with hydrazone amides to yield “peptoid hydrazones” of type
4 (Scheme 2).
Scheme 1. Peptoid Synthesis by the “Submonomer” Approach
Scheme 2. Synthesis of Peptoid Hydrazones (4) and Peptoid
Hydrazides (5) from a Common Hydrazide Precursor (3)
protein with the short peptide motif, “Pro-Thr/Ser-Ala-Pro”
(“PTAP”), located within the p6 region of the viral Gag
protein.6 An NMR solution structure of the PTAP-containing
p6Gag-derived 9-mer peptide, “P-E-P-T-A-P-P-E-E” bound
to Tsg101 indicated that the most important interactions were
derived from the “Ala-Pro” residues, which are in deep
depressions reminiscent of the “Xxx-Pro” pockets used by
WW and SH3 domains.7 The similarities shared by Tsg101
and SH3 domains in their recognition of key Pro residues
suggests that replacement of Pro residues with NSG con-
structs may also be beneficial for the preparation of PTAP-
based Tsg101 binding inhibitors.7
The solid-phase synthesis of NSG-containing libraries is
usually achieved by the “submonomer approach”, in which
the amino terminus of the growing peptide chain is bro-
moacetylated, then reacted with amines to yield the corre-
sponding NSG residues (Scheme 1).8 However, this approach
can be disadvantageous for long or difficult sequences.9 We
found such to be the case with the p6Gag-derived 9-mer
sequence “P-E-P-T-A-P-P-E-E”, where the Pro3 residue
could be satisfactorily replaced by an NSG residue by using
the submonomer approach, but replacement of the critical
Pro6 residue (changing P-E-P-T-A-P-P-E-E to P-E-P-T-A-
[NSG]-P-E-E) proved to be problematic. Although the
reasons for this difficulty appeared to be sequence related
and steric in nature, modifications that would be expected
to ameliorate steric crowding, such as replacement of the
Pro3 residue by Ala (i.e., P-E-P-T-A-[NSG]-A-E-E) or
resorting to a C-terminal pseudo-proline strategy10 (for
P-E-P-T-A-[NSG]-P-E-E-S), failed to overcome the prob-
lems. To work around the impasse presented above, we
envisioned substituting the traditional peptoid NSG unit (1)
Peptoid hydrazones would be advantageous over traditional
N-alkyl NSG residues for library synthesis, since variation
of each N-alkyl NSG residue requires the separate elaboration
of the entire peptide sequence amino-terminal of the NSG
residue. On the other hand, libraries of peptoid hydrazones
could be constructed by reacting a series of aldehydes
(Yn-CHO) with a single completed peptide bearing an
unsubstituted hyrazide (3). Furthermore, subjecting the re-
sulting peptoid hydrazones 4 to reducing conditions could
lead to library diversification by formation of the corre-
sponding N-substitued peptoid hydrazides (5). Although
several variations on traditional peptide amide bonds have
been reported, including azapeptoids,11 urea peptoids,12
amino-oxypeptoids,13 â-peptoids,14 hydrazine (retro)-pep-
toids,15 and azapeptides,11 hydrazone amides have found very
limited use.15 The current work represents one of the first
systematic examinations against an important biological
target of mixed peptide-peptoid constructs utilizing hydra-
zone (4) and hydrazide (5) based NSG residues.
The objective of the current study was to prepare a library
of Tsg101-directed peptides of the sequence “FTP-P-E-P-
T-A-X-P-E-E-amide”, where “X” represents “N(R-CdN)-
CH2C(O)” and “FTP” stands for amino-terminal “fluorescein
thiourea pentanoyl” functionality. The latter would be
required for analysis of Tsg101 binding affinities using
fluorescence anisotropy.16
The first attempt at solid-phase synthesis used a modified
submonomer approach that involved reacting tert-butyl
carbazate with the N-bromoacetylated peptide chain. How-
(11) Gibson, C.; Goodman, S. L.; Hahn, D.; Hoelzemann, G.; Kessler,
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