Biomedical Engineering Reference
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indicated between brackets. Theoretical studies have compared the steric
and electronic equivalence of different isosteres with the amide bond
[124,125]. It is clear that the different types of modification will influence
the physicochemical properties of the resulting pseudopeptide, such as the
polarity, flexibility, hydrogen bond donating or accepting character.
Therefore, it was soon realized that as well as preventing the enzymatic
cleavage and influencing the membrane permeability, peptide bond repla-
cements were also giving important information on the role of the amide
function in receptor interaction by influencing the affinity and selectivity.
Moreover, in many cases they also influenced the agonist or antagonist
character of the native peptide, and provided a method to design enzyme
inhibitors based on the concept of transition state analogues.
R
1
O
R
1
O
N
H
H
Ψ
( )
H
H
R
2
O
R
2
R
1
R
1
O
Y
O
R
1
R
1
O
O
N
N
H
N
H
N
H
N
H
H
H
H
H
R
2
R
2
R
2
R
2
X
Ψ
(CH
2
NH
2
)
Ψ
(CX=CY)
Ψ
(CH
2
-CH
3
)
Ψ
(cyclopropane)
X = H,F,CH
3
,CF
3
;
Y = H,CH
3
R
1
R
2
R
1
R
1
O
OH
O
N
H
H
H
H
H
H
R
2
OH
O
OH
R
2
OH
Ψ
(CHOH-CH
2
-NH), HEA isostere
Ψ
(CHOH-CH
3
)
Ψ
(CHOH-CH
2
OH)
R
1
R
1
R
1
R
1
O
O
O
O
O
O
O
O
S
S
S
H
H
H
H
H
H
H
H
R
2
R
2
R
2
R
2
Ψ
(CH
2
-OH)
Ψ
(CH
2
-SH)
Ψ
(CH
2
-SO)
Ψ
(CH
2
-SO
2
)
Figure 3.17 Examples of amide bond modifications
A comprehensive discussion would be beyond the scope of this chapter,
but the potential of this type of pseudopeptide modification will be
illustrated with some representative examples.
One of the most popular isosteres has been the reduced amide isostere:
C(CH
2
NH). Synthetically, it is one of the easiest modifications of the
peptide backbone, mostly obtained by reductive amination of the grow-
ing peptide with Boc- or Fmoc-protected aminoaldehydes, both in solu-
tion and on solid phase [126,127]. Recent alternatives such as Mitsunobu
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