3 Synthesis of Hydroxamic Acid-Containing Peptides
Cyclic peptides have gained interest as a chemotype for HDAC inhibition. Two
strategies have been followed in order to introduce a hydroxamic acid-containing
side chain in the structure for improving inhibitory properties (Fig. 4). The more
widespread route consists of the synthesis of a linear peptide, either in solution or
by solid-phase peptide synthesis (SPPS), containing protected L-α-aminosuberic
acid (Asu). Then, appropriate protecting group manipulation allows for selective
head-to-tail cyclization of the linear peptide, followed by deprotection of the
carboxylic acid side chain and functionalization with hydroxylamine (Fig. 4a)
[45–49]. On the other hand, a fully solid supported synthesis is also possible, either
by displacement from oxime resin using hydroxylamine as nucleophile [50] or with
various hydroxylamine-functionalized resins which generate a hydroxamic acid
moiety upon acidic cleavage [51–59]. For example, hydroxylamine-functionalized
2-chlorotrityl resin was employed by the group of M. Reza Ghadiri for the
synthesis of macrocyclic HDAC inhibitors (Fig. 4b) [60, 61].
NH
H
N
N
N
H
O
O
O
O
O t Bu
O
NH
H
N
N
N
H
O
O
O
O
H
N
O
OH
a) TFA, CH 2 Cl 2
b) H 2 NOH, PyBOP
HOBt, NEt 3 , DMF
a
b
a) Coupling
b) SPPS
c) Cyclization
O
OH
NHFmoc
O
OAllyl
H 2 NO-Trt(2-Cl)
+
HN
H
N
NH
N
H
O
O
O
NH
O
NHO-Trt(2-Cl)
O
HN
H
N
NH
N
H
O
O
O
NH
O
NHO-Trt(2-Cl)
O
HN
H
N
NH
N
H
O
O
O
NH
O
O
H
N OH
TFA/CH 2 Cl 2 (1:1)
Fig. 4 Synthesis of hydroxamic acid-containing cyclic peptides by functionalization of
L-α-aminosuberic acid (Asu) (a) in solution or (b) on solid support [49, 60]
Hydroxamic Acid-Containing Peptides in the Study of Histone Deacetylases
35