Ex Situ Gaseous Reagent for Multicomponent Amine Bioconjugation.

We report a minimalist gaseous sulfonyl-chloride-derived reagent for multicomponent bioconjugation with amine, phenol, or aniline reagents to afford urea or carbamate products. With the utilization of a gas-phase reagent for a reaction mediated by metal ions, a variety of biologically relevant molecules, such as saccharide, poly(ethylene glycol), fluorophore, and affinity tag, can be efficiently cross-linked to the N terminus or lysine side-chain amines on natural polypeptides or proteins.

Oxidative Nitrogen Insertion into Silyl Enol Ether C═C Bonds.

Here, we demonstrate a fundamentally new reactivity of the silyl enol ether functionality utilizing an in situ-generated iodonitrene-like species. The present transformation inserts a nitrogen atom between the silyl enol ether olefinic carbons with the concomitant cleavage of the C═C bond. Overall, this facile transformation converts a C-nucleophilic silyl enol ether to the corresponding C-electrophilic N-acyl-N,O-acetal. This unprecedented access to α-amido alkylating agents enables modular derivatization with carbon and heteroatom nucleophiles and the unique late-stage editing of carbon frameworks. The reaction efficiency of this transformation is well correlated with enol ether nucleophilicity as described by the Mayr N scale. Applications presented herein include late-stage nitrogen insertion into carbon skeletons of natural products with previously unattainable regioselectivity as well as modified conditions for 15N labeling of amides and lactams.

Enhanced dynamic covalent chemistry for the controlled release of small molecules and biologics from a nanofibrous peptide hydrogel platform.

Maintaining safe and potent pharmaceutical drug levels is often challenging. Multidomain peptides (MDPs) assemble into supramolecular hydrogels with a well-defined, highly porous nanostructure that makes them attractive for drug delivery, yet their ability to extend release is typically limited by rapid drug diffusion. To overcome this challenge, we developed self-assembling boronate ester release (SABER) MDPs capable of engaging in dynamic covalent bonding with payloads containing boronic acids (BAs). As examples, we demonstrate that SABER hydrogels can prolong the release of five BA-containing small-molecule drugs as well as BA-modified insulin and antibodies. Pharmacokinetic studies revealed that SABER hydrogels extended the therapeutic effect of ganfeborole from days to weeks, preventing Mycobacterium tuberculosis growth better than repeated oral administration in an infection model. Similarly, SABER hydrogels extended insulin activity, maintaining normoglycemia for six days in diabetic mice after a single injection. These results suggest that SABER hydrogels present broad potential for clinical translation.

Templated Synthesis of Copper Nanoclusters with a Hybrid Lysozyme-Polymer Material for Enhanced Fluorescence.

Hybrid materials that combine organic polymers and biomacromolecules offer unique opportunities for precisely controlling 3D chemical environments. Although biological or organic templates have been separately used to control the growth of inorganic nanoclusters, hybrid structures represent a relatively unexplored approach to tailoring nanocluster properties. Here, we demonstrate that a molecularly defined lysozyme-polymer resin material acts as a structural scaffold for the synthesis of copper nanoclusters (CuNCs) with well controlled size distributions. The resulting CuNCs have significantly enhanced fluorescence compared with syntheses based on polymeric or biological templates alone. The synergistic approach described here is appealing for the synthesis of biocompatible fluorescent labels with improved photostability.

Selective Macrocyclization of Unprotected Peptides with an Ex Situ Gaseous Linchpin Reagent.

Peptide cyclization has dramatic effects on a variety of important properties, enhancing metabolic stability, limiting conformational flexibility, and altering cellular entry and intracellular localization. The hydrophilic, polyfunctional nature of peptides creates chemoselectivity challenges in macrocyclization, especially for natural sequences without biorthogonal handles. Herein, we describe a gaseous sulfonyl chloride derived reagent that achieves amine-amine, amine-phenol, and amine-aniline crosslinking through a minimalist linchpin strategy that affords macrocyclic urea or carbamate products. The cyclization reaction is metal-mediated and involves a novel application of sulfine species that remains unexplored in aqueous or biological contexts. The aqueous method delivers unique cyclic or bicyclic topologies directly from a variety of natural bioactive peptides without the need for protecting-group strategies.