Combining Orthogonal Reactive Groups in Block Copolymers for Functional Nanoparticle Synthesis in a Single Step

Abstract

We report on the synthesis of polysarcosineblock-poly(S-alkylsulfonyl)-L-cysteine block copolymers, which combine three orthogonal addressable groups enabling sitespecific conversion of all reactive entities in a single step. The polymers are readily obtained by ring-opening polymerization (ROP) of corresponding α-amino acid N-carboxyanhydrides (NCAs) combining azide and amine chain ends, with a thiolreactive S-alkylsulfonyl cysteine. Functional group interconversion of chain ends using strain-promoted azide−alkyne cycloaddition (SPAAC) and activated ester chemistry with NHS-and DBCO-containing fluorescent dyes could be readily performed without affecting the cross-linking reaction between thiols and S-alkylsulfonyl protective groups. Eventually, all three functionalities can be combined in the formation of multifunctional disulfide core cross-linked nanoparticles bearing spatially separated functionalities. The simultaneous attachment of dyes in core and corona during the formation of core-cross-linked nanostructures with controlled morphology is confirmed by fluorescence cross-correlation spectroscopy (FCCS).

Reactive Precursor Particles as Synthetic Platform for the Generation of Functional Nanoparticles, Nanogels, and Microgels

“…Barz and co‐workers also took advantage of this high orthogonality of SPAAC in order to synthesize nanogels and add different functionalities in a single reaction step . The authors used polysarcosine‐ b ‐poly( S ‐alkylsulfonyl)‐ l ‐cysteine block copolymers with three reactive, orthogonally addressable groups.…”

“…Block copolymers were prepared having a combination of azides and amines as chain end groups and a thiol reactive S ‐alkylsulfonyl cysteine. The modification proceeded during the formation of core‐crosslinked nanostructures through the thiol reactive moieties, and involved the simultaneous introduction of fluorescent dyes previously modified with dibenzyl cyclooctyne and NHS for reaction via SPAAC and activated esters chemistry, respectively …”

Of Thiols and Disulfides: Methods for Chemoselective Formation of Asymmetric Disulfides in Synthetic Peptides and Polymers

“…The orthogonality of the thiol‐reactive moiety of the S ‐alkylsulfonyl protecting group towards strain‐promoted azide‐alkyne cycloaddition (SPAAC) and activated ester‐mediated amidation was investigated in amphiphilic polysarcosine‐ block ‐poly(S‐alkylsulfonyl)‐ l ‐cysteine block copolymers (Figure C). All three functionalities can be addressed independently, thus allowing for functional group interconversion of chain ends, as well as directed disulfide formation in the side chain of the PCys(SO 2 R) block in one step …”

“…All three functionalities can be addressed independently,t hus allowing for functional group interconversion of chain ends, as well as directed disulfide formation in the side chain of the PCys(SO 2 R) block in one step. [177] Ac ombination of this orthogonal direct disulfide formation with further functional polypeptidic segments, such as ac ationic poly-l-lysine block as mentioned above in the strategy for post-polymerization modification for disulfide stabilizedpolyplexes, [49] leads to the possibility of numerous multifunctional polypept(o)idic systems and suggests their use as material platform for biomedical applications.…”

Polypeptoids synthesis based on Ugi reaction: Advances and perspectives

“…Typically, two different synthetic strategies toward polypeptoids are possible: iterative submonomer route and ring‐opening polymerization (ROP) of N ‐substituted α‐amino acid‐ N ‐carboxyanhydrides (NNCAs) . Polypeptoids with absolute monodispersity and controlled sequence can be harvested by submonomer approach.…”