Biomedical Engineering Reference
In-Depth Information
synthetic accessibility and an amphiphilic structure with a hydrophobic
surface for recognition along one side and a polar edge for solubility
along the other side, Rebek designed pyridazine- and pyrrole-based
scaffolds [318,319]. These scaffolds can be assembled in a modular
way and should allow the targeting of a range of protein-protein inter-
actions. A similar modular assembly was used for the preparation of
1,4-dipiperidino benzenes [320]. An X-ray crystal structure of the
mimetic revealed a good similarity between the side chain orientations
and that in an a-helix.
In a recent study, Marshall computationally evaluated various helix
mimetic scaffolds and found that the terphenyl scaffold is not rigid but
can adopt 16 conformations with almost equal energy. Various other
a-helix mimetics, such as the terpyridyl scaffold (Figure 3.41), that should
be more effective than the terphenyl scaffold were proposed, based on
theoretical calculations [224,321].
Trisubstituted imidazoles, which can be prepared by van Leusen multi-
component reactions, were designed as alternatives to the Hamilton
terphenyl mimics (Figure 3.42). A good correspondence with the
i
,
i þ
3
and
i þ
7 positions in an a-helix was demonstrated by molecular model-
ling [322]. Selective inhibitors of the Bcl-w/Bak-BH
3
interaction with mM
potency were prepared.
O
RO
R
i
R
i
R
i
H
H
NH
N
O
i
N
N
()n
O
H
H
NH
O
H
N
N
O
O
N
()
n
R
i+3
N
R
i+3
N
H
R
i+4
COOBn
H
H
N
i+3
N
N
O
O
N
H
H
O
H
N
O
O
i=4
O
H
H
R
i+8
Ri
+7
R
i+7
O
O
polyether
imidazoles
bis-imidazole
triazine
Figure 3.42 Helix surface mimetics
In addition, ladder-like polyethers were developed by Hirama and
coworkers to mimic
i
,
i þ
4 and
i þ
8 positions in a helix [323,324].
A different approach was followed by Todd and collaborators, who
proposed a bis-imidazole scaffold in which the amino acids attached to
the imidazoles mimic the residues in the
i
and
i þ
4 positions of the helix
(Figure 3.42). The compound was shown to block HCV-E2 binding to
CD81 in mM concentration [325].
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