Compatible pairs of mutually orthogonal reagents are desirable to selectively label biomolecules for direct observation in biological processes. Pre-existing highly strained cyclooctynes face challenges in their synthesis, stability, and chemoselectivity, in addition to a lack of methods to easily increase their water solubility for biological applications. A modular approach to the highly polarizable heterocyclic cyclooctynes (SNO-OCTs) involves the aziridination of silyl allenes followed by ring expansion of the intermediate endocyclic methylene aziridine. This provides flexible substitution around the alkyne to control reactivity through stereoelectronic effects. The ability to predictably tune both rate and chemoselectivity in strained cycloalkynes enables opportunities to make orthogonal pairs. This work shows a series of SNO-OCT derivatives that underwent selective reaction with either Type I, Type II, or Type III dipoles. The new SNO-OCT library led to the discovery of mutually orthogonal pairs exhibiting fast reaction kinetics &gt;1 M-1s-1. Further investigation showcased that the SNO-OCT/dipole pairs are mutually orthogonal to some previously reported bioorthogonal pairs, including the widely available TCO/tetrazine system. The biorthogonal pairs allow us to establish a triple ligation system with the potential for simultaneously label multiple biological components in a cell. Stability and preliminary cell entry studies suggest promising in vivo multiple bioorthogonal labeling using SNO-OCT derivatives.

Modular SNO-OCT scaffolds for multiple, rapid bioorthogonal labeling

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.