Yingjie Zhang - Development of Tetrahydroisoquinoline-based Hydroxamic Acid Derivatives: Potent Histone Deacetylase Inhibitors with Marked in vitro and in vivo Antitumor Activities.

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  Publication Details (including relevant citation   information):

  J Med.   Chem.,   2011, 54  (8),   2823-2838.


  Inhibition   of histone deacetylase (HDACs) results in growth arrest,   differentiation and apoptosis in nearly all tumor cell lines,   promoting HDACs as promising targets for antitumor therapy. In   our previous study we developed a novel series of   1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as   HDACs inhibitors (HDACi), among which compound   7d exhibited promising HDAC8 inhibitory and   anti-proliferative activities. Herein, we report the design and   development of a new class of tetrahydroisoquinoline bearing   hydroxamic acid analogs as potential HDACi and anticancer agents.   In vitro biological evaluation of these compounds showed   improved HDAC8 inhibition (compounds 31a and   31b exhibited mid-nM IC50 values   against HDAC8) and potent growth inhibition in multiple tumor   cell lines. Most importantly, compounds 25e,   34a and 34b exhibited excellent   in vivo anticancer activities in a human breast   carcinoma (MDA-MB-231) xenograft model compared with   suberoylanilide hydroxamic acid (SAHA), an approved HDACi.   Collectively, our results indicate that tetrahydroisoquinoline   bearing a hydroxamic acid is an excellent template to develop   novel HDACi as potential anticancer agents.

  Address (URL): http://pubs.acs.org/doi/abs/10.1021/jm101605z