2. Academic Validation
  3. 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

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

  • J Med Chem. 2017 Jun 8;60(11):4714-4733. doi: 10.1021/acs.jmedchem.7b00533.
Michael Schnekenburger 1,  Eric Goffin 2,  Jin-Young Lee 3,  Jun Young Jang 3,  Aloran Mazumder 3,  Seungwon Ji 3,  Bernard Rogister 4,  Nafila Bouider 2,  Florence Lefranc 5,  Walter Miklos 6,  Véronique Mathieu 7,  Pascal de Tullio 2,  Kyu-Won Kim 8,  Mario Dicato 1,  Walter Berger 6,  Byung Woo Han 3,  Robert Kiss 7,  Bernard Pirotte 2,  Marc Diederich 3
Affiliations

Affiliations

  • 1 Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg , 9, Rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
  • 2 Laboratory of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège , 4000 Liège, Belgium.
  • 3 Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea.
  • 4 Nervous System Diseases and Treatment, GIGA-Neurosciences, University of Liège , 4000 Liège, Belgium.
  • 5 Service de Neurochirurgie, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium.
  • 6 Department of Medicine I, Comprehensive Cancer Center and Institute of Cancer Research, Medical University of Vienna , 1090 Vienna, Austria.
  • 7 Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles , 1050 Brussels, Belgium.
  • 8 SNU-Harvard Neurovascular Protection Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University , Seoul 151-742, Korea.
PMID: 28475330 DOI: 10.1021/acs.jmedchem.7b00533
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.

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