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Molecules 2015, 20
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readily hydrated in aqueous media at physiological pH. Trifluoromethyl ketones containing a thiophene
linker have been reported as Class IIa selective HDAC inhibitors. A recent study demonstrated that the
trifluoromethyl ketone moiety served as a potent zinc binding group [150]. The study also identified
silanediol as a zinc binding group with potential for future development of non-hydroxamate Class I and
Class IIb HDAC inhibitors. Figure 2 shows structures of some of the thioester and epoxide compounds
that are discussed here.
O
S
H
N
N
O
O
N
S
O
O
KD5170
1-Alaninechlamydocin
O
Br
O
N
O
N
H
O
S
O
Br
O
O
N
H
S
O
Thioester derivatives of psammaplin A
Depudecin
Figure 2. Structures of thioester- and epoxide-based HDAC inhibitors.
8. Toxicity in Clinical Trials
As with any class of anticancer agents, HDAC inhibitors are also associated with toxicities. The most
common grade 3 and 4 adverse events observed with the use of HDAC inhibitors were thrombocytopenia,
neutropenia, anemia, fatigue and diarrhea [48,56,74,86,108,109]. In some cases, HDAC-induced
thrombocytopenia can be rapidly reversible upon withdrawal of the drug [151]. Nausea, vomiting,
anorexia, constipation and dehydration were also seen in patients receiving HDAC inhibitors. Deaths have
been reported in clinical studies involving HDAC inhibitors. For example, when mocetinostat was tested
in patients with relapsed Hodgkin’s lymphoma four patients died, of which two were treatment-related
deaths [108]. Similarly deaths were also reported in clinical trials involving vorinostat [66], givinostat [152]
and many other HDAC inhibitors. Thus more studies are needed to determine the toxicity of HDAC
inhibitors before a clinical trial can be done, to minimize the cytotoxic effects in patients.
9. Basic Structure of Zinc Binding HDAC Inhibitors
As discussed here, a number of structurally distinct classes of HDAC inhibitors (hydroxamic acid,
benzamide, cyclic peptide, short chain fatty acid) have been tested in clinical trials. Interestingly, most
of the zinc-dependent HDAC inhibitors have common pharmacophores consisting of three distinct
domains: (1) cap group or a surface recognition unit, usually a hydrophobic and aromatic group, which
interacts with the rim of the binding pocket; (2) zinc binding domain (ZBD), such as the hydroxamic
acid, carboxylic acid or benzamide groups, which coordinates to the active site of Zn2+ ion; and (3) a
saturated or unsaturated linker domain with linear or cyclic structure, that connects the cap group to the
ZBD [153]. Crystallographic analyses of HDAC in complex with hydroxamate compounds have
revealed that the capping group is solvent exposed and interacts with the amino acids near the entrance