Peptide-Based Drug Design

226 Cudic and Stawikowski
4. Specific reagents including diethyl azodicarboxylate (DEAD) and derivatives,
triphenylphosphine (PPh3), 9-fluorenylmethoxycarbonyl chloride (Fmoc-Cl),
isobutyl chloroformate (iBu-CO-Cl), methanesulfonyl chloride (MsCl),
4-nitrophenylethyl chloroformate (NPEOC), 4-nitrophenyl chloroformate,
hydrogen peroxide, thionyl chloride, thioacetic acid (HSAc), cesium carbonate
(Cs2CO3), palladium on activated carbon (10% Pd) (Pd/C), and celite (diatomaceous
earth, diatomaceous silica) can be purchased from Sigma-Aldrich, Fisher,
VWR, or other commercial sources.
5. Resins for solid-support synthesis can be obtained from Rapp-Polymere
(Germany), Novabiochem (USA), Advanced ChemTech (USA), ChemImpex, and
other suppliers.
3. Methods
From the synthetic point of view, the methods for assembly of peptidosulfonamides,
phosphonopeptides, oligoureas, depsides, depsipeptides, peptoids, and
peptomers parallel those for standard solid-phase peptide synthesis, although
different reagents and different coupling and protecting strategies need to
be used. Since these peptidomimetics can be constructed in a modular way
from orthogonally protected monomeric building blocks and they are therefore
suitable for potential combinatorial chemistry diversity, the solid-phase methodology
is the method of choice for their synthesis. Particularly attractive is Fmoc
solid-phase methodology since it is now a standard approach for the routine
peptide synthesis. Therefore, in this chapter we describe only modifications of
the peptide main chain using the solid-phase methodology that includes or is
fully compatible with the Fmoc chemistry.
3.1. Peptidosulfonamide Synthesis, Ψ [CH2-SO2-NH]
The tetrahedral achiral sulfur atom bonded to the two oxygen atoms possesses
geometry similar to the high-energy intermediate formed during the amidebond
hydrolysis or amide-bond formation (13,14). Therefore, peptidosulfonamides
are at the same time stable to proteolytic hydrolysis and capable
of significantly altering polarity and H-bonding patterns of native peptides.
Because of the relative acidic N-H in a sulfonamide moiety, it can be expected
that H-bonds involving this amide surrogate will be stronger as compared
to the amide analogs. These sulfonamides’ properties made the peptidosulfonamides
attractive building blocks for synthesis of peptidomimetics with
enhanced metabolic stability and potentially potent enzyme inhibitory activities.
Due to the intrinsic chemical instability of α-peptidosulfonamides, most of
the peptidomimetics containing a sulfonamide bond have been limited to more
stable β-peptidosulfonamides (15). However, this peptidomimetic approach is