Biomedical Engineering Reference
In-Depth Information
O
NH
2
O
R
N
R
H
H
H
N
H
H
OH
O
Scheme 9.2
development was designed based on the classical KLK3/PSA substrate: His-
Ser-Ser-Lys-Leu-Gln, selected form semenogelin II, which is a KLK3/PSA
natural protein substrate.
113
Glu at the C-terminus is not recommended for
aldehyde modification due to hemiaminal formation (Scheme 9.2)
114
and also
Glu boronic acid modifications are not feasible to produce.
112
Successful replacement of Gln by Leu or nor-Leu was carried out. Leu led to
the production of 9.23.
112
Despite the fact that 9.23 had a marginal effect in
subcutaneous prostate-tumor xenografts,
112
it may find applications in diag-
nosis as described below. Boronic acid led to powerful inhibitors, since the
aldehyde-modified peptide Cbz-Ser-Ser-Lys-Leu-Leu-CHO exhibited a K
i
of
6.51 mM which is 100-fold higher than the boronic acid analog 9.23.
115
In
addition, nor-Leu replacement led to development of the Cbz-Ser-Ser-Lys-Leu-
n(boro)-L inhibitor that exhibited an even lower K
i
of 25 nM.
116
NH
2
OH
OH
O
O
O
N
NH
OH
O
H
H
H
B
O
O
OH
OH
OH
9.23
O
NH
2
OH
O
O
O
N
N
OC
OC
N
N
+
OC
Re
N
OH
OC
H
H
H
B
N
O
O
OH
OH
9.24
9.4.3 Imaging Based on KLK3/PSA
The highly specific expression of KLK3/PSA in the prostate gland makes it
ideal for imaging purposes. In vivo imaging is based on designing specific
