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 (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.
['Zhang|Yingjie|Y|', 'Liu|Chunxi|C|', 'Chou|C James|CJ|', 'Wang|Xuejian|X|', 'Jia|Yuping|Y|', 'Xu|Wenfang|W|']
D000818:Animals D000970:Antineoplastic Agents D045744:Cell Line, Tumor D049109:Cell Proliferation D015195:Drug Design D005260:Female D056572:Histone Deacetylase Inhibitors D006801:Humans D006877:Hydroxamic Acids D007546:Isoquinolines D051379:Mice D008807:Mice, Inbred BALB C D008819:Mice, Nude D009369:Neoplasms
oral active histone deacetylases inhibitor antitumor tetrahydroisoquinoline valproic acid