Biomedical Engineering Reference
In-Depth Information
Broken bonds indicate an alternate site for cyclization
O
O
O
O
R
R
C
C
N
C
N
H
C
H
N
C
N
C
H 2 C
(CH 2 ) n
CH 2
C
(CH 2 ) n
O
Alkylation
O
Acylation
O
R
O
O
O
R
C
N
N
C
N
C
H
C
CN H
C
(CH 2 ) n
H 2 C
S
(CH 2 ) n
HN
H
trans -Guanidation
Thioether
O
R
O
R
O
O
O
N
N
O
N
O
N
NH 2
NH 2
Re
Re
R
N
O
S
R
N
S
O
O
Anti
Syn
FIGURE 8.7
Other cyclic constrains.
By restricting the l exibility the number of conformations of linear peptides can be reduced. To
reduce these dynamic degrees of freedom, cyclization is an excellent protocol that has revolution-
ized the discipline of peptide chemistry. Such global modii cations within a linear biologically
active peptide offer essential advantages such as: (a) increasing agonist and antagonist potency; (b)
reducing proteolytic degradation; (c) increasing receptor selectivity; (d) enhancing bioavailability;
and (e) providing conformational insight for receptor/acceptor binding and drug design.
Global constraints can be established by introducing a covalent bond between any two given
positions along the peptide chain. The classic examples include, lactam bridges, disuli de bonds,
or by introduction of spacers like a succinyl [
] moiety. These linkages or bridges
can be broadly categorized into four distinct ways: (1) side chain to side chain; (2) side chain to N- or
C-terminus; (3) N- to C-terminal; and (4) backbone residue to backbone residue (for instance, N or C α
of the backbone).
A classic and natural example is oxytocin, which has a disuli de bridge that is necessary for its
full biological activity. Among synthetic constrained peptides, DPDPE (H-Tyr-c[d-Pen-Gly-Phe-d-
Pen]-OH) and MT-II (Ac-Nle-c[Asp-His-d-Phe-Arg-Trp-Lys]-NH 2 ) are well-known examples of
side chain to side chain cyclized bioactive superagonists toward the
CO
(CH 2 ) 2
CO
-opioid and melanocortin
receptors-respectively (Figure 8.6). DPDPE, which is derived from the linear enkephlin pharma-
cophore, bears the disuli de linkage from the side chains of d-penicillamine. Ligands like DPDPE
are of high interest for development of potent and selective ligands that can exhibit high efi cacy and
facilitate development of drugs toward neuropathic pain. Another example of side chain cyclization
is MT-II and SHU9119 (Figure 8.6), which exhibit totally opposite biological proi les toward certain
melanocortin receptors. These ligands were the result of a careful structure-activity relationship
δ
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