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  • br Trifluoromethylketones This group of


    Trifluoromethylketones This group of compounds was demonstrated to bind the zinc Voreloxin Hydrochloride in the active site due to its easy hydration, forming the required chelating intermediate. Ontaria et al. [92] have proposed variations around the cap group of trifluoromethylthiophene as the core motif for the binding group showing its importance in selectivity modulation.
    Benzamides Benzamide HDAC inhibitors such as entinostat 16 (Fig. 7B) have a monoacylated ortho diaminobenzene unit speculated to be the ZBG. This hypothesis was recently confirmed with two X-ray structures [93] confirming their zinc-binding capability. This also demonstrated that the internal cavity of class I HDACs is a key feature for class I selectivity. Substituted glycinoanilides were proposed as alternative cap groups. The compound 46 (Fig. 14) was equivalent to entinostat for global HDAC inhibition. The Mai’s group [94] designed oxadiazole as alternative cap group for selective class I HDAC inhibitors. Compounds including aryl and cinnamyl benzamides and hydroxamic acids were produced. The best compound was the entinostat-like benzamide 47 followed by the hydroxamate 48. The presence of the naphtyl group gave highest activities for HDAC1 and HDAC4 inhibitions (Table 4). Cinnamyl compounds like 49 were selective for HDAC1 while hydroxamates like 48 showed preference for HDAC6. Compounds 47 and 48 have almost the same anti-proliferative effects on several cancer cell lines, mainly leukemic cells, and equivalent results in combination with doxorubicin in U937 AML cell lines. Compound 50 was developed [95] as a selective HDAC3 inhibitor in the context of Friedreich Ataxia to improve pharmacokinetics of the compound 51 that retains 10-fold less potency for HDAC1. Wang et al. [96] have developed the ferulic benzamide 52, as well as its hydroxamate version. Global HDAC and anti-proliferative assays gave inhibition at the micromolar level. Marson et al. [96] discovered the chiral compound 53 (Fig. 14B), with 12 nM potency for HDAC3 inhibition, 8-fold less potent on HDAC2 and about 2 log less for HDAC1. In vitro growth inhibition assays on several cancer cell lines showed μM potency for several compounds. Molecular modelling with HDAC3 confirmed the classical π-stacking of the two Phe144 and Phe200 residues in the access tunnel, and showed some hydrophobic interactions with the phenylthiazole part and Phe199 and Leu266.
    Cyclic peptides and cyclic-like peptides The total synthesis of azumamides by Olsen’s group [105] demonstrated the importance of the stereochemistry in β2 position, and the methylation pattern in this β2 position [106]. Compounds such as 67 with two methyl groups were inactive while removing the methyl group as in compound 68 lowered activity. All new compounds were about 100-fold less active than the reference compounds and showed almost no selectivity.
    Thiols Alkylthiols not related to cyclic peptides are HDAC inhibitors. Islam et al. [107] have proposed thiol-based version of the SAHA derivative SK-658. Thioesters and disulphides were produced. Compounds 69 and 70 (Fig. 16SAHA) showed the most promising results (see Table 6), and high cellular activity for compound 69. Sekizawa et al. [108] have prepared alkylthiol HDAC inhibitors based on NHC-31 compound. The aim was to introduce at later stages various cap groups by means of boronic acid coupling chemistry to orient the search for isoform selectivity with focus on HDAC1, HDAC6 and HDAC9. As the key compounds were inhibitors active at nM concentrations, the authors observed that two of them were only micromolar HDAC6 inhibitors, suggesting the idea of HDAC6-insensitive inhibitors. Molecular docking in HDAC1 with compound 71 revealed that the fluorine atom induced a NH hydrogen bonding leading to a different position of the phenyl ring and explaining the higher activity compared to NHC-31. In contrast, both a fluorine and methyl group, as in compound 72, lead to a steric clash with Arg673 disrupting the hydrogen bond between His651 and the oxygen atom of the amide group, resulting in loss of HDAC6 inhibition compared to NHC-31. A strategy towards psammaplin analogues has been proposed by Bahhaj et al. [109] prepared by superacid chemistry. Compound 73 was prepared and showed small preference for HDAC class I. Biological studies confirmed the need for such compounds to be activated in cells in oxidative conditions.