Dual-Bioorthogonal Molecular Tool: “Click-to-Release” and “Double-Click” Reactivity on Small Molecules and Material Surfaces

Abstract

The development of reactive moieties that enable molecular control of bond-forming and bond-breaking reactions within complex media is highly important in materials and biomaterials research as it provides opportunities to carefully manipulate small molecules and material surfaces in a reliable manner. Despite recent advances in the realization of new ligation strategies and “click-and-release” systems, there has been little development of multifunctional moieties that feature a broad range of chemical capabilities. To address this challenge, we designed a molecular tool that can utilize four well-defined bioorthogonal chemistries interchangeably for the attachment, replacement, and release of molecules within a system: the Staudinger–Bertozzi ligation (SBL), perfluoroaryl azide Staudinger reaction (PFAA-SR), strain-promoted alkyne–azide cycloaddition (SPAAC), and strain-promoted alkyne–nitrone cycloaddition (SPANC). We demonstrate “click-to-release” and “double-click” reactivity on small molecules and gold nanoparticles (AuNPs) as a model material substrate. As a proof of concept for material derivatization, we employed 5 nm AuNPsfunctionalized with a Rhodamine B derivative and biotin through the double-click strategyand showed their potential as a pretargeted delivery nanocarrier. This multifunctional molecular tool enables the design and production of molecular and material systems with unique, modular, and tunable dynamic properties that can be altered under mild and bioorthogonal conditions.

Sequential conjugation methods based on triazole formation and related reactions using azides

“…23A). 57 Indeed, the generation of cyclooctyne with an ortho-alkoxycarbonyl-substi-tuted triarylphosphine moiety from 148 enabled the SPAAC reaction with azide 6 followed by a rapid Staudinger reaction with tetrafluorophenyl azide 149, yielding stable aza-ylide 150. In 2019, Yi, Xi, and coworkers developed diazide platform 151 (Fig.…”

Multifluorinated Aryl Azides for the Development of Improved H2S Probes, and Fast Strain‐promoted Azide‐Alkyne Cycloaddition and Staudinger Reactions

“…Similarly, in 2019 Workentin and coworkers employed four well-defined bioorthogonal chemistries (the Staudinger-Bertozzi ligation, NSR, SPAAC, and strain-promoted alkyne-nitrone cycloaddition) for the attachment, replacement, and release of molecules with a designed bifunctional molecular tool. [46] We further believe that the combination of NSR with other bioorthogonal reactions could provide a generally useful strategy for one-pot multiple bioconjugations. [47]…”

Nitrone-Modified Gold Nanoparticles: Synthesis, Characterization, and Their Potential as 18F-Labeled Positron Emission Tomography Probes via I-SPANC

“…The bioorthogonal nanomaterial template allows for the facile and covalent modification of the nanomaterial’s surface with reactions that are chemoselective, biocompatible, fast, high yielding, and, most importantly, orthogonal to the surface chemistry of the nanomaterial. 46−52…”