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Description

A cell-permeable carbazolohydroxamate that acts as a highly potent HDAC6-selective inhibitor (IC50 = 15 nM) with much reduced or no activity against other known HDACs. Effectively prevents neuronal cell death (by >=95% at 10 µ,M) upon oxidative stress induction by HCA and selectively induces cellular alpha-tubulin, but not histone H4, hyperacetylation (2.5 to 5 µ,M) in primary rat cortical neuron cultures., A cell-permeable carbazolohydroxamate whose zinc-chelating hydroxamic acid moiety and catalytic channel rim-targeting aromatic cap structure render it a highly potent HDAC6-selective inhibitor (IC50 = 15 nM against recombinant human HDAC6) with much reduced or no activity against HDAC8, HDAC1 (IC50 = 0.854 and 16.4 µ,M, respectively), and other known HDACs (HDAC2/3/4/5/7/9/10/11, IC50 >30 µ,M). Shown to selectively block HDAC6-, but not HDAC1-, dependent cellular deacetylation as evidenced by its selective induction (2.5 to 5 µ,M) of alpha-tubulin, but not histone H4, hyperacetylation in cultured primary rat cortical neurons. Although failing to block cellular glutathione depletion by homocysteic acid (HCA), Tubastatin A nevertheless is reported to prevent neuronal cell death upon oxidative stress induction by HCA in a dose-dependent manner (>=95% protection at 10 µ,M), presumably by preventing peroxiredoxins deacetylation.