Synthesis of a selective HDAC6 inhibitor active in neuroblasts

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Zwick, Vincent¹  Simoes-Pires, Claudia A.¹  Nurisso, Alessandra^1,2  Petit, Charlotte¹  Passos, Carolina Dos Santos¹  Randazzo, Giuseppe Marco¹  Martinet, Nadine³  Bertrand, Philippe^4,5  Cuendet, Muriel¹ 

[1] Univ Lausanne, Univ Geneva, Sch Pharmaceut Sci, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland

[2] Univ Montreal, Dept Biochim, Montreal, PQ H3C 3J7, Canada

[3] UNSA, CNRS, Inst Chim, UMR 7272, F-06108 Nice, France

[4] CNRS, Inst Chim Milieux & Mat Poitiers, UMR 7285, TSA 521106,B28, 4 Rue Michel Brunet, F-86073 Poitiers, France

[5] Reseau Epigenet Canc Opole Grand Ouest, Nantes, France

关键词: Histone deacetylases;    Isoform selectivity;    HDAC6;    PAMPA;    Neuroblastoma cells;   

DOI  :  10.1016/j.bmcl.2016.09.011

来源: Elsevier

【 摘 要 】

In recent years, the role of HDAC6 in neurodegeneration has been partially elucidated, which led some authors to propose HDAC6 inhibitors as a therapeutic strategy to treat neurodegenerative diseases. In an effort to develop a selective HDAC6 inhibitor which can cross the blood brain barrier (BBB), a modified hydroxamate derivative (compound 3) was designed and synthetized. This compound was predicted to have potential for BBB penetration based on in silico and in vitro evaluation of passive permeability. When tested for its HDAC inhibitory activity, the IC50 value of compound 3 towards HDAC6 was in the nM range in both enzymatic and cell-based assays. Compound 3 showed a cell-based selectivity profile close to that of tubastatin A in SH-SY5Y human neuroblastoma cells, and a good BBB permeability profile. (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

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