Peptide-Based Drug Design

Peptidomimetics 227
not without its disadvantages. The greatest disadvantage of peptidosulfonamide
peptidomimetics is the ability of sulfonamide moiety to disrupt any defined
secondary structure of the parent peptide in solution, even if present at the
N-terminus (16,17). The following structural features of the sulfonamide moiety
may contribute to this phenomenon:
1. Sulfonamide N-H is more acidic than amide N-H and therefore a better H-bond
donor but a poorer H-bond acceptor.
2. The presence of two sulfonamide oxygens as H-bond acceptors may also impair a
H-bonding network which holds together a secondary structure.
3. The sulfonamide oxygens can assume varying positions due to less energydemanding
rotation about the sulfonamide bond. This may also prevent a proper
alignment of the H-bonds necessary for a particular secondary structure.
Despite these sulfonamide peptidomimetic disadvantages, the pharmacological
properties of peptides may be improved by introducing the sulfonamide
residue at one of several possible positions within the peptide sequence while
maintaining the desired biological activity (18,19).
3.1.1. Synthesis of Peptidosulfonamide Monomeric Building Blocks
The key step in the synthesis of peptidosulfonamides is the conversion of
an amino acid into corresponding activated sulfonic acid derivatives such as
sulfinyl- and sulfonyl chloride (Fig. 2) (16,20). Typical synthesis of Fmocprotected
β-substituted-β-aminoalkylsulfonyl chlorides include reduction of
Fmoc-protected amino acid to corresponding alcohol, conversion of the alcohol
to sulfonic acid, and, in a final step, chlorination with thionyl chloride (21,22),
phosgene (17,23–25), or triphosgene (18,26). Since traces of triphosgen can
significantly lower coupling yields during the peptidosulfonamide solid-phase
assembly (23) and phosgene is highly toxic, the use of thionyl chloride as a
chlorinating agent represents the most practical approach. Another interesting
R 1
R 2 -(H)N COOH
Cs 2 CO 3 , HSAc,
DMF, 50 °C
1) NMM, DME, iBuO-CO-Cl
2) NaBH 4 , H 2 O, –15 °C
R 2 -(H)N
R 1
R1 = amino acid's side chain
R2 = Fmoc, Boc, Cbz, phthalimide
SAc
1) H 2 O 2 , HOAc
2) Pd/C
R 2 -(H)N
R 2 -(H)N
R 1
OH
R1 O O
S
OH
MsCl, Et 3 N,
CH 2 Cl 2 ,0 °C to r.t.
SOCl 2 or
SOCl 2 /DMF
R 2 -(H)N
R 2 -(H)N
Fig. 2. Synthesis of protected sulfonyl chloride building blocks.
R 1
OMs
R1 O O
S
Cl