Submonomer Approach to Peptoid Synthesis

Although the nature of the peptoid backbone is quite similar to the nature of the peptide backbone, these new unnatural oligomers display some peculiar characteristics (i) the peptoid backbone is achiral (ii) peptoids are devoid of amide protons, which decrease their polarity and should increase their oral bioavailability (iii) they lack the NH-donor bond and, therefore, they do not have the possibility to form intra- or intermolecular H-bonding through the backbone (iv) they can be more flexible and adopt altered conformations and (v) they contain only tertiary amide bonds, which display a higher protease stability [7], 

The NSG oligomers derive from an alternated sequence of acylation reactions and SN2-reactions which allowed to obtain homo- and heteropentamers in high yield and purity, 

Recently, a combinatorial library of cationic peptoids has been used to discover reagents for gene delivery. A series of NSG oligomers, up to 36 residues in length, were shown to condense plasmid DNA into small peptides, to protect it from nuclease degradation, and to mediate the transfection of several cell lines [10]. 

These examples show how the combinatorial peptoid approach holds enormous potential for the discovery of novel lead structures for drug development. In this context a postmodification on solid-phase of peptoid side chains, bearing alkene and alkyne moieties, via [3 + 2] cyclo-addition of nitrile oxides, enhances further the molecular diversity and the possibility to find new therapeutic agents [11]. Moreover, polymers of N-substituted glycines containing chiral side chains display interesting conformational preferences [12]. NMR and CD data indicate that the major species adopts in methanol a stable right-handed helical structure with o. v-amidc bonds. 

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