Design and Synthesis of a Tetrahydroisoquinoline‐Based Hydroxamate Derivative ( ZYJ ‐34v), An Oral Active Histone Deacetylase Inhibitor with Potent Antitumor Activity

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 .