Design, synthesis, and biological activity of boronic acid-based histone deacetylase inhibitors.

Article Details

Citation

Suzuki N, Suzuki T, Ota Y, Nakano T, Kurihara M, Okuda H, Yamori T, Tsumoto H, Nakagawa H, Miyata N

Design, synthesis, and biological activity of boronic acid-based histone deacetylase inhibitors.

J Med Chem. 2009 May 14;52(9):2909-22. doi: 10.1021/jm900125m.

PubMed ID
19419205 [ View in PubMed
]
Abstract

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 (IC(50)), i.e., GI(50)/IC(50), 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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
VorinostatHistone deacetylase 1IC 50 (nM)350N/AN/ADetails
VorinostatHistone deacetylase 2IC 50 (nM)250N/AN/ADetails
VorinostatHistone deacetylase 6IC 50 (nM)28N/AN/ADetails