In the case of linear peptides, Schwabe and coworkers also utilized such a resin
for immobilization of protected Asu through its side chain carboxylate. Then,
orthogonal deprotection of the C- and N-terminal groups of the building block
allowed for bidirectional elongation of the peptide, followed by acidic cleavage to
yield the hydroxamic acid-containing peptides [62]. Even though this is a successful
strategy, efficient and versatile synthesis of long peptides benefits from availability
of a protected L-α-aminosuberic hydroxamic acid (Asuha) building block compatible with standard SPPS. Such a building block has been prepared by a number of
groups using Asu as starting material and already presented as potential tool for the
investigation of HDACs using substrate mimics [63]. Standard Fmoc SPPS was used
for the synthesis of a histone 2B fragment analogue containing a surrogate of lysine
12 (H2BK12Asuha), and the hydroxamic acid group of Asuha was protected with a
4-methoxybenzyl (PMB) group during SPPS (Fig. 5). A similar synthetic strategy
was followed by Schwarzer and coworkers employing tert-butyl as protecting group,
although its deprotection required longer acidic treatment than common groups used
for SPPS [64].
4 Structure-Activity Relationship of Macrocyclic HDAC
Inhibitors
Trapoxin A (TpxA, Fig. 6 compound 6.18) was the first of a series of naturally
occurring cyclic peptides described to inhibit histone deacetylation by targeting
HDACs [22]. The structural characteristics of these compounds are interesting for
the design of HDAC inhibitors, since their macrocyclic scaffold acts as the “capping
group” of the pharmacophore model and is able to interact with a large surface area
H 2 N
OH
O
OH
O
a) FmocOsu, NaHCO 3 ,
1,4-dioxane:H 2 O (1:1)
b) Paraformaldehyde, p-TsOH, toluene
c) i) (COCl) 2 , cat. DMF, CH 2 Cl 2
ii) H 2 NOPMB, NEt 3, CH 2 Cl 2
N
H
O
OPMB
HN
O
O
d) THF:1 N NaOH (1:1)
e) FmocOSu, NaHCO 3 ,
acetone:H 2 O (1:1)
N
H
O
OPMB
FmocHN
OH
O
Fig. 5 Synthesis of protected L-α-aminosuberic hydroxamic acid (Asuha) building block for
SPPS [63]
36
C. Moreno-Yruela and C. A. Olsen
for immobilization of protected Asu through its side chain carboxylate. Then,
orthogonal deprotection of the C- and N-terminal groups of the building block
allowed for bidirectional elongation of the peptide, followed by acidic cleavage to
yield the hydroxamic acid-containing peptides [62]. Even though this is a successful
strategy, efficient and versatile synthesis of long peptides benefits from availability
of a protected L-α-aminosuberic hydroxamic acid (Asuha) building block compatible with standard SPPS. Such a building block has been prepared by a number of
groups using Asu as starting material and already presented as potential tool for the
investigation of HDACs using substrate mimics [63]. Standard Fmoc SPPS was used
for the synthesis of a histone 2B fragment analogue containing a surrogate of lysine
12 (H2BK12Asuha), and the hydroxamic acid group of Asuha was protected with a
4-methoxybenzyl (PMB) group during SPPS (Fig. 5). A similar synthetic strategy
was followed by Schwarzer and coworkers employing tert-butyl as protecting group,
although its deprotection required longer acidic treatment than common groups used
for SPPS [64].
4 Structure-Activity Relationship of Macrocyclic HDAC
Inhibitors
Trapoxin A (TpxA, Fig. 6 compound 6.18) was the first of a series of naturally
occurring cyclic peptides described to inhibit histone deacetylation by targeting
HDACs [22]. The structural characteristics of these compounds are interesting for
the design of HDAC inhibitors, since their macrocyclic scaffold acts as the “capping
group” of the pharmacophore model and is able to interact with a large surface area
H 2 N
OH
O
OH
O
a) FmocOsu, NaHCO 3 ,
1,4-dioxane:H 2 O (1:1)
b) Paraformaldehyde, p-TsOH, toluene
c) i) (COCl) 2 , cat. DMF, CH 2 Cl 2
ii) H 2 NOPMB, NEt 3, CH 2 Cl 2
N
H
O
OPMB
HN
O
O
d) THF:1 N NaOH (1:1)
e) FmocOSu, NaHCO 3 ,
acetone:H 2 O (1:1)
N
H
O
OPMB
FmocHN
OH
O
Fig. 5 Synthesis of protected L-α-aminosuberic hydroxamic acid (Asuha) building block for
SPPS [63]
36
C. Moreno-Yruela and C. A. Olsen