Access to Poly-β-Peptides with Functionalized Side Chains and End Groups via Controlled Ring-Opening Polymerization of β-Lactams

Abstract

Poly-beta-peptides are attractive for biomedical applications because the backbone is similar enough to that of proteins for biocompatibility, but the backbone is sufficiently unnatural that these polymers evade proteolytic degradation. Prior investigations of poly-beta-peptides have been hindered by two principal limitations: (1) most known examples are insoluble, and (2) the range of accessible side chain functionality has been quite limited (mostly simple hydrocarbon units). The present study describes innovations in poly-beta-peptide synthesis that enable the preparation of diversely functionalized examples and provide the basis for broad exploration of the properties and applications of these nylon-3 materials. We describe several beta-lactams with a protected amino group in their side chain that readily undergo ring-opening polymerization (ROP). These monomers are available in large quantities via N-chlorosulfonylisocyanate (CSI) cycloaddition reactions with functionalized alkenes; previously CSI reactions have been limited to alkenes with hydrocarbon substituents. Postpolymerization deprotection of the amino groups leads to water-soluble poly-beta-peptides. In addition, we introduce a simple co-initiation strategy that allows placement of a wide variety of functional groups at the N-termini of poly-beta-peptide chains. ROP involving the new beta-lactams and co-initiation strategy exhibits characteristics of a controlled polymerization and enables the preparation of amphiphilic block copolymers. We have recently shown that cationic copoly-beta-peptides made available by these innovations mimic the selective antibacterial activity of host-defense peptides; the results described here provide the foundation for further exploration of this valuable activity and for the pursuit of other biological applications such as DNA/siRNA delivery and tissue engineering.

Two interdependent mechanisms of antimicrobial activity allow for efficient killing in nylon-3-based polymeric mimics of innate immunity peptides

“…The nylon-3 backbone, comprised of β-amino acid residues, should be similar to the polyamide backbone of proteins in terms of physicochemical properties. Binary hydrophobic-cationic nylon-3 materials are readily prepared via anionic ring-opening polymerization of appropriate pairs of β-lactams [56]. …”

Functionally Diverse Nylon-3 Copolymers from Readily Accessible β-Lactams

“…2 Recently we have developed β -lactams (e.g., 1 and 2 ) that bear a protected primary amino group in a side chain and enable the preparation of cationic nylon-3 polymers. 3 This synthetic advance allowed us to identify nylon-3 cationic/hydrophobic copolymers that display a variety of interesting biological activities. 4 However, the range of functional groups that can be incorporated into nylon-3 polymers via CSI-derived precursors remains limited.…”

“…Each of the new β -lactams proved to be compatible with the AROP conditions (treatment with LiN[Si(CH 3 ) 3 ] 2 and an acylating agent, the latter for in situ co-initiator generation 3b ), but their reactivities were variable. The side chain protecting groups could be removed under acidic conditions after polymerization.…”

“…25 units derived from 6 , was synthesized through a previously described approach. 3b Treatment of the protected copolymer with trifluoroacetic acid generated the corresponding zwitterionic di-block copolymer. Polymer P8- b -6 is fully soluble in aqueous buffer solution at low pH or at high pH, but solutions near neutral pH are turbid (Figure S1).…”

“…7 β -Lactam 9 leads, after polymerization and deprotection, to a subunit with two hydroxyl groups in each side chain; this building block is considerably easier to prepare than is a β -lactam we have previously described that generates a different type of di-hydroxyl subunit. 3a After removal of the cyclic acetal protecting group, a nylon-3 random copolymer ( P9- r -13 ) (Chart 3; M n = 5.8 k, M w /M n = 1.07 for the protected polymer) generated from 9 and cyclohexyl β -lactam 13 was readily soluble in water regardless of pH.…”