Romidepsin and the Zinc‐Binding Thiol Family of Natural Product HDAC Inhibitors

Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight

“…A masked thiol prodrug features once again in the depsipeptide family of HDAC inhibitors, either as a reducible disulfide in the bacterial natural products romidepsin (FK228, 3) and spiruchostatin A (4) or as a hydrolytically labile thioester in largazole ( 5) of cyanobacterial origin. 42 Upon metabolism, the free thiol common to all three natural products becomes the zinc binding group, as observed in the X-ray structure of largazole with HDAC8. While trichostatin A with its simple aromatic cap is a nonselective HDAC inhibitor, both romidepsin and largazole contain larger macrocyclic caps that contribute to their enzyme affinity as well as enable isoform discrimination.…”

“…Since thiols have poor bioavailability, the disulfide protection ensures higher stability and cell permeability prior to metabolic activation. A masked thiol prodrug features once again in the depsipeptide family of HDAC inhibitors, either as a reducible disulfide in the bacterial natural products romidepsin (FK228, 3 ) and spiruchostatin A ( 4 ) or as a hydrolytically labile thioester in largazole ( 5 ) of cyanobacterial origin . Upon metabolism, the free thiol common to all three natural products becomes the zinc binding group, as observed in the X-ray structure of largazole with HDAC8.…”

Epigenetic drug discovery: a success story for cofactor interference

“…While the zinc-binding group is critical, the rest of the molecule in HDAC inhibitors is important for additional binding interactions that augment potency and influence selectivity between the 11 human isoforms [36,37]. Compared with the minimal structure of vorinostat, which is a pan-HDAC inhibitor, the more elaborate scaffolds present in romidepsin 14 and tucidinostat 15 are more potent and display selectivity levels of greater than 1000-fold between isoforms that are potentially useful in reducing on-target toxicity [38,39]. Meanwhile, the interesting question arises whether zinc-binding is obligatory if the additional interactions are sufficiently strong to impose tight binding.…”

Total Synthesis of Altissimacoumarin D, a Small Molecule Sirtuin1 Activator

“…11 The depsipeptide romidepsin, a histone deacetylase inhibitor of bacterial origin, is a particularly impressive case as it has progressed from discovery to an approved epigenetic drug for the treatment of T-cell lymphoma. 12,13 The zinc-dependent histone deacetylases (HDACs) are enzymes that hydrolyze acyl-lysine (chiefly acetyl-lysine) residues in proteins and revert them to native lysine, usually with a gene silencing effect as a consequence.…”