Here we report a visible light-triggered, catalyst free bioorthogonal reaction that proceeds via a distinct pathway from reported bioorthogonal reactions. The prototype of this bioorthogonal reaction was the photocycloaddition of 9,10-phenanthrenequinone with electron-rich alkenes to form fluorogenic [4+2] cycloadducts. The bioorthogonal photoclick cycloaddition was readily initiated using a conventional visible light source such as a hand-held LED lamp. The reaction proceeded rapidly under biocompatible conditions, without observable competition from side reactions such as nucleophilic additions by water or common nucleophilic species. The bioorthogonal functionality in this reaction did not cross react with various alkynes and electron-deficient alkenes such as monomethyl fumarate. We demonstrated orthogonal labeling of two proteins using this reaction together with a strain promoting azide−alkyne click reaction or the UV-triggered reaction of tetrazole with monomethyl fumarate. The application of this reaction in the temporal and spatial labeling of live cells was also demonstrated.Communication pubs.acs.org/JACS

Bring to light: The first visible‐light‐promoted somophilic isocyanide insertion occurs using an iridium photocatalyst. This efficient synthetic approach provides a rapid entry to 6‐alkylated phenanthridine derivatives (see scheme). The reactions proceed at room temperature in good to excellent yields with broad substrate scope and under environmentally friendly conditions.

Activatable multimodal probes that show enhancement of multiplex imaging signals upon interaction with their specific molecular target have become powerful tools for rapid and precise imaging of biological processes. Herein, we report a stimuli-responsive disassembly approach to construct a redox-activatable fluorescence/F-MRS/H-MRI triple-functional probe 1. The small molecule probe 1 itself has a high propensity to self-assemble into nanoparticles with quenched fluorescence, attenuated F-MRS signal, and highH-MRI contrast. Biothiols that are abundant in reducing biological environment were able to cleave the disulfide bond in probe 1 to induce disassembly of the nanoparticles and lead to fluorescence activation (∼70-fold), F-MRS signal amplification (∼30-fold) and significant r relaxivity reduction (∼68% at 0.5 T). Molecular imaging of reducing environment in live cells and in vivo was realized using probe 1. This approach could facilitate the development of other stimuli-responsive trimodal probes for molecular imaging.

BRAF plays an indispensable role in activating the MEK/ERK pathway to drive tumorigenesis. Receptor tyrosine kinase and RAS-mediated BRAF activation have been extensively characterized, however, it remains undefined how BRAF function is fine-tuned by stimuli other than growth factors. Here, we report that in response to proinflammatory cytokines, BRAF is subjected to lysine 27-linked poly-ubiquitination in melanoma cells by the ITCH ubiquitin E3 ligase. Lysine 27-linked ubiquitination of BRAF recruits PP2A to antagonize the S365 phosphorylation and disrupts the inhibitory interaction with 14–3–3, leading to sustained BRAF activation and subsequent elevation of the MEK/ERK signaling. Physiologically, proinflammatory cytokines activate ITCH to maintain BRAF activity and to promote proliferation and invasion of melanoma cells, whereas the ubiquitination-deficient BRAF mutant displays compromised kinase activity and reduced tumorigenicity. Collectively, our study reveals a pivotal role for ITCH-mediated BRAF ubiquitination in coordinating the signals between cytokines and the MAPK pathway activation in melanoma cells.

Peptide‐mediated self‐assembly is a prevalent method for creating highly ordered supramolecular architectures. Herein, we report the first example of orthogonal C−X⋅⋅⋅X−C/C−X⋅⋅⋅π halogen bonding and hydrogen bonding driven crystalline architectures based on synthetic helical peptides bearing hybrids of l‐sulfono‐γ‐AApeptides and natural amino acids. The combination of halogen bonding, intra‐/intermolecular hydrogen bonding, and intermolecular hydrophobic interactions enabled novel 3D supramolecular assembly. The orthogonal halogen bonding in the supramolecular architecture exerts a novel mechanism for the self‐assembly of synthetic peptide foldamers and gives new insights into molecular recognition, supramolecular design, and rational design of biomimetic structures.