In our previous study, we developed a novel series of tetrahydroisoquinoline‐based hydroxamic acid derivatives as histone deacetylase inhibitors (Bioorg Med Chem, 2010, 18, 1761–1772; J Med Chem, 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 Med Chem, 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 Western 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.
