A number of academic groups have completed total syntheses of the depsipeptide
natural products including a multigram scale preparation of largazole [64, 65]. These
routes have been applied to the preparation of synthetic analogues that have illuminated the SAR within this series [66]. While the zinc-bearing thiol and its stereochemistry are necessary for potent enzyme inhibition, the remaining amino acid
sidechains can be varied, as illustrated by the incorporation of a β-amino acid to give
a ring-expanded largazole analogue 30 (Fig. 12) [67], the romidepsin-largazole
hybrid 31 [68], and the bipyridyl analogue 32 [69]. An intriguing example is Olsen’s
romidepsin analogue 33 and largazole analogue 34 in which the zinc-binding thiol
Table 4 The IC 50 values of the active forms of depsipeptide HDAC inhibitors against individual
isoforms, based on data taken from reference [61]
Isoform
Romidepsin IC 50 (nM)
Largazole IC 50 (nM)
Thailandepsin A IC 50 (nM)
HDAC1
0.8
0.4
14
HDAC2
1.0
0.9
3.5
HDAC3
1.3
0.7
4.8
HDAC8
26
100
>1,000
HDAC4
470
>1,000
>1,000
HDAC5
>1,000
>1,000
HDAC7
>1,000
>1,000
>1,000
HDAC9
>1,000
>1,000
>1,000
HDAC6
330
42
380
HDAC10
0.9
0.5
HDAC11
0.3
>1,000
31
HDAC1 IC 50 3 nM
30
HeLa HDAC IC 50 3 nM
32
HDAC1 IC 50 21 nM
O
O
O
N
H
N
N
O
H
N
S
S
HS
O
O
O
N
H
N
N
H
O
HN
O
S
HS
O
O
O
N
H
O
HN
N
N
HS
O
O
O
N
H
O
N
H
N
H
O
HN
O
O
O
O
N
H
N
N
O
HN
S
S
33
HDAC1 K i 690 nM
HDAC2 K i 370 nM
HDAC3 K i 800 nM
34
H
N
O
O
SH
35
HeLa HDAC IC 50 150 nM
Fig. 12 Examples of synthetic HDAC inhibitors based on a thiol zinc-binding group
Targeting the Zinc-Dependent Histone Deacetylases (HDACs) for Drug Discovery
13