Biomedical Engineering Reference
In-Depth Information
SCHEME 8.8
Diversity-oriented synthesis of macrocyclic peptidomimetics using “click
chemistry.”
compounds. Interestingly, the approach provides two synthetically related classes of
macrocycles that differ by their degree of rigidity and topology. Thus,
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can be
obtained from
45
by diketopiperazine formation. Diversity stems from the choice
of building blocks
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and
48
, which governs the orientation and chemical nature of
appendages as well as ring size. Building block assembly used standard peptide cou-
pling, whereas macrocyclization was performed by “click” chemistry following the
build/couple/pair (B/C/P) scheme developed by Nielsen and Schreiber [66]. Using
principal components analysis (PCA), the authors demonstrated that this collection
of 12 analogs covered a distinct and broad chemical space compared to a set of 657
approved drugs.
8.4.3 Macrocyclic Peptoid Libraries
Peptoids (N-alkylated glycine oligomers) are known to be proteolytically stable
and can be accessed easily with broad diversity. They have been associated with
increased cell permeability compared to native peptides [67]. Grubbs and co-workers
recently reported the optimization of a synthetic method for solid-phase synthe-
sis of cyclic peptoids (Scheme 8.9). The authors reported high RCM yields of
precursor
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to yield resin-supported macrocycle
50
using the Hoveyda-Grubbs
