Design, Synthesis, and Biological Activity of Boronic Acid-Based Histone Deacetylase Inhibitors

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• 作者：Nobuaki Suzuki ; Takayoshi Suzuki ; Yosuke Ota ; Tatsuya Nakano ; Masaaki Kurihara ; Haruhiro Okuda ; Takao Yamori ; Hiroki Tsumoto ; Hidehiko Nakagawa ; Naoki Miyata
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：May 14, 2009
• 年：2009
• 卷：52
• 期：9
• 页码：2909-2922
• 全文大小：293K
• 年卷期：v.52,no.9(May 14, 2009)
• ISSN：1520-4804

文摘

Guided by the proposed catalytic mechanism of histone deacetylases (HDACs), we designed and synthesized a series of boronic acid-based HDAC inhibitors bearing an α-amino acid moiety. In this series, compounds (S)-18, 20, and 21 showed potent HDAC-inhibitory activity, highlighting the significance of the (S)-amino acid moiety. In cancer cell growth inhibition assays, compounds (S)-18, 20, and 21 exerted strong activity, and the values of the ratio of the concentration causing 50% growth inhibition (GI₅₀) to the concentration causing 50% enzyme inhibition (IC₅₀), i.e., GI₅₀/IC₅₀, were low. The potency of these compounds was similar to that of clinically used suberoylanilide hydroxamic acid (SAHA) (2). The results of Western blot analysis indicated that the cancer cell growth-inhibitory activity of compounds (S)-18, 20, and 21 is the result of HDAC inhibition. A molecular modeling study suggested that the hydrated boronic acid interacts with zinc ion, Tyr residue, and His residue in the active site of HDACs. Our findings indicate that these boronic acid derivatives represent an entry into a new class of HDAC inhibitors.