A cysteine-selective bioconjugation using aromatic cyclopropenium cations is reported. The reaction proceeds rapidly under aqueous conditions, enabling site-selective installation of tetrasubstituted...

Like many drugs, ruthenium-based photoactivated chemotherapy (PACT) complexes are hard to follow in cells due to their absence of emissive properties. Here, two alkyne-functionalized Ru-based PACT compounds with the formula [Ru(HCC-tpy)(N̂N)(Hmte)](PF6)2 were synthesized, where HCC-tpy = 4′-ethynyl-2,2′:6′,2″-terpyridine, N̂N = 3,3′-biisoquinoline (i-biq, [2](PF6)2) or di(isoquinolin-3-yl)amine (i-Hdiqa, [4](PF6)2), and Hmte = 2-(methylthio)ethanol. Their challenging synthesis involved a protection–deprotection strategy to avoid the reaction of the free alkyne group with the coordinatively unsaturated ruthenium center. The thermal stability and photosubstitution quantum yield (Φ[2] = 0.022 and Φ[4] = 0.080) of the PACT complexes were essentially preserved upon alkyne functionalization. Interestingly, however, cellular uptake was doubled after alkyne functionalization, resulting in increased cytotoxicity against A549 cancer cells for both complexes in the dark and after green light activation (EC50,light = 5 and 7 μM, respectively). To follow the complexes and see the effect of light activation, post-treatment fluorophore labeling via copper-catalyzed azide–alkyne cycloaddition was realized in fixed cells at 2 different time points, which allowed for imaging the otherwise invisible molecules. The images showed that the Ru complexes accumulated in the cytoplasm only after light irradiation and that they colocalized with the lysosomes and the Golgi apparatus. Moreover, we combined this approach with metabolic labeling of DNA, and showed by dual click imaging that DNA replication was inhibited by complex 4. The strategy described herein, pioneered for nonemissive, photosubstitutionally active ruthenium complexes, opens a new avenue for investigating the selective attack of lung cancer cells by PACT.

Data reveal how the global challenge to reduce deaths and infections from drug-resistant bacteria is not going according to plan.

Natural coumarins represent a diverse group of secondary metabolites with a wide range of biological activities. However, their specific molecular targets have remained largely unexplored. Employing chemical proteomics, a comprehensive analysis of the protein targets of the natural coumarin fraxetin has been

Protein O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) plays a crucial role in regulating essential cellular processes. The disruption of the homeostasis of O-GlcNAcylation has been linked to various human diseases, including cancer, diabetes, and neurodegeneration. However, there are limited chemical tools for protein- and site-specific O-GlcNAc modification, rendering the precise study of the O-GlcNAcylation challenging. To address this, we have developed heterobifunctional small molecules, named O-GlcNAcylation TArgeting Chimeras (OGTACs), which enable protein-specific O-GlcNAcylation in living cells. OGTACs promote O-GlcNAcylation of proteins such as BRD4, CK2α, and EZH2 in cellulo by recruiting FKBP12F36V-fused O-GlcNAc transferase (OGT), with temporal, magnitude, and reversible control. Overall, the OGTACs represent a promising approach for inducing protein-specific O-GlcNAcylation, thus enabling functional dissection and offering new directions for O-GlcNAc-targeting therapeutic development.

Nature - A new class of molecules can recruit downstream transcription factors or endogenous cancer drivers to cell death promoters and activate the expression of these genes.

Nature Chemistry - Profiling subcellular multi-omics with spatiotemporal resolution remains a key challenge in cell biology. Now an orthogonal photocatalytic labelling strategy has been developed...

Nature Chemical Biology - A chemoproteomic approach is developed that examines changes in ligand binding-induced accessibility by globally labeling reactive proteinaceous lysines, revealing the...

Over the past decade, numerous metabolomics techniques have been developed using liquid chromatography–mass spectrometry (LC-MS). These methodologies have yielded significant findings and facilitated ...

Structurally diverse natural products are a promising source of antibiotics. Here, the authors report the collective asymmetric total synthesis of polycyclic xanthene myrtucommulone D and five related...

A naturally occurring stand-alone and intermolecular Diels–Alderase, MaDA, has been identified from Morus alba cell cultures. MaDA is a FAD-dependent enzyme, which catalyses the intermolecular [4+2] c...

Peptide sequencing is critical to the advancement of proteomics research. Here, the authors present π-PrimeNovo, a non-autoregressive deep learning model that achieves high accuracy and up to 89x fast...

The fraction of sp3-hybridized carbons (Fsp3) and the fraction of stereogenic carbons (FCstereo) are two widely employed scores of molecular complexity with strong links to biologically relevant features. However, they do not comprehensively express molecular topology, and they often do not match the chemical intuition of complexity. We propose the spacial score (SPS) as an empirical scoring system that builds upon the principle underlying Fsp3 and FCstereo and expresses the spacial complexity of a compound in a uniform manner on a highly granular scale. The size-normalized SPS (nSPS) can differentiate distributions of natural products and synthetic compounds and is applicable in the analysis of biological activity data. Analysis of the ChEMBL database revealed general trends of increasing selectivity and potency with increasing nSPS. SPS can also be used advantageously in planning and analysis of synthesis programs for direct comparison of chemical transformations and intermediates in reaction sequences.

Mass-spectrometry-based phosphoproteomics enables the analysis of thousands of protein phosphorylation events across the human proteome. However, there is a lack of scalable, hypothesis-free, and stat...