compound 6.1 at positions 1 and 2 of the macrocycle, further supporting a common
pharmacophore [49].
X-ray crystal structures are available for examples of these macrocyclic inhibitors. In particular, the crystal structure of compound 6.1 was solved in the absence of
a biological target. Interestingly, inhibitors co-crystallized with HDACs maintain the
same conformational features observed in the absence of protein, as shown in Fig. 8.
The three-dimensional distribution of the 12-membered ring is almost identical for
isolated 6.1 and co-crystallized compound 6.18, being both of them potent inhibitors
of several HDAC isotypes. Peptide 6.10, however, exhibits conformational differences at position 2 of the cycle, which is also in agreement with a lower inhibitory
potency of this scaffold. It is reasonable to say that the conformation of these
cyclic peptides is highly optimized for binding to a region of the HDAC surface,
which is common among several HDACs and particularly isotypes 1–3.
More extensive structural studies including, for example, the LDLD diastereomeric derivatives mentioned above would also be useful for rationalizing membrane
permeability and establishing a more detailed pharmacophore model.
4.1 Biological Activity of Selected Inhibitors
Three macrocyclic hydroxamic acid-containing HDAC inhibitors have been studied
in more detail biologically, including effects in mice and patients. Compound T1.2, a
hydroxamic acid-containing derivative of cyl-1 bearing LDLD configuration
(Table 1), is the best characterized to date. This compound enhances transgene and
not endogenous gene expression in rat 2 fibroblasts (DLD1 and MKN7 cell lines)
and human keratinocytes (HaCaT, NHEK, and NHDF cell lines), measured by βgalactosidase and green fluorescent protein (GFP) expression [82, 83]. This effect
was observed after 72 h of exposure, and it lasted up to 7 days in the case of rat
Fig. 8 Crystal structure of
the scaffold of apicidin (6.1,
green, CCDC code: 274844)
overlayed with the crystal
structures of those of
HC-toxin from a complex
with zebrafish HDAC6
(6.10, pink, PDB code:
5EFJ) and trapoxin A from a
complex with human
HDAC8 (6.18, cyan, PDB
code: 5VI6)
Hydroxamic Acid-Containing Peptides in the Study of Histone Deacetylases
43
pharmacophore [49].
X-ray crystal structures are available for examples of these macrocyclic inhibitors. In particular, the crystal structure of compound 6.1 was solved in the absence of
a biological target. Interestingly, inhibitors co-crystallized with HDACs maintain the
same conformational features observed in the absence of protein, as shown in Fig. 8.
The three-dimensional distribution of the 12-membered ring is almost identical for
isolated 6.1 and co-crystallized compound 6.18, being both of them potent inhibitors
of several HDAC isotypes. Peptide 6.10, however, exhibits conformational differences at position 2 of the cycle, which is also in agreement with a lower inhibitory
potency of this scaffold. It is reasonable to say that the conformation of these
cyclic peptides is highly optimized for binding to a region of the HDAC surface,
which is common among several HDACs and particularly isotypes 1–3.
More extensive structural studies including, for example, the LDLD diastereomeric derivatives mentioned above would also be useful for rationalizing membrane
permeability and establishing a more detailed pharmacophore model.
4.1 Biological Activity of Selected Inhibitors
Three macrocyclic hydroxamic acid-containing HDAC inhibitors have been studied
in more detail biologically, including effects in mice and patients. Compound T1.2, a
hydroxamic acid-containing derivative of cyl-1 bearing LDLD configuration
(Table 1), is the best characterized to date. This compound enhances transgene and
not endogenous gene expression in rat 2 fibroblasts (DLD1 and MKN7 cell lines)
and human keratinocytes (HaCaT, NHEK, and NHDF cell lines), measured by βgalactosidase and green fluorescent protein (GFP) expression [82, 83]. This effect
was observed after 72 h of exposure, and it lasted up to 7 days in the case of rat
Fig. 8 Crystal structure of
the scaffold of apicidin (6.1,
green, CCDC code: 274844)
overlayed with the crystal
structures of those of
HC-toxin from a complex
with zebrafish HDAC6
(6.10, pink, PDB code:
5EFJ) and trapoxin A from a
complex with human
HDAC8 (6.18, cyan, PDB
code: 5VI6)
Hydroxamic Acid-Containing Peptides in the Study of Histone Deacetylases
43