Biomedical Engineering Reference
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widespread application of this type of isostere. Synthetic methods for the
C(CH
¼
CH) isostere have been reviewed [164], and new ones are still
being developed [165,166]. A recent report on a solid-phase procedure to
assemble the alkene isostere using aziridine building blocks might
improve this situation [166,167]. Despite the differences in polar and
steric character, alkene replacements have resulted in active and stable
pseudopeptides. The Leu
13
C[(E)-CH
¼
CH]Leu
14
bombesin(6-14) ana-
logue turned out to be an antagonist, like its C(CH
2
NH) analogue [168].
Recently, C(CH
¼
CH)-containing dipeptide mimics have been con-
verted into cyclopropane amide bond isosteres (CPDIs), which have a
more flexible backbone. These CPDIs should have a greater resistance to
oxidative metabolism that the corresponding alkene isosteres [169].
Other rigid replacements mimicking an amide bond use aromatic or
heteroaromatic rings. The 1,2,4-oxadiazole and 1,2,4-triazole rings
mimic the
trans
amide bond geometry [170,171], while the o-substituted
benzene (o-AMPA), the tetrazole and the pyrole rings mimic the
cis
amide
bond geometry [172-174]. The 1,2,3-triazole motif has recently become
an attractive isostere because of its easy synthesis through Cu(I)-catalysed
Huisgen 1,3-dipolar cycloaddition chemistry [175,176] (Figure 3.20).
O
R
2
R
1
H
R
1
O
N
NH
H
H
H
O
R
2
O
O
O
R
2
R
1
R
2
R
1
O
H
H
N
N
H
H
H
H
N
O
N
N
N
1,2,4-oxadiazole
o-AMPA
tetrazole
O
R
1
O
O
R
2
N
H
H
H
H
N
N
HN
N
H
N
H
N
1,2,4-triazole
1,2,3-triazole
1,2-pyrole
Figure 3.20 (Hetero)aromatic ring replacements for the amide bond
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