Biomedical Engineering Reference
In-Depth Information
SCHEME 8.9
Solid-phase synthesis of cyclic peptoids using RCM as the macrocyclization
reaction.
second-generation catalyst [68]. This follows a number of reports on the use of RCM
for the solid-phase synthesis of surrogates of
-helices [69], cyclic peptides [70], and
macrocyclic semipeptides targeting RNA [71].
8.4.4 Semipeptidic Macrocycles
Several groups have focused on the synthesis of semipeptidic macrocycles incor-
porating both peptidic and nonpeptidic fragments, with the goal of improving the
physicochemical and PK-ADME profile of the resulting molecules by reducing its
peptidic character while conserving the preorganized structure of the macrocycle
and its concomitant advantages in terms of target potency and selectivity. Marsault
et al. reported the synthesis of
20,000 macrocycles using the strategy shown in
Scheme 8.10 [72]. In this approach, 14- to 22-membered macrocycles were syn-
thesized using a solid-phase approach [19]. The tripeptide group was anchored to
the resin via a semilabile thioester linker, which prevented the use of Fmoc chem-
istry. Accordingly, Ddz was chosen as a highly acid-labile protective group for the
>
-amino group of amino acids, allowing side-chain protection with acid-labile
t
-Bu
ethers, esters, and Boc carbamates. The third amino acid was protected as a benzothia-
zolyl sulfonamide (Bts) to give peptidic fragment
51
, which enabled attachment of the
nonpeptidic tether component under mild Fukuyama-Mitsunobu conditions to pro-
vide macrocyclization precursor
52
. Deprotection of the Ddz group was followed by
concomitant macrolactamization release, which delivered crude compounds of gen-
eral formula
53
with acceptable purity since any uncyclized materials remained on
the resin and were removed by filtration [73]. In this case, macrocyclization benefited
from on-resin pseudo-high dilution [74]. Finally, Bts removal using a solid-supported
thiophenoxide followed by side-chain acidolysis delivered crude macrocycles which
were tested as such by high-throughput screening (HTS). Not surprisingly, macrolac-
tamization yields were found to be very sensitive to tripeptide sequence, ring size, and
the chirality of the amino acid side chains. Presumably due to easier chain folding,
heterochiral sequences cyclized more readily than do their homochiral counterparts,
and the use of silver(I) activation was found to be beneficial for both yield and
monomer/dimer ratio [19]. Alternative approaches, such as RCM-mediated cyclative
