Synthesis and characterisation of novel isoform-selective histone deacetylase inhibitors (HDACi) and HDACi-based multi-target ligands

Abstract

In the quickly evolving field of epigenetic therapy, histone deacetylases (HDACs) have emerged as preferred targets for the treatment of cancer and other conditions such as viral infections, neurodegenerative disorders, and inflammatory diseases. With several HDAC inhibitors (HDACi) already on the market, the focus has recently shifted to developing isoform-specific inhibitors rather than unselecive drugs. Of the eleven HDAC isoforms known to date, HDAC6 is of particular impotance for drug discovery due to its versatile biological functions. The selective inhibition of HDAC6 can moreover be used to exploit synergistic activites with other epigenetic drugs, especially proteasome inhibitors. <br /> The design and synthesis of pan-HDACi and selective HDAC6i accomplished in this work covers a range of different scaffolds. Accessible through multicomponent protocols such as the Ugi four-component reaction and the Ugi-azide four component reaction, two libraries of peptoid-capped HDACi have been assessed in terms of their inhibitory activities and antiproliferative potential as single agents or in combination therapies. Another project realised through multi-step synthesis afforded eleven dual HDAC/proteasome inhibitors with the ability to inhibit both targets through one scaffold. In comparison to combination therapies, such multi-target drugs bring the advantage of more predictable pharmacokinetic profiles and simpler dosing schedules. Lacking the risk of drug-drug interactions, they are moreover expected to induce less severe side-effects. <br /> A drawback shared by most current HDACi on the market is the intrinsic toxicity and mutagenic potential of the hydroxamate motif which happens to be the most common zinc-binding group (ZBG) for HDACi. In addition to overcoming the associated risks, alternative ZBGs offer new means to introduce isoform-selectivity into the otherwise highly constricted HDACi pharmacophore model. To this end, one of the projects presented in this work focused on developing a new (difluoromethyl)-1,3,4-oxadiazole-based ZBG for selective HDAC6i.