Biomedical Engineering Reference
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developed a tris-benzamide scaffold with substituents that mimic the
i
,
i þ
4 and
i þ
7 positions of an ideal a-helix. This scaffold is easy to
synthesize and possesses a slightly higher conformational flexibility
than the corresponding tris-pyridyl amide, due to the lack of a hydrogen
bond between the amide and the nitrogen on the pyridine ring. According
to the authors, this results in a less flattened structure, which gives a better
topological correspondence with the a-helix [315]. The terphenyl scaf-
fold has recently been replaced by a terephtalamide scaffold, which has
an increased water solubility and membrane permeability [316].
Antagonists of the Bcl-x
L
/Bak protein interaction with mM potency
were obtained.
COOH
Ac
CH
3
H
COOH
O
O
N
CH
3
HN
O
O
O
O
i
N
R
i
R
i
R
i
R
i
R
i
O
i+3
H
R
i+3
N
O
i+4
N
O
H
R
i+1
/
i+4
R
i+4
R
i+1
O
N
R
i+4
R
i+4
O
R
i+7
R
i+7
i+7
H
O
N
O
N
H
O
N
R
i+7
Horwell indane
R
i+7
O
COOH
COOH
CH
3
O
HN
O
H
Hamilton terphenyls
tris-pyridylamide
tris-benzamide
Bn
R
i
R
i
R
i
R
i
R
i
R
i
HOOC
R
i
N
N
N
HN
O
N
O
N
O
N
H
N
R
i+3
R
i+4
R
i+3
N
R
i+3
R
i+4
N
R
i+3
O
H
R
i+4
N
HN
N
O
N
N
O
R
i+7
R
i+7
R
i+7
O
N
R
i+7
R
i+7
N
N
R
i+7
N
CH
3
O
R
i+7
N
N
N
N
Ac
Ac
Bn
terephtalamide
enaminone
pyridazin
pyrrole
dipiperidinobenzene
terpyridyl
Figure 3.41 Helix surface mimetics
Considering that six-membered ring hydrogen bonds can impart
structural rigidity, Hamilton recently designed an enaminone helix
mimetic. This scaffold can be considered as a simplified terphenyl scaf-
fold in which the central phenyl ring has been replaced by a more polar
ring [317]. As alternatives for the terphenyl scaffold, with better
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