Biomedical Engineering Reference
In-Depth Information
character of the peptide bond, its hydrogen bond donor and acceptor func-
tions, or its steric bulk. Therefore, substituted alkenes have been prepared
(Figure 3.19). The fluoroalkene isostere restores the polarity of the original
amide function, and several stereoselective synthetic approaches to this
isostere have been developed [156].
O
X
N
N
N
N
N
H
O
O
O
Y
O
O
X
N
N
Y
NH
N
N
O
O
O
O
Figure 3.19 Alkene isosteres as
trans
and
cis
amide bond mimics
The (E)- and (Z)-fluoroalkene and alkene isosteres were used to probe
the structural requirements for dipeptide recognition by the peptide trans-
porter PEPT1. A preference for the
trans
amide equivalents was found, but
contrary to the expectation, no increased affinity for the fluoroalkene
versus the alkene isostere was observed [157]. Fluoroalkene tripeptide
analogues were proposed as ground-state analogue inhibitors for thermo-
lysin: they bound to thermolysin about one order of magnitude more
thightly than the substrates [158]. A CF
3
-substituted (E)-alkene isostere
was proposed to provide an improved mimicry of the electrostatic poten-
tial surface of the amide bond, as well as of its dipole moment [159].
Efficient synthetic methods for the asymmetric synthesis of this dipeptide
isostere have been reported [160,161]. Methyl-substituted alkenes were
shown to induce b-turn conformations in a peptide [159,162]. In
Gramicidins S, the incorporation of the LeuC[(E)-C(CF
3
)
¼
CH]
D
-Phe
isostere resulted in a better agreement with the secondary structure of
the native Gramicidin S, than was that of the LeuC[(E)-
C(CH
3
)
¼
CH]
D
-Phe isostere [160]. In the same cyclic peptide, the
D
-PheC[(E)-C(CH
3
)
¼
CH]Ala dipeptide isostere was shown to be an
effective replacement for
D
-Phe-Pro in a type II
0
b-turn conformation [163].
In contrast to the C(CH
2
NH) analogues, the synthesis of the alkene
isosteres
requires
a
considerable
synthetic
effort.
This
limits
the
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