General Description
A cell-permeable S-isobutyryl prodrug that is processed intracellularly to form the potent HDAC inhibitor NCH-31 (IC50 = 48 and 170 nM, respectively, using partially purified HDAC1 or HeLa nuclear extract) that is predicted to exhibit a similar HADC binding mode as that of SAHA with its sulfhydryl replacing SAHA′s hydroxamate as the active-site zinc-targeting group. NCH-51 is shown to exhibit comparable antiproliferative (mean IC
50 = 3.8 μM vs. 3.7 μM for SAHA; 48 h treatment) and apoptotic activity as SAHA against various cancer cell lines, but not PBMCs from 4 healthy individuals (IC
50 >30 μM with either drug), and the antioxidant N-Acetyl-L-Cysteine (NAC; Cat. No. 106425) at 2 mM is reported to abolish the cell-growth inhibition caused by either 3 μM NCH-51 or SAHA in the Multiple Myeloma U266 cultures. Half-life in human plasma at 37 °C = 24 h.
References
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[2]. suzuki t, nagano y, kouketsu a, et al. novel inhibitors of human histone deacetylases: design, synthesis, enzyme inhibition, and cancer cell growth inhibition of saha-based non-hydroxamates. j med chem, 2005, 48(4): 1019-1032.
[3]. sanda t, okamoto t, uchida y, et al. proteome analyses of the growth inhibitory effects of nch-51, a novel histone deacetylase inhibitor, on lymphoid malignant cells. leukemia, 2007, 21(11): 2344-2353.
[4]. victoriano af, imai k, togami h, et al. novel histone deacetylase inhibitor nch-51 activates latent hiv-1 gene expression. febs lett, 2011, 585(7): 1103-1111.
