Potent and selective HDAC6 inhibitory activity of N-(4-hydroxycarbamoylbenzyl)-1,2,4,9-tetrahydro-3-thia-9-azafluorenes as novel sulfur analogues of Tubastatin A

Abstract

Eight N-(4-hydroxycarbamoylbenzyl)-1,2,4,9-tetrahydro-3-thia-9-azafluorenes were efficiently prepared as sulfur analogues of Tubastatin A and thus evaluated as new HDAC6 inhibitors. All compounds exhibited potency against HDAC6, and four of them were active in the nanomolar range (IC(50) = 1.9-22 nM). Further analysis revealed that the sulfone derivatives (designated as Tubathians) are superior to their non-oxidized sulfide analogues, and the two most active sulfones showed good to excellent HDAC6 selectivity compared to all other HDAC isoform classes.

Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models

“…16,22 Compared to literature on enzymatic HDAC inhibition by other HDAC6i (Tubastatin A, Tubacin and Ricolinostat) or non-selective inhibitors (Vorinostat), Tubathian A showed superior HDAC6 selectivity (Fig. IC 50 HDAC1 = 11 μM).…”

“…16 The purity of this compound exceeded 99% as measured by 1 H-NMR and LC-MS analysis. 16 The purity of this compound exceeded 99% as measured by 1 H-NMR and LC-MS analysis.…”

“…14 Numerous HDAC6i have been developed since, with Tubastatin A being one of the most active compounds available to date. 16,17 The selective inhibition of HDAC6 has been claimed to result in a variety of anti-cancer properties such as a reduction in cell growth, motility and angiogenesis. 16,17 The selective inhibition of HDAC6 has been claimed to result in a variety of anti-cancer properties such as a reduction in cell growth, motility and angiogenesis.…”

Targeting Selective Autophagy of Insoluble Protein Aggregates

“…The efficacy of 5.38b in cellular assays related to Tregs-dependent suppression of T cell-dependent immune responses is similar to tubastatin [156]. The sulfone analogue of tubastatin (tubathian A, 5.39) is as potent and selective in vitro as its parent compound, and may represent another structural avenue for further optimization of HDAC6-selective inhibitors [157].…”

Towards Selective Inhibition of Histone Deacetylase Isoforms: What Has Been Achieved, Where We Are and What Will Be Next

“…Both compounds are substantially less active against HDAC8 with K i values of around 6 mm. [161] Another approach towards HDAC6-selective inhibitors was undertaken by introducing a branched linking group. [87,159] The exploration of polycyclic molecules as selective HDAC6 inhibitors resulted in the discovery of tricyclic carbazole or carboline hydroxamates.…”