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

被引:71
作者
Suzuki, Nobuaki [1 ]
Suzuki, Takayoshi [1 ]
Ota, Yosuke [1 ]
Nakano, Tatsuya [2 ]
Kurihara, Masaaki [3 ]
Okuda, Haruhiro [3 ]
Yamori, Takao [4 ]
Tsumoto, Hiroki [1 ]
Nakagawa, Hidehiko [1 ]
Miyata, Naoki [1 ,3 ]
机构
[1] Nagoya City Univ, Grad Sch Pharmaceut Sci, Mizuho Ku, Aichi 4678603, Japan
[2] Natl Inst Hlth Sci, Div Med Safety Sci, Setagaya Ku, Tokyo 1588501, Japan
[3] Natl Inst Hlth Sci, Div Organ Chem, Setagaya Ku, Tokyo 1588501, Japan
[4] Japanese Fdn Canc Res, Ctr Canc Chemotherapy, Div Mol Pharmacol, Koto Ku, Tokyo 1358550, Japan
基金
日本学术振兴会;
关键词
CELL-LINES; ANTITUMOR-ACTIVITY; TRICHOSTATIN-A; ENZYME-INHIBITION; CRYSTAL-STRUCTURE; ANTICANCER DRUGS; LEUKEMIC-CELLS; HUMAN HDAC8; IN-VITRO; CLASS-II;
D O I
10.1021/jm900125m
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Guided by the proposed catalytic mechanism of histone deacetylases (HDACs), we designed and synthesized a series of boronic acid-based HDAC inhibitors bearing an alpha-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 (GI(50)) to the concentration causing 50% enzyme inhibition (IC50), i.e., GI(50)/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.
引用
收藏
页码:2909 / 2922
页数:14
相关论文
共 65 条
[1]  
Adams J, 1999, CANCER RES, V59, P2615
[2]   Potent and selective inhibitors of the proteasome: Dipeptidyl boronic acids [J].
Adams, J ;
Behnke, M ;
Chen, SW ;
Cruickshank, AA ;
Dick, LR ;
Grenier, L ;
Klunder, JM ;
Ma, YT ;
Plamondon, L ;
Stein, RL .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1998, 8 (04) :333-338
[3]   Aminosuberoyl hydroxamic acids (ASHAs): A potent new class of HDAC inhibitors [J].
Belvedere, Sandro ;
Witter, David J. ;
Yan, Jiaming ;
Secrist, J. Paul ;
Richon, Victoria ;
Miller, Thomas A. .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (14) :3969-3971
[4]   Epigenetics - An epicenter of gene regulation: Histones and histone-modifying enzymes [J].
Biel, M ;
Wascholowski, V ;
Giannis, A .
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2005, 44 (21) :3186-3216
[5]   Unexpected deacetylation mechanism suggested by a density functional theory QM/MM study of histone-deacetylase-like protein [J].
Corminboeuf, C ;
Hu, P ;
Tuckerman, ME ;
Zhang, YK .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2006, 128 (14) :4530-4531
[6]  
Dan S, 2002, CANCER RES, V62, P1139
[7]   Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation [J].
Dompierre, Jim P. ;
Godin, Juliette D. ;
Charrin, Benedicte C. ;
Cordelieres, Fabrice P. ;
King, Stephen J. ;
Humbert, Sandrine ;
Saudou, Frederic .
JOURNAL OF NEUROSCIENCE, 2007, 27 (13) :3571-3583
[8]   Stereospecific synthesis of EET metabolites via Suzuki-Miyaura coupling [J].
Falck, JR ;
Kumar, PS ;
Reddy, YK ;
Zou, G ;
Capdevila, JH .
TETRAHEDRON LETTERS, 2001, 42 (41) :7211-7212
[9]   Syntheses of amamistatin fragments and determination of their HDAC and antitumor activity [J].
Fennell, Kelley A. ;
Miller, Marvin J. .
ORGANIC LETTERS, 2007, 9 (09) :1683-1685
[10]   Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors [J].
Finnin M.S. ;
Donigian J.R. ;
Cohen A. ;
Richon V.M. ;
Rifkind R.A. ;
Marks P.A. ;
Breslow R. ;
Pavletich N.P. .
Nature, 1999, 401 (6749) :188-193