Véronique Mathieu, Pascal de Tullio, Kyu-Won Kim, Mario Dicato, Walter Berger, Byung Woo Han, Robert Kiss, Bernard Pirotte, Marc Diederich
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 60 Issue 11 Pg. 4714-4733 (06 08 2017) ISSN: 1520-4804 [Electronic] United States
• PMID: 28475330 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzopyrans
• Histone Deacetylase Inhibitors

Topics

• Antineoplastic Agents (pharmacology)
• Benzopyrans (chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cells, Cultured
• Drug Discovery
• Drug Screening Assays, Antitumor
• Histone Deacetylase Inhibitors (pharmacology)
• Humans