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Design and Synthesis of a Tetrahydroisoquinoline‐Based Hydroxamate Derivative ( ZYJ ‐34v), An Oral Active Histone Deacetylase Inhibitor with Potent Antitumor Activity
Author(s) -
Zhang Yingjie,
Liu Chunxi,
Chou C. James,
Wang Xuejian,
Jia Yuping,
Xu Wenfang
Publication year - 2013
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12144
Subject(s) - histone deacetylase , histone deacetylase inhibitor , chemistry , in vivo , hydroxamic acid , pharmacology , potency , in vitro , hdac8 , tetrahydroisoquinoline , histone deacetylase 5 , stereochemistry , biochemistry , histone , biology , gene , microbiology and biotechnology
In our previous study, we developed a novel series of tetrahydroisoquinoline‐based hydroxamic acid derivatives as histone deacetylase inhibitors ( B ioorg M ed C hem , 2010, 18, 1761–1772; J M ed C hem , 2011, 54, 2823–2838), among which, compound ZYJ ‐34c ( 1 ) was identified and validated as the most potent one with marked in vitro and in vivo antitumor potency ( J M ed C hem , 2011, 54, 5532–5539.). Herein, further modification in 1 afforded another oral active analog ZYJ ‐34v ( 2 ) with simplified structure and lower molecular weight. Biological evaluation of compound 2 showed efficacious inhibition against histone deacetylase 1, 2, 3, and 6, which was confirmed by W estern blot analysis results. Most importantly, compound 2 exhibited similar even more potent in vitro and in vivo antitumor activities relative to the approved histone deacetylase inhibitor SAHA .