Neoglycopeptidomimetics

Solid phase glycopeptide synthesis is now routine operation in laboratories and has been used to prepare multivalent sialyl LewisX by chemoenzymatic combination [60]. Such a strategy allows investigators to obtain oligomers of varied valency (up to 8) and interspaced by determined numbers of amino acid residues. While this strategy is conceptually appealing, it still lacks the advantages conferred to peptidomimetics if therapeutically valuable products are foreseen. The design of peptide isosteres would be highly preferable, following common practice in drug developments. The recent development of peptoids derived from simple N-substituted oligoglycines seems to fulfill the required criteria of metabolic stability and synthetic simplicity [61]. Our laboratory has been involved in the design of related N- [62] and O-linked [63] glycopeptoids.

Once model glycopeptoid syntheses had been established, we decided to prepare sialic acid oligopeptoids having controlled distances both between the backbone and between the repeating units [52]. To this end, a convergent blockwise approach with orthogonally protected derivatives was chosen. The following example illustrates the synthesis of linear sialic acid oligomers interspaced by two N-substituted glycine residues onto which was attached a 6-aminocaproic acid spacer (Scheme 6).

a-Sialosyl azide 8 was transformed into Cbz-protected amine derivative, which upon hydrogenolysis afforded amine 31. A similar strategy has been used by Sabesan [64] to prepare saccharopeptides. This approach allows the preparation of the required a anomer because this configuration is absolutely critical for the sialic acid's biological activity. Amine 31 was then transformed into key building block 32 following initial treatment with ferf-butylbromoacetate (75%) and N-bromoacetylation with bromoacetic anhydride (92%). This orthogonally protected intermediate 32 can be elongated from either direction depending on the strategy chosen. N-Alkylation of 32 by amine 31 afforded dimer 33 which has been N-acetylated to end group 34 (AcCl, 91%) or to middle group 35 after Cbz protection (89%). Sequential depro-tection of ferf-butyl ester or Cbz group followed by amide coupling (DCC) of the resulting amino acid derivatives afforded tri-, tetra-, hexa-, and octamers such as 36, after protecting group removal under standard conditions. The resulting ''sialopep-toids'' were thus made available for biological evaluation. Unfortunately, their inhibitory properties against influenza virus hemagglutination were rather negligible compared with dendrimers or polymers (see below).

Was this article helpful?

0 0

Post a comment